A pentapyrrocyclic compound, its intermediate and preparation method thereof

Abstract

The present invention discloses a pentaperture heterocyclic compound, an intermediate thereof, and a preparation method thereof. The present invention provides a pentaperture heterocyclic compound represented by Formula X, an intermediate thereof, and a preparation method thereof. The preparation method comprises the following steps: reacting a compound represented by Formula IX with citric acid in a solvent to form a salt to obtain a compound represented by Formula X. The compound represented by Formula IX and the compound represented by Formula X are KRAS G12C inhibitors that can be used to prevent and / or treat diseases mediated by KRAS G12C mutations. The preparation method provided by the present invention can achieve 2kg-scale production of the pentaperture heterocyclic compound, demonstrating feasibility for industrial production.

Description

Technical Field

[0001] The present invention relates to a pentahedral heterocyclic compound, an intermediate thereof and a preparation method thereof. Background Art

[0002] RAS proteins are 21kDa guanine trinucleotide phosphate (GTP)-binding proteins located on the cell membrane, composed of 188 or 189 amino acids. The activity of RAS proteins influences cell growth, differentiation, the cytoskeleton, protein trafficking, and secretion. Their activity is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When bound to GDP, RAS proteins are in an "inactive" state. Upon stimulation by specific upstream growth factors, guanine nucleotide exchange factors (GEFs) catalyze the release of GDP from RAS proteins, allowing them to bind to GTP and enter an "activated" state. GTP-bound RAS proteins can activate downstream proteins and signaling pathways. RAS proteins possess weak GTPase activity, hydrolyzing GTP to GDP, thereby transitioning from an active to an inactive state. This hydrolysis process also requires the participation of GTPase-activating proteins (GAPs), which interact with RAS proteins and significantly enhance their ability to hydrolyze GTP to GDP. Any mutation in the RAS protein that affects its own GTPase activity, its interaction with GAP, or its ability to hydrolyze GTP to GDP will cause the RAS protein to be in a prolonged activated state. The prolonged activated RAS protein continues to give growth signals to downstream proteins, leading to continuous cell growth and differentiation, and may eventually lead to cancer.

[0003] Approximately 30% of human tumors harbor some form of RAS gene mutation. Among RAS family members, oncogenic mutations are most common in V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (85%), while neuroblastoma RAS viral oncogene homolog (NRAS) (12%) and V-Ha-Ras murine Harvey sarcoma viral oncogene homolog (HRAS) (3%) are less common. Among KRAS mutations, the most common mutations occur at glycine 12 (G12), glycine 13 (G13), and glutamine 61 (Q61), with G12 mutations accounting for 83% of all mutations. The G12C mutation is one of the most common KRAS mutations, specifically a mutation of glycine at position 12 of KRAS to cysteine. This mutation is present in approximately 14% of non-small cell lung cancer (NSCLC), 4% of colorectal cancer, and 2% of pancreatic cancer. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to develop a new KRAS G12C inhibitor. To this end, the present invention provides a pentacyclic heterocyclic compound (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one or a salt thereof; the present invention also provides a method for preparing the above-mentioned pentacyclic heterocyclic compound or its salt. The above-mentioned preparation method can achieve the preparation of the above-mentioned pentacyclic heterocyclic compound or its salt on a 2kg scale and has the feasibility of industrial production.

[0005] The present invention relates to a method for preparing a compound as shown in Formula X, which comprises the following steps: in a solvent, reacting a compound as shown in Formula IX with citric acid to form a salt to obtain a compound as shown in Formula X.

[0006]

[0007] In the salt-forming reaction, the citric acid can be one or more of anhydrous citric acid, citric acid containing crystal water, and a combination of a citrate and an acid.

[0008] In the salt-forming reaction, preferably, when the citric acid is citric acid containing crystal water, the citric acid is citric acid monohydrate.

[0009] In the salt-forming reaction, the solvent is a conventional solvent in the art, preferably one or more of water, ketone solvents, alcohol solvents and nitrile solvents; more preferably water and / or ketone solvents; and most preferably 85% acetone aqueous solution.

[0010] In the salt-forming reaction, the volume-to-mass ratio of the solvent to the compound represented by Formula IX is conventional in the art, preferably 1-20 ml / g, more preferably 4-15 mL / g, for example 8 mL / g, 12 mL / g or 13 mL / g.

[0011] In the salt-forming reaction, the molar ratio of the compound represented by Formula IX to citric acid is a conventional molar ratio in the art, preferably 1:(1-1.2), more preferably 1:1.

[0012] In the salt-forming reaction, when citric acid is added, it is preferably added dropwise to a citric acid solution, wherein the citric acid solution is prepared by mixing citric acid monohydrate with an 85% acetone aqueous solution.

[0013] In the salt-forming reaction, the reaction time of the salt-forming reaction is conventional in the art, preferably 0.5-8 hours, more preferably 0.5-1 hour.

[0014] In the salt-forming reaction, the reaction temperature is a conventional temperature in the art, preferably 15-60°C, more preferably 45-50°C.

[0015] In the present invention, the method for preparing the compound represented by Formula X may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may further include the following steps: after the salt formation reaction is completed, adding seed crystals of the compound represented by Formula X, recrystallization, solid-liquid separation, and solid drying.

[0016] In the post-treatment, the mass of the seed crystals of the compound represented by Formula X added is 0.5%-5%, for example, 1%, of the mass of the compound represented by Formula IX.

[0017] In the post-treatment, when recrystallization is performed, the recrystallization solvent is water and / or acetone; preferably acetone.

[0018] In the post-treatment, when recrystallization is performed, the recrystallization temperature is 10-60°C; preferably 15-50°C.

[0019] In the post-treatment, when recrystallization is performed, the recrystallization time is 1-48 hours, preferably 16-34 hours.

[0020] In the post-processing, when solid-liquid separation is performed, the solid-liquid separation method is a conventional method in the art, preferably filtration. The solid after solid-liquid separation can be washed with acetone to remove impurities.

[0021] In the post-treatment, when the solid is dried, the temperature for drying the solid is conventional in the art, preferably 45-50°C.

[0022] In the preparation method of the compound shown in Formula X, the preparation method of the compound shown in Formula X may further include the preparation method of the compound shown in Formula IX. The preparation method of the compound shown in Formula IX may be any of the following schemes:

[0023] Scheme 1 comprises the following steps: in a solvent, in the presence of an inorganic base and a phase transfer catalyst, subjecting the compound represented by Formula VIII to an elimination reaction to obtain a compound represented by Formula IX;

[0024] Scheme 2 comprises the following steps: in a solvent, in the presence of an organic base, subjecting the compound represented by Formula VIII to an elimination reaction to obtain a compound represented by Formula IX;

[0025]

[0026] In Scheme 1, the inorganic base is a conventional inorganic base in the art, preferably potassium carbonate.

[0027] In Scheme 1, the phase transfer catalyst is a conventional phase transfer catalyst in the art, preferably TBAB.

[0028] In Scheme 1, the solvent is a conventional solvent in the art, preferably water and / or an ether solvent; more preferably one or more of water, 2-methyltetrahydrofuran and tetrahydrofuran.

[0029] In Scheme 1, the molar ratio of the compound represented by Formula VIII to the inorganic base is a conventional molar ratio in the art, preferably 1:(2-15), for example 1:14.43.

[0030] In Scheme 1, the molar ratio of the compound represented by Formula VIII to the phase transfer catalyst is a conventional molar ratio in the art, preferably 1:(1.5-4), for example 1:2.62.

[0031] In Scheme 1, the elimination reaction temperature is a conventional temperature in the art, preferably 25-30°C.

[0032] In Scheme 1, the progress monitoring method of the elimination reaction can adopt conventional methods in the art, such as TLC, HPLC, GC or NMR.

[0033] In Scheme 1, preferably, when the progress monitoring method of the elimination reaction is HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula VIII is less than 1%, for example, less than 0.1%.

[0034] In Scheme 1, the preparation method of the compound represented by Formula IX further includes post-treatment. The post-treatment method can adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: extraction, desolvation, recrystallization, secondary recrystallization, solid-liquid separation, and solid drying.

[0035] In the post-treatment of Scheme 1, when extraction is performed, the extraction method is a conventional method in the art. Preferably, the organic phase solvent in the extraction is one or more of dichloromethane, 2-methyltetrahydrofuran and tetrahydrofuran, and the aqueous phase in the extraction is an aqueous potassium dihydrogen phosphate solution and / or saturated brine, wherein, when the extraction is completed, the pH value of the organic phase is 6-7.

[0036] In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization solvent is one or more of water, acetone, 2-methyltetrahydrofuran and tetrahydrofuran;

[0037] In the post-treatment of Scheme 1, during recrystallization, the recrystallization temperature is 15-60°C, preferably 20-55°C.

[0038] In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization time is 1-24 hours, preferably 1-15 hours.

[0039] In the post-treatment of Scheme 1, when the secondary recrystallization is performed, the solvent for the secondary recrystallization is acetone, water and DMSO; preferably, the volume ratio of acetone:DMSO:water is 12:1:10.

[0040] In the post-treatment of Scheme 1, when the secondary recrystallization is performed, the temperature of the secondary recrystallization is 15-60°C, preferably 20-55°C.

[0041] In the post-treatment of Scheme 1, when solid-liquid separation is performed, the method of solid-liquid separation is a conventional method in the art, preferably filtration.

[0042] In the post-treatment of Scheme 1, when the solid is dried, the temperature for drying the solid is a conventional temperature in the art, preferably 45-50°C.

[0043] In Scheme 2, the organic base is a conventional organic base in the art, preferably DBU.

[0044] In Option 2, the solvent is a conventional organic solvent in the art, preferably an ether solvent and / or a halogenated hydrocarbon solvent, more preferably one or more of 2-methyltetrahydrofuran, tetrahydrofuran and dichloromethane.

[0045] In Scheme 2, the molar ratio of the compound represented by Formula VIII to the organic base is a conventional molar ratio in the art, preferably 1:(1-4), for example 1:3.5.

[0046] In the second scheme, the elimination reaction temperature is a conventional temperature in the art, preferably 0-5°C.

[0047] In Scheme 2, the preparation method of the compound represented by Formula IX further includes post-treatment. The post-treatment method can adopt conventional post-treatment methods in the art. In the present invention, the post-treatment may include the following steps: extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

[0048] In the post-treatment of Scheme 2, when extraction is performed, the extraction method is a conventional method in the art. Preferably, the organic phase solvent in the extraction is dichloromethane, the aqueous phase in the extraction is potassium dihydrogen phosphate aqueous solution, and the pH value of the organic phase is 6-7.

[0049] In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization method is a conventional method in the art. Preferably, the solvents used in the recrystallization are acetone and water, more preferably, the volume ratio of acetone to water is 1:(0.5-2).

[0050] In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization temperature is 15-60°C, preferably 20-50°C.

[0051] In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization time is 1-24 hours, preferably 0.5-5 hours.

[0052] In the post-treatment of Option 2, when solid-liquid separation is performed, the solid-liquid separation method is a conventional method in the art, preferably filtration. The solid after solid-liquid separation can be washed with a mixed solution of acetone and purified water, wherein the volume ratio of acetone to purified water is 2:1.

[0053] In the post-treatment of Option 2, when the solid is dried, the temperature for drying the solid is a conventional temperature in the art, preferably 45-50°C.

[0054] In the preparation method of the compound represented by Formula X, the preparation method of the compound represented by Formula IX may further include the preparation method of the compound represented by Formula VIII. The preparation method of the compound represented by Formula VIII may include the following steps: in a solvent, in the presence of a base, subjecting the compound represented by Formula VII or a salt thereof to an amidation reaction with 3-chloropropionyl chloride to obtain the compound represented by Formula VIII.

[0055]

[0056] In the amidation reaction, the salt of the compound represented by Formula VII is the product of the reaction of the compound represented by Formula VII with an acid, wherein the acid is an organic acid (such as citric acid or trifluoroacetic acid) or an inorganic acid (such as hydrochloric acid, sulfuric acid or nitric acid).

[0057] In the amidation reaction, preferably, the salt of the compound represented by Formula VII may be the hydrochloride of the compound represented by Formula VII, for example, the compound represented by Formula VII-1.

[0058]

[0059] In the amidation reaction, the base is a conventional base in the art, preferably potassium phosphate.

[0060] In the amidation reaction, the solvent is a conventional solvent in the art, preferably water and / or an ether solvent, more preferably one or more of water, 2-methyltetrahydrofuran and tetrahydrofuran.

[0061] In the amidation reaction, the molar ratio of the compound represented by Formula VII or its salt to the base is a conventional molar ratio in the art, preferably 1:(1.0-1.5), for example 1:1 or 1:1.46.

[0062] In the amidation reaction, the molar ratio of the compound of Formula VII or its salt to the 3-chloropropionyl chloride is a conventional molar ratio in the art, preferably 1:(1.1-1.4), for example 1:1.2 or 1:1.35.

[0063] In the amidation reaction, the volume mass ratio of the solvent to the compound represented by Formula VII or its salt is 1-18 mL / g, preferably 4-15 mL / g, for example 12 mL / g or 14 mL / g.

[0064] In the amidation reaction, the temperature of the amidation reaction is conventional in the art, preferably -20-25°C; more preferably -5-5°C.

[0065] In the amidation reaction, the reaction time of the amidation reaction is conventional in the art, preferably 0.5-6 hours.

[0066] In the present invention, the preparation method of the compound represented by Formula VIII may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: after the amidation reaction is completed, extraction, and desolvation.

[0067] In the post-treatment, when extraction is performed, the extraction method is a conventional method in the art. Preferably, the organic phase solvent in the extraction is 2-methyltetrahydrofuran and / or tetrahydrofuran.

[0068] In the method for preparing the compound of Formula X, the method for preparing the compound of Formula VIII may further include a method for preparing the compound of Formula VII or a salt thereof. The method for preparing the compound of Formula VII or a salt thereof may comprise the following steps: subjecting the compound of Formula VI to amino deprotection reaction in a solvent under the action of an acid to obtain the compound of Formula VII or a salt thereof,

[0069]

[0070] In the amino deprotection reaction, the acid is an acid commonly used in the art for deprotecting the amino protecting group Boc, preferably hydrochloric acid and / or trifluoroacetic acid.

[0071] In the amino deprotection reaction, when the acid is hydrochloric acid, the reaction temperature of the amino deprotection reaction is a conventional temperature in the art, preferably 10-55°C.

[0072] In the amino deprotection reaction, when the acid is hydrochloric acid, the salt of the compound represented by Formula VII is the hydrochloride of the compound represented by Formula VII, preferably the compound represented by Formula VII-1.

[0073]

[0074] In the amino deprotection reaction, when the acid is trifluoroacetic acid, the reaction temperature of the amino deprotection reaction is a conventional temperature in the art, preferably 20-30°C, more preferably 20-25°C.

[0075] In the amino group deprotection reaction, the solvent is a conventional solvent in the art, preferably a halogenated hydrocarbon solvent and / or an alcohol solvent, more preferably dichloromethane and / or methanol.

[0076] In the amino deprotection reaction, the reaction time of the amino deprotection reaction is conventional in the art, preferably 1-6 hours, more preferably 5-6 hours, and most preferably 2-3 hours.

[0077] In the amino deprotection reaction, the volume mass ratio of the collected solvent to the compound of Formula VI is 1-10 mL / g, preferably 2-8 mL / g, for example 5 mL / g or 6 mL / g.

[0078] In the amino deprotection reaction, the progress of the amino deprotection reaction can be monitored by conventional methods in the art, such as TLC, HPLC, GC or NMR.

[0079] In the amino deprotection reaction, when the progress of the amino deprotection reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula III is less than 1%, for example, less than 0.4%.

[0080] In the present invention, the method for preparing the compound represented by Formula VII or a salt thereof may further include post-treatment, which may be performed using conventional post-treatment methods in the art. In the present invention, the post-treatment may include the following steps: after the amino deprotection reaction is completed, optionally acid-base neutralization, slurrying, solid-liquid separation, and solid drying.

[0081] In the post-treatment, when the acid and base are neutralized, the base used for the acid-base neutralization is a base conventionally used in the art to neutralize the acid, preferably an inorganic base, more preferably a carbonate and / or bicarbonate; most preferably one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

[0082] In the post-treatment, when beating, the beating solvent is one or more of nitrile solvents, alcohol solvents and ether solvents; preferably one or more of acetonitrile, methanol and methyl tert-butyl ether.

[0083] In the post-treatment, when beating, the beating temperature is 15-50°C, preferably 20-30°C.

[0084] In the post-treatment, when beating, the beating time is 1-24 hours, preferably 1-15 hours.

[0085] In the post-processing, when the solid-liquid separation is performed, the solid-liquid separation method is a conventional method in the art, preferably filtration. The solid after the solid-liquid separation can be washed with methyl tert-butyl ether.

[0086] In the post-treatment, when the solid is dried, the temperature for drying the solid is conventional in the art, preferably 45-50°C.

[0087] In the preparation method of the compound represented by Formula X, the preparation method of the compound represented by Formula VII or its salt may also include the preparation method of the compound represented by Formula VI. The preparation method of the compound represented by Formula VI comprises the following steps: in a solvent, a compound represented by Formula V, a compound represented by Formula V-1, a palladium catalyst, a base and a chiral phosphine ligand are subjected to a coupling reaction to obtain a compound represented by Formula VI.

[0088]

[0089] In the coupling reaction, the palladium catalyst is a conventional palladium catalyst in the art, preferably Pd2(dba)3.

[0090] In the coupling reaction, the base is a conventional base in the art, preferably CsF.

[0091] In the coupling reaction, the chiral phosphine ligand is a conventional phosphine ligand in the art, preferably BaryPhos.

[0092] In the coupling reaction, the molar ratio of the compound represented by Formula V to the compound represented by Formula V-1 is a conventional molar ratio in the art, preferably 1:(2-6), for example 1:4.

[0093] In the coupling reaction, the molar ratio of the compound represented by Formula V to the base is a conventional molar ratio in the art, preferably 1:(2-6), for example 1:4.

[0094] In the coupling reaction, the molar ratio of the compound represented by Formula V to the palladium catalyst is a conventional molar ratio in the art, preferably 1:(0.01-0.1), for example 1:0.015.

[0095] In the coupling reaction, the molar ratio of the compound represented by Formula V to the chiral phosphine ligand is a conventional molar ratio in the art, preferably 1:(0.01-0.2), for example 1:0.06.

[0096] In the coupling reaction, the volume mass ratio of the solvent to the compound represented by Formula V is 10-30 mL / g, preferably 15-25 mL / g, for example 20 mL / g.

[0097] In the coupling reaction, the temperature of the coupling reaction is a conventional temperature in the art, preferably 60-65°C.

[0098] In the coupling reaction, the coupling reaction time is conventional in the art, preferably 12-16 hours.

[0099] The coupling reaction is preferably carried out under an oxygen-free condition, for example, under one or more of nitrogen, neon and argon.

[0100] In the coupling reaction, the progress of the coupling reaction can be monitored by conventional methods in the art, such as TLC, HPLC, GC or NMR.

[0101] In the coupling reaction, when the progress of the coupling reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula V is less than 1%, for example, less than 0.3%.

[0102] In the present invention, the preparation method of the compound represented by Formula VI may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: after the coupling reaction is completed, palladium removal, extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

[0103] In the post-treatment, the palladium removal is performed at least twice. The palladium removal method is to add a cysteine ​​potassium carbonate aqueous solution to the organic phase after the coupling reaction. The cysteine ​​potassium carbonate aqueous solution is prepared according to the weight ratio of cysteine: potassium carbonate: water = 1:1.14:15.

[0104] In the post-treatment, the extraction method is a conventional method in the art. Preferably, the organic phase solvent in the extraction is 2-methyltetrahydrofuran, and the aqueous phase is one or more of water, saline solution and potassium carbonate aqueous solution.

[0105] In the post-treatment, the solvent used in the recrystallization is water and / or an alcohol solvent; preferably water and / or methanol, and more preferably the volume ratio of methanol to water is 8:3.5.

[0106] In the post-treatment, the recrystallization temperature is 15-70°C, preferably 25-70°C.

[0107] In the post-treatment, the recrystallization time is 1-24 hours, preferably 1-15 hours.

[0108] In the post-processing, the solid-liquid separation method is a conventional method in the art, preferably filtration.

[0109] In the post-treatment, the temperature for drying the solid is conventional in the art, preferably 45-50°C.

[0110] In the preparation method of the compound represented by Formula X, the preparation method of the compound represented by Formula VI may further include the preparation method of the compound represented by Formula V. The preparation method of the compound represented by Formula V may include the following steps: in a solvent, at 20-30° C., subjecting the compound represented by Formula IV, an organic phosphine, and an azodicarboxylate to a cyclization reaction to obtain the compound represented by Formula V, wherein the organic phosphine is a trialkylphosphine or a triarylphosphine.

[0111]

[0112] In the cyclization reaction, when the organic phosphine is a trialkylphosphine, the trialkylphosphine may be trimethylphosphine or tributylphosphine.

[0113] In the cyclization reaction, when the organic phosphine is a triarylphosphine, the triarylphosphine may be triphenylphosphine.

[0114] In the cyclization reaction, the azodicarboxylate can be one or more of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and di-tert-butyl azodicarboxylate (DBAD); preferably, diisopropyl azodicarboxylate.

[0115] In the cyclization reaction, the solvent is a conventional solvent in the art, preferably an aprotic solvent, more preferably one or more of benzene, toluene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, DMF and dichloromethane, and most preferably ethyl acetate.

[0116] In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the organic phosphine is a conventional molar ratio in the art, preferably 1:(1.2-1.6), for example 1:1.5.

[0117] In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the azodicarboxylate is a conventional molar ratio in the art, preferably 1:(1.2-1.6), for example 1:1.5.

[0118] In the cyclization reaction, the volume mass ratio of the solvent to the compound represented by Formula IV is 1-15 mL / g, preferably 5-12 mL / g, for example 12 mL / g or 10 mL / g;

[0119] In the cyclization reaction, the cyclization reaction time is conventional in the art, preferably 1-3 hours.

[0120] In the cyclization reaction, the temperature of the cyclization reaction is conventional in the art, preferably 20-30°C.

[0121] In the cyclization reaction, the progress of the cyclization reaction can be monitored by conventional methods in the art, such as TLC, HPLC, GC or NMR.

[0122] In the cyclization reaction, when the progress of the cyclization reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula IV is less than 1%, for example, less than 0.5%.

[0123] In the present invention, the preparation method of the compound represented by Formula IV may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: extraction after the cyclization reaction, desolventization, recrystallization, solid-liquid separation, and solid drying.

[0124] In the post-treatment, the extraction method is a conventional method in the art. Preferably, the organic phase solvent in the extraction is ethyl acetate, and the aqueous phase is water, sodium chloride aqueous solution or ammonium chloride aqueous solution.

[0125] In the post-treatment, the solvent used in the recrystallization is an alcohol solvent, preferably methanol.

[0126] In the post-treatment, the recrystallization temperature is 15-66°C.

[0127] In the post-treatment, the recrystallization time is 1-24 hours, preferably 1-15 hours.

[0128] In the post-processing, the solid-liquid separation method is a conventional method in the art, preferably filtration.

[0129] In the post-treatment, the temperature for drying the solid is conventional in the art, preferably 45-55°C.

[0130] In the preparation method of the compound shown in Formula X, the preparation method of the compound shown in Formula V may also include the preparation method of the compound shown in Formula IV. The preparation method of the compound shown in Formula IV may include the following steps: in a solvent, a compound shown in Formula III, a fluoride, and acetic acid are subjected to a hydroxyl deprotection reaction to obtain a compound shown in Formula IV, wherein the fluoride is potassium fluoride and / or tetrabutylammonium fluoride,

[0131]

[0132] In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the fluoride is a conventional molar ratio in the art, preferably 1:(1.05-1.3), more preferably 1:(1.1-1.2), for example 1:1.2.

[0133] In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the acetic acid is a conventional molar ratio in the art, preferably 1:(2-5), more preferably 1:(2-3), for example 1:3.

[0134] In the deprotection reaction of the hydroxyl group, the deprotection reaction time is the conventional reaction time in the art, preferably 2-4 hours.

[0135] In the deprotection reaction of the hydroxyl group, the deprotection reaction temperature is a conventional reaction temperature in the art, preferably 20-40°C, more preferably 28-33°C.

[0136] In the deprotection reaction of the hydroxyl group, the volume mass ratio of the solvent to the compound represented by Formula III is 1-15 mL / g, preferably 2-12 mL / g, for example 8 mL / g.

[0137] In the deprotection reaction of the hydroxyl group, the progress of the deprotection reaction of the hydroxyl group can be monitored by conventional methods in the art, such as TLC, HPLC, GC or NMR.

[0138] In the hydroxyl deprotection reaction, when the progress of the hydroxyl deprotection reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula III is less than 1%, preferably less than 0.35%.

[0139] In the present invention, the preparation method of the compound represented by Formula IV may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: after the deprotection reaction of the hydroxyl group is completed, extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

[0140] In the post-treatment, the extraction method is a conventional method in the art. Preferably, the organic phase solvent in the extraction is dichloromethane and / or tetrahydrofuran, and the aqueous phase is water, sodium bicarbonate aqueous solution or sodium chloride aqueous solution.

[0141] In the post-treatment, the solvent used in the recrystallization is an ether solvent; preferably tetrahydrofuran;

[0142] In the post-treatment, the recrystallization temperature is 15-70°C.

[0143] In the post-treatment, the recrystallization time is 1-12 hours, preferably 1-4 hours, such as 1-2 hours.

[0144] In the post-processing, the solid-liquid separation method is a conventional method in the art, preferably filtration.

[0145] In the post-treatment, the temperature for drying the solid is conventional in the art, preferably 45-55°C.

[0146] In the preparation method of the compound shown in Formula X, the preparation method of the compound shown in Formula IV may also include the preparation method of the compound shown in Formula III. The preparation method of the compound shown in Formula III may include the following steps: in a solvent, in the presence of a base, subjecting the compound shown in Formula I to a substitution reaction with the compound shown in Formula II to obtain the compound shown in Formula III, wherein the base is an alkoxide,

[0147]

[0148] In the substitution reaction, the alkoxide is a compound in which the hydrogen in the alcohol molecule is replaced by a metal, preferably a lithium salt of an alcohol (such as lithium tert-butoxide) and / or a potassium salt of an alcohol (such as potassium tert-butoxide).

[0149] In the substitution reaction, the solvent is a conventional solvent in the art, preferably one or more of an ether solvent, an alcohol solvent and a nitrile solvent; more preferably an ether solvent (such as 2-methyltetrahydrofuran).

[0150] In the substitution reaction, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is a conventional molar ratio in the art, preferably 1:(1.05-1.3), more preferably 1:(1.1-1.2), for example 1:1.2.

[0151] In the substitution reaction, the molar ratio of the compound represented by Formula I to the alkoxide is a conventional molar ratio in the art, preferably 1:(1.5-3.5), more preferably 1:(2-3), for example 1:2.5 or 1:3.

[0152] In the substitution reaction, the volume mass ratio of the solvent to the compound represented by Formula I is 1-15 mL / g, preferably 5-12 mL / g, for example 12 mL / g.

[0153] In the substitution reaction, the reaction time of the substitution reaction is the conventional reaction time in the art, preferably 15-24 hours.

[0154] In the substitution reaction, the reaction temperature is a conventional reaction temperature in the art, preferably 20-35°C.

[0155] In the substitution reaction, the progress of the substitution reaction can be monitored by conventional methods in the art, preferably TLC, HPLC, GC or NMR.

[0156] In the substitution reaction, when the progress of the substitution reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound shown in Formula I is less than 1%.

[0157] In the present invention, the preparation method of the compound represented by Formula III may further include post-treatment, and the post-treatment method may adopt a conventional post-treatment method in the art. In the present invention, the post-treatment may include the following steps: after the substitution reaction is completed, quenching, extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

[0158] In the post-treatment, when quenching, the reagent for quenching the alkoxide is a reagent conventionally used in the art; preferably, dihydrogen phosphate or an aqueous solution thereof; more preferably, KH2PO4 or a 10% KH2PO4 aqueous solution.

[0159] During post-treatment, the system temperature was controlled at 20-30°C during quenching.

[0160] In the post-treatment, when recrystallization is performed, the solvent used in the recrystallization can be a nitrile solvent and / or water; preferably acetonitrile and water, and more preferably the volume ratio of acetonitrile to water is 3:1.

[0161] In the post-treatment, when recrystallization is performed, the recrystallization temperature is 15-70°C.

[0162] In the post-treatment, when recrystallization is performed, the recrystallization time is 1-24 hours, preferably 1-15 hours.

[0163] In the post-processing, when the solid-liquid separation is performed, the solid-liquid separation method is a conventional method in the art, preferably filtration.

[0164] In post-treatment, the separated solid can be washed with a mixed solvent of acetonitrile and water to remove impurities.

[0165] During post-treatment, when the solid is dried, the temperature for drying the solid can be a conventional temperature in the art, preferably 50-60°C.

[0166] The present invention also relates to a method for preparing a compound as shown in Formula IX, which comprises the following steps:

[0167] Scheme 1 comprises the following steps: in a solvent, in the presence of an inorganic base and a phase transfer catalyst, subjecting the compound represented by Formula VIII to an elimination reaction to obtain a compound represented by Formula IX;

[0168] Scheme 2 comprises the following steps: in a solvent, in the presence of an organic base, subjecting the compound represented by Formula VIII to an elimination reaction to obtain a compound represented by Formula IX;

[0169]

[0170] In the method for preparing the compound represented by Formula IX, the reaction conditions and operations can be the same as described above.

[0171] The present invention also relates to a method for preparing a compound as shown in Formula VIII, comprising the following steps: subjecting a compound as shown in Formula VII or a salt thereof to an amidation reaction with 3-chloropropionyl chloride in a solvent in the presence of a base to obtain a compound as shown in Formula VIII.

[0172]

[0173] In the method for preparing the compound represented by Formula VIII, the reaction conditions and operations can be the same as described above.

[0174] The present invention also relates to a method for preparing a compound as shown in Formula VII or a salt thereof, comprising the following steps: subjecting a compound as shown in Formula VI to an amino group deprotection reaction in a solvent under the action of an acid to obtain a compound as shown in Formula VII or a salt thereof;

[0175]

[0176] In the method for preparing the compound represented by Formula VII or its salt, the reaction conditions and operations can be the same as described above.

[0177] The present invention also relates to a method for preparing a compound as shown in Formula VI, which comprises the following steps: in a solvent, coupling a compound as shown in Formula V, a compound as shown in Formula V-1, a palladium catalyst, a base and a chiral phosphine ligand to obtain a compound as shown in Formula VI,

[0178]

[0179] In the method for preparing the compound represented by Formula VI, the reaction conditions and operations can be the same as those described above.

[0180] The present invention also relates to a method for preparing a compound as shown in Formula V, comprising the following steps: in a solvent, at 20-30° C., subjecting a compound as shown in Formula IV, an organic phosphine, and an azodicarboxylate to a cyclization reaction to obtain a compound as shown in Formula V, wherein the organic phosphine is a trialkyl phosphine or a triaryl phosphine;

[0181]

[0182] In the method for preparing the compound represented by Formula V, the reaction conditions and operations can be the same as those described above.

[0183] The present invention also relates to a method for preparing a compound as shown in Formula IV, comprising the following steps: in a solvent, subjecting a compound as shown in Formula III, a fluoride, and acetic acid to a hydroxyl group deprotection reaction to obtain a compound as shown in Formula IV, wherein the fluoride is potassium fluoride and / or tetrabutylammonium fluoride;

[0184]

[0185] In the method for preparing the compound represented by Formula IV, the reaction conditions and operations can be the same as those described above.

[0186] The present invention also relates to a method for preparing a compound as shown in Formula III, which comprises the following steps: in a solvent, in the presence of a base, subjecting a compound as shown in Formula I to a substitution reaction with a compound as shown in Formula II to obtain a compound as shown in Formula III, wherein the base is an alkoxide;

[0187]

[0188] In the method for preparing the compound represented by Formula III, the reaction conditions and operations can be the same as described above.

[0189] The present invention also relates to a compound as shown in formula X,

[0190]

[0191] The present invention also relates to a compound selected from any one of the following structures,

[0192]

[0193] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0194] The reagents and raw materials used in the present invention are commercially available.

[0195] The positive progress of the present invention is that: the present invention provides the above-mentioned five-heterocyclic compound (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one or its salt, which is a KRAS G12C inhibitor and can be used to prevent and / or treat diseases mediated by KRAS G12C mutations. The present invention also provides a preparation method thereof, which can achieve 2kg-level scale preparation of the above-mentioned five-heterocyclic compound or its salt, and has the feasibility of industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0196] Figure 1 The single crystal structure of the compound shown in Formula X DETAILED DESCRIPTION

[0197] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0198] The abbreviations of the compounds in the present invention correspond to the following

[0199]

[0200]

[0201] In the examples, V represents the volume of solvent corresponding to the mass of the material; for example, if the mass of the material is 10 g, 2V represents the volume of solvent is 20 mL; if the mass of the material is 1 kg, 2V represents the volume of solvent is 2 L.

[0202] In the embodiment, X represents the weight of the solvent corresponding to the mass of the material; for example, if the mass of the material is 10 g, 2X represents the weight of the solvent is 20 g; if the mass of the material is 1 kg, 2X represents the weight of the solvent is 2 kg.

[0203] Example 1: Synthesis of compound of formula III

[0204]

[0205] Option 1:

[0206] 2-MeTHF (10 V) and t-BuOLi (2.5 eq.) were added to the system, and stirring was started. The system temperature was controlled at 20-30°C. A 2-MeTHF (2 V) solution (1.2 eq.) of the compound of Formula II was added dropwise to the system. The temperature was controlled at 20-30°C. After the addition was complete, the mixture was stirred for 10-30 minutes. The compound of Formula I (2 kg) was then added to the system in batches. The temperature was controlled at 20-30°C. After the addition was complete, the mixture was stirred for 10-20 minutes. The temperature was then raised to 30-35°C and the reaction was allowed to proceed for 15-24 hours. The reaction was completed by HPLC (compound of Formula I <1%), and the system was cooled to 20-25°C. A 10% KH2PO4 aqueous solution (8V) was added dropwise to the system, with the temperature controlled at 20-30°C. After the addition was complete, the mixture was stirred for 10-15 minutes, and the layers were separated. The organic phase was washed twice with water (5V) (a total of 10V), each time stirred for 5-15 minutes. The layers were separated, and the organic phase was concentrated under reduced pressure. Acetonitrile (2V) was stripped once, and acetonitrile (15V) was added. The system was heated to 60-70°C, stirred at the temperature for 0.5-1 hour, and then water (5V, followed by a 2.5V addition of water) was added dropwise to the system at 55-70°C. After the addition was complete, the mixture was cooled naturally to 15-25°C, stirred overnight, and filtered. The filter cake was rinsed with an acetonitrile / water solution (4V, 3 / 1), and then dried at 50-60°C overnight. The resulting product was 2.5 kg. Yield: 85.5%.

[0207] 1 H NMR (400MHz, DMSO-d6) δ10.608-10.586(m,1H),7.793-7.790(m,1H),4.636-4.546(m,1H),4.275-4.146(m,1H),4.071(s,3H),3. 839-3.767(m,1H),3.415-3.239(m,15H),2.989-2.921(m,1H),2.817-2.768(m,1H),2.507-2.498(m,14H),1.450-1.427(m,12H).

[0208] The percentage of moisture and alcohol solvents in the material and the percentage of free base in lithium tert-butoxide will affect the conversion rate of the raw materials and the yield of the product.

[0209] Option 2:

[0210] 2-MeTHF (10 V) and t-BuOK (3.0 eq.) were added to the system, and stirring was initiated. The system temperature was maintained at 0-10°C. A 2-MeTHF (2 V) solution (1.2 eq.) of the compound of Formula II was added dropwise to the system, and the temperature was maintained at 0-10°C. After the addition was complete, the system was stirred for 10-30 minutes. The compound of Formula I (2 kg) was then added portionwise to the system. The reaction was highly exothermic, and the temperature was maintained at 20-30°C. After the addition was complete, the system was stirred for 10-20 minutes, and the temperature was maintained at 20-30°C for 2-3 hours. The reaction was determined to be complete by HPLC (compound of Formula I <1%). A 10% KH2PO4 aqueous solution (8V) was added dropwise to the system, with the temperature controlled at 20-30°C. After the addition was complete, the mixture was stirred for 10-15 minutes, and the layers were separated. The organic phase was washed twice with water (5V) (a total of 10V), each time stirred for 5-15 minutes. The layers were separated, and the organic phase was concentrated under reduced pressure. Acetonitrile (2V) was added with distillation, and acetonitrile (15V) was added. The system was heated to 60-70°C, stirred at the temperature for 0.5-1 hour, and then water (5V, followed by a 2.5V addition of water) was added dropwise to the system at 55-70°C. After the addition was complete, the mixture was cooled to 15-25°C, stirred overnight, and filtered. The filter cake was rinsed with an acetonitrile / water solution (4V, 3 / 1), and then dried at 50-60°C overnight. Approximately 2.5 kg of material was recovered. Yield: 85.5%.

[0211] Example 2: Synthesis of compound of formula IV

[0212]

[0213] THF (8 V) and the compound of Formula III (1.0 eq., 2.5 kg) were added to the system, stirring was initiated, and the system temperature was controlled at 20-30°C. A mixed solution of TBAF (1.2 eq., 1 M in THF) and acetic acid (3.0 eq.) was added dropwise to the system. The temperature was controlled at 20-30°C. After the addition was complete, the mixture was stirred for 10-15 minutes and allowed to react at 28-33°C for 2-4 hours. HPLC analysis indicated that the reaction was complete (<0.35% of the compound of Formula III). The system was then cooled to 15-25°C. DCM (8 V) and water (5 V) were added and stirred for 10-15 minutes. The mixture was allowed to stand for separation, and the aqueous phase was back-extracted once with DCM (2 V). The organic phases were combined, stirred with 8% aqueous sodium bicarbonate (5 V), stirred for 5-15 minutes, and washed once with 25% aqueous sodium chloride (1 V). The organic phase was then washed twice with 4% aqueous sodium chloride (6 V) for a total of 12 V. The organic phase was concentrated under reduced pressure, distilled once with THF (2V), and then THF (8V) was added. The temperature was raised to 60-70°C for reflux, refluxed for 1-2 hours, then cooled to 15-25°C, filtered, rinsed with THF (2V), and the filter cake was dried at 45-55°C overnight. 2.05 kg of material was collected. Yield: 96.6%.

[0214] 1 H NMR(400MHz,DMSO-d6)δ10.505(s,1H),7.796(s,1H),5.754-5.721(m,1H),4.6 63-4.569(m,1H),4.285-4.151(m,1H),3.853-3.789(m,1H),3.736-3.585(m,4H ),3.325-3.253(m,4H),3.030-2.955(m,1H),2.838(m,1H),2.378-2.330(m,2H) ,2.126-2.067(m,2H),1.804-1.727(m,3H),1.611(m,2H),1.456-1.431(m,9H).

[0215] Comparative Example: The basic experimental conditions and operations were the same as those in Example 2, unless otherwise specified in the table, the conditions in the table were followed.

[0216]

[0217] Conclusion: The pH of the reaction system affects the yield of the reaction product. 3 equivalents of acetic acid adjust the reaction system to be weakly acidic. Otherwise, alkaline conditions will increase the by-products of Smiles rearrangement.

[0218] Example 3: Synthesis of Compound V

[0219]

[0220] The reactor was purged with nitrogen once, and the following materials were added: EA (10 V), the compound of Formula IV (1.0 eq., 2.05 kg), and TPP (1.5 eq.). Stirring was initiated and the atmosphere was purged with nitrogen three times. The system temperature was controlled at 20-30°C. A solution of DIAD (1.5 eq.) in EA (2 V) was added dropwise, and the temperature was controlled at 20-30°C. After the addition was complete, the reaction was stirred at 20-30°C for 1-3 hours. HPLC analysis indicated that the reaction was complete (compound of Formula IV <0.5%). The system was washed once with 3% aqueous sodium chloride (5.5 V), stripped once with EA (2 V), and the organic phases were combined. The mixture was washed once with 10% aqueous ammonium chloride (5 V), stirred for 5-15 minutes, and then washed once with water (5 V), stirred for 5-15 minutes, and combined. Concentrate under reduced pressure, distill once with methanol (2V), then add MeOH (10V), raise the temperature to 60-66°C, stir for 1-3 hours, then cool to 15-25°C, stir overnight, filter, rinse with methanol (2V), and dry the filter cake at 45-55°C overnight. 1.4 kg of material was collected. Yield: 70.2%.

[0221] 1H NMR(400MHz,DMSO-d6)δ7.819(d,J=1.2Hz,1H),4.673-4.548(m,2H),4.371- 4.142(m,2H),3.915-3.852(m,1H),3.499-3.472(m,1H),3.317-3.293(d,J=9 .6Hz,8H),3.043-2.976(m,2H),2.892-2.776(m,2H),2.416(s,3H),2.328-2. 307(m,1H),2.029-1.932(m,1H),1.860-1.701(m,3H),1.515-1.451(m,12H).

[0222] Example 4: Synthesis of compound of formula VI

[0223]

[0224] The reactor was purged with argon twice, stirred, and charged with 2-MeTHF (20 V), water (4 V), the compound of Formula V (1.0 eq., 1.3 kg), the compound of Formula V-1 (4.0 eq.), CsF (4.0 eq.), Pd2(dba)3 (1.5%), and the ligand Baryphos (6%). The argon atmosphere was replaced five times, and the external bath temperature was raised to 60-65°C. The reaction was then controlled and allowed to react for 12-16 hours. The reaction was complete upon HPLC analysis (compound of Formula V <0.3%), and the system was cooled to 15-30°C. The reaction solution was added with a cysteine ​​potassium carbonate aqueous solution (5V, configuration: cysteine: potassium carbonate: water weight ratio = 1:1.14:15) to remove palladium once, stirred for 1-2 hours, separated, the organic phase was filtered once, and the filtrate was again added with a cysteine ​​potassium carbonate aqueous solution (5V, configuration: cysteine: potassium carbonate: water weight ratio = 1:1.14:15) to remove palladium once, stirred for 1-2 hours, separated, water (5V) was added to the organic phase, stirred for 5-15 minutes, and allowed to stand for stratification. The emulsion was broken with saturated brine (1V). The organic phase was concentrated under reduced pressure. Methanol (4V) was distilled once, and MeOH (8V) was added. The temperature was raised to 65-70°C. Water (3.5V) was added dropwise at 65-70°C. After the addition was complete, the temperature was maintained at 65-70°C, and the mixture was stirred for 1-3 hours. The temperature was then naturally lowered to 25-30°C, stirred overnight, filtered, and rinsed with a MeOH / water solution (8V / 3.5V, 1V). The filter cake was dried at 45-50°C overnight. The yield was 0.8 kg. Yield: 58.6%.

[0225] 1H NMR(400MHz,DMSO-d6)δ10.173(s,1H),7.797(s,1H),7.372-7.313(q,J=8,7.6Hz,1H),6 .857-6.773(m,2H),4.697-4.564(m,2H),4.350-4.157(m,2H),3.934-3.869(m,1H),3.5 16-3.490(m,1H),3.121-3.037(m,2H),2.908-2.879(m,1H),2.754(s,1H),2.411(s,3H) ,2.329-2.287(m,1H),2.009-1.933(m,1H),1.861-1.698(m,3H),1.461-1.432(m,13H).

[0226] Among them, the dechlorination and debromination by-product impurities and the percentage of axial chiral isomers directly affect the synthesis yield and purification yield of the product and the difficulty of product purification.

[0227] Example 5: Synthesis of compound of formula VII

[0228]

[0229] Option 1:

[0230] Compound VI (1.0 eq., 2.3 kg) and MeOH (6 V) were added dropwise to the system. Concentrated hydrochloric acid (1 V) was then added dropwise at a temperature of 10-45°C. Stirring was continued for 10-20 minutes, and the system was heated to 50-55°C for 2-3 hours. The reaction was complete (<0.4% of compound VI) by HPLC, and the temperature was lowered to 20-25°C. MTBE (3 V) was added dropwise to the system at a temperature of 20-25°C. Stirring was continued overnight at 20-25°C, and the mixture was filtered. The filter cake was rinsed with MTBE (1 V) and then dried at 45-50°C overnight. 2 kg of the product was collected. Yield: 86.6%. The water content was 5.8% by KF determination, and the chlorine content was 10.54% by an automatic potentiometric titrator and electronic balance.

[0231] 1H NMR(400MHz,DMSO-d6)δ10.372-10.333(m,2H),7.807(s,1H),7.372-7.313(m,1H),6.934-6.9 13(m,1H),6.812-6.768(m,1H),5.113(d,J=10Hz,1H),4.769(d,J=11.6Hz,1H),4.291(s,1H), 4.041-4.005(m,1H),3.861-3.827(m,1H),3.713-3.626(m,3H),3.450-3.353(m,2H),3.242-3 .162(m,2H),2.940(s,3H),2.331-2.247(m,1H),2.116-1.993(m,3H),1.706(d,J=6.8Hz,3H).

[0232] Option 2:

[0233] Dissolve the compound of Formula VI (1.0 eq. 2.3 K) in DCM (5 V) with mechanical stirring. Replace the mixture with nitrogen 2-3 times, then activate nitrogen protection. Adjust the temperature to 20-25°C (target value around 22°C). Add TFA (1.5 V) dropwise, maintaining the temperature at 20-30°C. After the addition is complete, maintain the temperature at 20-25°C (target value 22°C) and stir for 5-6 hours. Take a control sample from the reaction solution and perform HPLC analysis: (Compound of Formula VI / Compound of Formula VII-1 ≤ 1.0%). Concentrate the reaction solution under reduced pressure to 2-3 V (target value 2.5 V). Add MeOH (5 V) to the system. Concentrate the mixture under reduced pressure to 2-3 V (target value 2.5 V). Add water (5 V) and stir to dissolve. Slowly add the above solution dropwise to a potassium carbonate aqueous solution (10 V) at 20-25°C. If bubbles are generated, control the degassing rate by adjusting the addition rate. After the addition is complete, continue stirring for >30 minutes. A white amorphous solid precipitates. Filter under negative pressure to obtain a wet product. Dissolve the wet product in ACN (10V) and stir to dissolve. Concentrate under reduced pressure to 2-3V (target value 2.5V). Dissolve in ACN (6V) again. Stir at 20-30°C for 1-2h. Filter under negative pressure to obtain a wet product. Dry overnight and collect the sample to obtain a nearly white solid with a yield of 80.5%. The product is the free form of the compound of formula VII-1 (neutral compound, unsalted form of the compound of formula VII-1).

[0234] Example 6: Synthesis of compound of formula VIII

[0235]

[0236] Option 1:

[0237] Add water (5V) and potassium phosphate (1.46 eq.) to the system and stir until the solution is clear. Then add the compound of Formula VII-1 (1.0 eq., 1.95 kg) and THF (5V). Stir the system for 30-40 minutes, cool it to -5-5°C, and then dropwise add a solution of 3-chloropropionyl chloride (1.35 eq.) in THF (2V) to the system, controlling the temperature at 0-5°C. After the addition is complete, maintain the temperature at 0-5°C and stir for 0.5-1 hour. HPLC analysis indicates the reaction is complete (<0.15% of the compound of Formula VII-1). Extract the system with water (5V) and 2-MeTHF (7V). Heat the system to 20-25°C, control the temperature at 20-25°C, stir for 20-40 minutes, separate the layers, and back-extract the aqueous phase once with 2-MeTHF (10V). Separate the layers, and combine the organic phases for direct use in the next reaction.

[0238] Option 2:

[0239] Add the compound of Formula VII-1 (1.0 eq.), THF (7V), and purified water (5X) to the reaction system in sequence. Start mechanical stirring and stir under nitrogen for 5-10 minutes. Add K3PO4 (1.0 eq.) and stir for 5-10 minutes. Adjust the internal temperature to 0-5°C. Slowly add a solution of 3-chloropropionyl chloride (1.2 eq.) in THF (2V) dropwise over a period of approximately 0.5 hours. After the addition is complete, maintain the temperature at 0-5°C and stir for 0.5-1 hour. Take a sample for in-process control (post-processing after passing IPC testing: the ratio of compound of Formula VII-1 to compound of Formula VIII is ≤ 0.1%). Purified water (5V), KH2PO4 (2.0eq.), and 2-MeTHF (9V) were added to the system, and the temperature was raised to 15-20°C. The system was stirred for 0.5-1h, allowed to stand for separation (the product was in the upper organic phase), and the layers were separated. 2-MeTHF (5V) was added to the aqueous phase, and the mixture was stirred for 0.5-1h. The layers were allowed to stand for separation (the product was in the upper organic phase), and the layers were separated. The organic phases were combined, washed once with saturated aqueous NaCl solution (5V), and allowed to stand for separation. The organic phase was concentrated to dryness under reduced pressure at 25-40°C, and replaced with THF (4V) 2-3 times, each time concentrated to dryness, to obtain a concentrated crude product of the compound of Formula VIII, which was used directly in the next reaction.

[0240] Example 7: Synthesis of Compound of Formula IX

[0241]

[0242] Option 1:

[0243] Add potassium carbonate (14.43 eq.) and TBAB (2.62 eq.) in water (10 V) to the system and stir for 30-40 minutes. Add the treated solution of the compound of Formula VIII to the system continuously. Heat the system to 25-30°C and react for 35-40 hours. HPLC analysis indicates completion (compound of Formula VIII <0.1%). The layers were separated and the liquid was separated. 10% potassium dihydrogen phosphate aqueous solution (2V) + saturated brine (5V) was added to the organic phase (2-MeTHF or THF) and stirred for 5-15 minutes. The layers were separated and the organic phase (pH: 6-7) was concentrated under reduced pressure to 2V volume. Acetone (6V) was added and the system was heated to 50-55°C and stirred for 2 hours. Water (5V) was added dropwise at 50-55°C. After the addition was complete, the temperature was controlled at 50-55°C and stirred for 1-2 hours. The temperature was lowered to 20-25°C and stirred overnight. The mixture was filtered and the filter cake was washed with acetone / water solution (6V / 5V, 1V). The filter cake was dried at 45-50°C overnight to yield 1.65 kg.

[0244] Secondary purification: acetone (6V), DMSO (0.5V), and the crude compound of formula IX (2.18Kg) were added to the system, stirring was started, the system was heated to 50-55°C, water (5V) was added dropwise to the system, the temperature was controlled at 50-55°C, and the temperature was naturally cooled to 20-25°C. After filtering, the filter cake was rinsed with acetone / water solution (6V / 5V, 2V) four times (5-10 minutes each time), and the filter cake was dried at 45-50°C overnight to obtain 2Kg of material.

[0245] The total yield of the two steps of Example 6 and Example 7 was 86%. The purity of the compound of Formula IX measured by HPLC was 99.18% chemical purity.

[0246] 11H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.85 - 7.79 (m, 1H), 7.34 (td, J = 8.3, 6.9 Hz, 1H), 7.00 (dd, J = 16.8, 10.6 Hz, 1H), 6.88–6.75 (m, 2H), 6.14 (dd, J = 16.8, 2.4 Hz, 1H), 5.80–5.67 (m, 1H), 4.77–4.69 (m, 1H), 4.69–4.52 (m, 2H), 4.33 (ddd, J = 10.6, 4.5, 2.3 Hz, 1H), 4.00 (dd, J = 19.0, 4.3 Hz, 1H), 3.80 (dd, J = 14.3, 4.1 Hz, 1H), 3.23–3.09 (m, 1H), 3.06–2.86 (m, 2H), 2.73 (dt, J = 9.4, 4.8 Hz, 1H), 2.40 (s, 3H), 2.28 (td, J = 9.3, 7.0 Hz, 1H), 2.09 (s, 1H), 1.98 (dq, J = 12.5, 9.0 Hz, 1H), 1.90–1.66 (m, 3H), 1.53 (dd, J = 18.0, 6.6 Hz, 3H).

[0247] 13 13C NMR (101 MHz, DMSO-d6) δ 165.12, 163.94, 159.45, 157.19, 153.55, 152.34, 138.17, 131.48, 130.40, 129.26, 127.60, 122.28, 117.63, 116.98, 112.12, 108.38, 108.19, 106.15, 105.93, 77.08, 65.77, 57.63, 55.81, 51.59, 44.18, 42.61, 39.41, 37.52, 27.03, 23.82, 14.95.

[0248] 19 19F NMR (400 MHz, DMSO-d6) δ -119, -113.

[0249] Scheme 2:

[0250] Dissolve the concentrated crude product of Formula VIII (1.0 eq.) in DCM (10 V), stir, and control the temperature to 0-5°C. Slowly add DBU (3.5 eq.) dropwise to the system, exotherming the addition. Control the temperature and add for approximately 0.5 h. Upon completion, control the temperature of the reaction solution to 13-17°C and stir for 6-8 h. Take a sample for control (IPC testing is performed after passing the post-processing, with a Formula VIII / Formula IX ratio of ≤ 0.1%). Add KH2PO4 (4.0 eq.) aqueous solution (10 V) to the system, stir for 0.5-1 h, and allow the mixture to stand until the pH reaches 6-7. Separate the layers (the product is in the upper organic phase). Extract the aqueous phase once with DCM (5 V). Wash the combined organic phases once with 5% KH2PO4 aqueous solution (5 V). Concentrate the organic phase under reduced pressure to dryness to obtain the crude product of Formula IX.

[0251] Dissolve the crude compound of Formula IX in acetone (5-6V), heat to 50°C, and slowly add water (3-6V) dropwise. After the addition is complete, control the temperature to 50°C and stir for 1-2 hours. Then, cool to 40°C (approximately 0.5 hour), control the temperature at 40°C and stir for 0.5 hour. Next, cool to 30°C (approximately 0.5 hour), control the temperature at 30°C and stir for 0.5 hour. Finally, cool to 20°C (approximately 0.5 hour), control the temperature at 20°C and stir for 0.5 hour. Filter, and rinse the filter cake with a mixture of acetone and purified water (1-2V, 2:1). Dry the filter cake in a vacuum at 45°C for 15-24 hours to obtain a white solid with a yield of 80%.

[0252] Example 8: Synthesis of Compound X

[0253]

[0254] The system was purged with nitrogen once, stirring was initiated, and 85% aqueous acetone (8V) and the compound of Formula IX (1.0 eq., 1.9 kg) were added to the system. The system was then purged with nitrogen three times. The temperature was raised to 45-50°C, and a citric acid monohydrate / acetone / water solution (1.0 eq. citric acid monohydrate, 4V 85% aqueous acetone) was added dropwise to the system. The temperature was maintained at 45-50°C. Upon completion of the addition, the elution funnel was rinsed with 85% aqueous acetone (1V), and the mixture was stirred for 0.5-1 hour. Solid seed crystals of the compound of Formula X (1% of the total amount of the compound of Formula IX) were added to the system, and the mixture was stirred at 45-50°C for 4-10 hours. Acetone (7V) was added dropwise to the system, the temperature maintained at 45-50°C. Upon completion of the addition, the mixture was maintained at 45-50°C with stirring for 8-18 hours. The temperature was then lowered to 15-25°C for 2-3 hours, the temperature maintained at 15-25°C with stirring for 2-3 hours, and the mixture was filtered. The filter cake was rinsed with acetone (1V) and vacuum-dried at room temperature for 2-4 hours. The mixture was then heated to 45-50°C and dried in a vacuum oven overnight. 2.2 kg of the product was obtained. Yield: 86%. The chemical purity of the compound of formula X was 99.69% as determined by HPLC.

[0255] 1 H NMR(500MHz,DMSO-d6)δ10.24(br,2H),7.86-7.85(m,1H),7.37-7.33(q,J=8Hz,1H),7.04-6.97(dd,J=16.5,10.5Hz,1H),6.90(d,1H),6.80(t,J=8Hz,1H),6.17-6.14(dd,J=17,2Hz,1H),5.78-5.71(m,1H),5.12(d,J=15Hz,1H),4.75-4.74(m,1H),4.68-4.62(m,3H),4.42(br,1H),4.04-4.00(m,1H),3.84-3.81(dd,J=14.5,3.5Hz,1H),3.37-3.14(m,4H),3.01-2.92(m,1H),2.70-2.54(m,8H),2.11-2.05(m,1H),1.95-1.84(m,3H),1.57-1.51(m,3H).

[0256] 13 C NMR(125MHz,DMSO)175.59,171.22,165.06,164.65,163.31,163.25,161.09,159.16,156.68,156.63,155.37,153.33,151.30,137.88,137.86,131.13,131.03,130.96,130.87,130.25,130.12,130.09,128.72,128.04,127.60,127.06,122.03,121.83,121.80,117.71,117.56,117.43,116.89,116.55,116.38,111.64,111.62,107.79,107.63,105.57,105.40,74.06,73.92,71.86,65.86,56.72,55.27,51.09,47.55,43.75,43.60,43.40,40.78,40.67,40.04,39.88,39.71,37.02,32.98,24.98,24.82,22.49,15.97,14.42.

[0257] 19 F NMR(400MHz,DMSO-d6)δ-117.63,-117.68,-111.89。

[0258] Single crystal preparation method:

[0259] Weigh 20 mg of the compound represented by the above formula X and dissolve it in 1 mL of dichloromethane / methanol (volume ratio 1:1) at room temperature. The sample solution is placed in a 4 mL semi-sealed sample vial and slowly evaporated at room temperature to obtain block crystals for single crystal analysis.

[0260] Single crystal X-ray diffraction (SCXRD) test conditions:

[0261] Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer equipped with a HyPix-6000HE area detector. Cryogenic system: Oxford Cryostream 800. Cu: 50W, Microfocus source: with multilayer mirror (μ-CMF). Distance between crystal and CCD detector: d = 35mm. Tube voltage: 50kV. Tube current: 1mA.

[0262] SCXRD data:

[0263] It belongs to the monoclinic P21 space group. α=90°, β=109.972(2)°, γ=90°, Z=2. Figure 1 The single crystal structure of the compound represented by Formula X comprises one molecule of citric acid and one molecule of water.

[0264] Test Example 1: Proliferation inhibitory activity on Ba / F3 KRAS-G12C, NCI-H358 and MIA PaCa-2 cells containing KRAS G12C mutation

[0265] Used to determine the in vitro proliferation inhibitory activity of the compound or its salt on the Ba / F3 KRAS-G12C cell line of mouse primary B cells Ba / F3 stably expressing KRAS G12C mutant protein, the non-small cell lung cancer NCI-H358 cell line expressing KRAS G12C mutant protein, and the pancreatic cancer MIA PaCa-2 cell line.

[0266] Cell sources: Ba / F3 KRAS-G12C was purchased from Kangyuan Broad Biotechnology (Beijing) Co., Ltd., catalog number KC-1260; NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., Ltd.; MIAPaCa-2 was purchased from Shanghai Dio Biotechnology Co., Ltd.

[0267] Logarithmically growing cells were seeded in 96-well plates (Ba / F3 KRAS-G12C, NCI-H358, and MIAPaCa-2 cells, 5000, 3000, and 1000 cells / well, respectively, in 90 μl / well). After incubation at 37°C, 5% CO₂ for one day, a serial dilution of the test compound or its salt was added. Specifically, a 10 mM stock solution of the compound or its salt, previously dissolved in DMSO, was diluted four-fold to a series of 10 concentrations. This solution was then diluted to 10-fold the target concentration in culture medium in a separate 96-well plate. Then, 10 μl / well of the compound or its salt solution was added to the 96-well plate seeded with cells to achieve the target concentrations (10,000, 2,500, 625, 156, 39, 10, 2.5, 0.6, 0.15, and 0.04 nM). Three replicates were performed for each concentration, and a blank control was included. After culturing for 72 h at 37°C and 5% CO2, 50 μl CellTiter- 2.0 reagent (luciferase ATP bioluminescence detection reagent, purchased from Promega, product number G9243), shake for 2 minutes, incubate at room temperature for 8 minutes, and then measure the fluorescence intensity (light collection time is 100ms). Calculate the inhibition rate of cell proliferation at each concentration of compound or its salt (cell proliferation inhibition rate = [(luminescence intensity 72小时培养基对照组 -Luminous intensity 72小时化合物或其盐组 ) / (luminous intensity 72小时培养基对照组 – Luminous intensity 0小时培养基对照组 )] × 100%), and the data were analyzed using GraphPad Prism 5.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC was calculated accordingly. 50 The results are shown in Table 1.

[0268]

[0269] The test results show that the compound of the present invention or its salt has good proliferation inhibitory activity on Ba / F3KRAS-G12C, NCI-H358 and MIA PaCa-2 cells containing KRAS G12C mutation.

Claims

1. A method for preparing a compound as shown in formula X, characterized in that: It includes the following steps: In a solvent, the compound represented by formula IX is reacted with citric acid to form a salt to obtain a compound represented by formula X.

2. The method for preparing the compound of formula X according to claim 1, wherein One or more of the following conditions are met: (1) In the salt-forming reaction, the citric acid is one or more of anhydrous citric acid, citric acid containing crystal water, and a combination of a citrate and an acid; (2) In the salt-forming reaction, the solvent is one or more of water, ketone solvents, alcohol solvents and nitrile solvents; (3) In the salt-forming reaction, the volume mass ratio of the solvent to the compound represented by Formula IX is 1-20 mL / g; (4) In the salt-forming reaction, the molar ratio of the compound represented by Formula IX to citric acid is 1:(1-1.2); (5) In the salt-forming reaction, when citric acid is added, a citric acid solution is added dropwise, wherein the citric acid solution is prepared by mixing citric acid monohydrate with an 85% acetone aqueous solution; (6) In the salt-forming reaction, the reaction time of the salt-forming reaction is 0.5-8 hours; (7) In the salt-forming reaction, the reaction temperature of the salt-forming reaction is 15-60°C; (8) The method for preparing the compound of Formula X further includes post-treatment, wherein the post-treatment further includes the following steps: after the salt formation reaction is completed, adding seed crystals of the compound of Formula X, recrystallizing, solid-liquid separation, and drying the solid.

3. The method for preparing the compound of formula X according to claim 2, wherein: One or more of the following conditions are met: (1) In the salt-forming reaction, when the citric acid is citric acid containing crystal water, the citric acid is citric acid monohydrate; (2) In the salt-forming reaction, the solvent is water and / or a ketone solvent; (3) In the salt-forming reaction, the volume mass ratio of the solvent to the compound represented by Formula IX is 4-15 mL / g; (4) In the salt-forming reaction, the molar ratio of the compound represented by Formula IX to citric acid is 1:1; (5) In the salt-forming reaction, the reaction time of the salt-forming reaction is 0.5-1 hour; (6) In the salt-forming reaction, the reaction temperature of the salt-forming reaction is 45-50°C.

4. The method for preparing the compound of formula X according to claim 3, wherein: One or more of the following conditions are met: (1) In the salt-forming reaction, the solvent is 85% acetone aqueous solution; (2) In the salt-forming reaction, the volume mass ratio of the solvent to the compound represented by Formula IX is 8 mL / g, 12 mL / g or 13 mL / g.

5. The method for preparing the compound of formula X according to any one of claims 2 to 4, wherein: One or more of the following conditions are met: (1) During the post-treatment, the mass of the seed crystals of the compound represented by Formula X is 0.5% to 5% of the mass of the compound represented by Formula IX; (2) During post-treatment, when recrystallization is performed, the solvent for the recrystallization is water and / or acetone; (3) During post-treatment, when recrystallization is performed, the recrystallization temperature is 10-60°C; (4) During post-treatment, when recrystallization is performed, the recrystallization time is 1-48 hours; (5) In post-processing, when solid-liquid separation is performed, the solid-liquid separation method is filtration, and the solid after solid-liquid separation is washed with acetone to remove impurities; (6) During post-treatment, when the solid is dried, the temperature of the solid is 45-50°C; (7) It comprises a method for preparing a compound as shown in Formula IX, wherein the method for preparing a compound as shown in Formula IX is any of the following schemes: Option 1 includes the following steps: In a solvent, in the presence of an inorganic base and a phase transfer catalyst, the compound represented by formula VIII is subjected to an elimination reaction to obtain a compound represented by formula IX; Scheme 2 comprises the following steps: in a solvent, in the presence of an organic base, subjecting the compound represented by Formula VIII to an elimination reaction to obtain a compound represented by Formula IX; 6. The method for preparing the compound of formula X according to claim 5, wherein: One or more of the following conditions are met: (1) During the post-treatment, the mass of the seed crystals of the compound represented by Formula X added is 1% of the mass of the compound represented by Formula IX; (2) During post-treatment, when recrystallization is performed, the solvent for the recrystallization is acetone; (3) During post-treatment, when recrystallization is performed, the recrystallization temperature is 15-50°C; (4) In the post-treatment, when recrystallization is performed, the recrystallization time is 16-34 hours.

7. The method for preparing the compound of formula X according to claim 5, wherein: The method for preparing the compound of Formula IX satisfies one or more of the following conditions: (1) In scheme 1, the inorganic base is potassium carbonate; (2) In scheme 1, the phase transfer catalyst is TBAB; (3) In solution 1, the solvent is water and / or an ether solvent; (4) In Scheme 1, the molar ratio of the compound represented by Formula VIII to the inorganic base is 1:(2-15); (5) In Scheme 1, the molar ratio of the compound represented by Formula VIII to the phase transfer catalyst is 1:(1.5-4); (6) In Scheme 1, the elimination reaction temperature is 25-30°C; (7) In Scheme 1, the progress of the elimination reaction is monitored by TLC, HPLC, GC or NMR; (8) In Scheme 1, the method for preparing the compound represented by Formula IX further comprises post-treatment, wherein the post-treatment comprises the following steps: extraction, desolvation, recrystallization, secondary recrystallization, solid-liquid separation, and solid drying; (9) In scheme 2, the organic base is DBU; (10) In the second embodiment, the solvent is an ether solvent and / or a halogenated hydrocarbon solvent; (11) In Scheme 2, the molar ratio of the compound represented by Formula VIII to the organic base is 1:(1-4); (12) In Scheme 2, the elimination reaction temperature is 0-5°C; (13) In Scheme 2, the method for preparing the compound represented by Formula IX further includes post-treatment, which includes the following steps: extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

8. The method for preparing the compound of formula X according to claim 7, wherein: The method for preparing the compound of Formula IX satisfies one or more of the following conditions: (1) In scheme 1, the solvent is selected from one or more of water, 2-methyltetrahydrofuran and tetrahydrofuran; (2) In Scheme 1, the molar ratio of the compound represented by Formula VIII to the inorganic base is 1:14.43; (3) In Scheme 1, the molar ratio of the compound represented by Formula VIII to the phase transfer catalyst is 1:2.62; (4) In Scheme 1, the progress of the elimination reaction is monitored by TLC, HPLC, GC, or NMR. When the progress of the elimination reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula VIII is less than 1%; (5) In the second embodiment, the solvent is selected from one or more of 2-methyltetrahydrofuran, tetrahydrofuran and dichloromethane; (6) In Scheme 2, the molar ratio of the compound represented by Formula VIII to the organic base is 1:3.

5.

9. The method for preparing the compound of formula X according to claim 8, wherein In the method for preparing the compound represented by Formula IX, in Scheme 1, the progress of the elimination reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the elimination reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula VIII is less than 0.1%.

10. The method for preparing the compound of formula X according to any one of claims 7 to 9, wherein: The method for preparing the compound of Formula IX satisfies one or more of the following conditions: (1) In the post-treatment of Scheme 1, during the extraction, the organic phase solvent in the extraction is one or more of dichloromethane, 2-methyltetrahydrofuran, and tetrahydrofuran, and the aqueous phase in the extraction is an aqueous potassium dihydrogen phosphate solution and / or saturated saline, wherein, when the extraction is completed, the pH value of the organic phase is 6-7; (2) In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization solvent is one or more of water, acetone, 2-methyltetrahydrofuran and tetrahydrofuran; (3) In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization temperature is 15-60°C; (4) In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization time is 1-24 hours, (5) In the post-treatment of Scheme 1, when the secondary recrystallization is performed, the solvent for the secondary recrystallization is acetone, water and DMSO; (6) In the post-treatment of Scheme 1, when the secondary recrystallization is performed, the temperature of the secondary recrystallization is 15-60°C; (7) In the post-treatment of Scheme 1, when the solid and liquid are separated, the method of solid-liquid separation is filtration; (8) In the post-treatment of Scheme 1, when the solid is dried, the temperature of the solid drying is 45-50°C; (9) In the post-treatment of Scheme 2, during extraction, the organic phase solvent in the extraction is dichloromethane, the aqueous phase in the extraction is an aqueous potassium dihydrogen phosphate solution, and the pH value of the organic phase is 6-7; (10) In the post-treatment of Scheme 2, when recrystallization is performed, the solvents used in the recrystallization are acetone and water; (11) In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization temperature is 15-60°C; (12) In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization time is 1-24 hours; (13) In the post-treatment of Scheme 2, when the solid-liquid separation is performed, the solid-liquid separation method is filtration; the solid after the solid-liquid separation is washed with a mixed solution of acetone and purified water, wherein the volume ratio of acetone to purified water is 2:1; (14) In the post-treatment of Scheme 2, when the solid is dried, the temperature of the solid drying is 45-50°C; (15) It includes a method for preparing a compound as shown in Formula VIII, which comprises the following steps: in a solvent, in the presence of a base, subjecting a compound as shown in Formula VII or a salt thereof to an amidation reaction with 3-chloropropionyl chloride to obtain a compound as shown in Formula VIII, 11. The method for preparing the compound of formula X according to claim 10, wherein: The method for preparing the compound of Formula IX satisfies one or more of the following conditions: (1) In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization temperature is 20-55°C; (2) In the post-treatment of Scheme 1, when recrystallization is performed, the recrystallization time is 1-15 hours; (3) In the post-treatment of Scheme 1, during the secondary recrystallization, the solvents for the secondary recrystallization are acetone, water, and DMSO, and the volume ratio of acetone:DMSO:water is 12:1:10; (4) In the post-treatment of Scheme 1, during the secondary recrystallization, the temperature of the secondary recrystallization is 20-55°C; (5) In the post-treatment of Scheme 2, when recrystallizing, the solvents used in the recrystallization are acetone and water, and the volume ratio of acetone to water is 1:(0.5-2); (6) In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization temperature is 20-50°C; (7) In the post-treatment of Scheme 2, when recrystallization is performed, the recrystallization time is 0.5-5 hours.

12. The method for preparing the compound of formula X according to claim 10, wherein: The method for preparing the compound represented by Formula VIII satisfies one or more of the following conditions: (1) In the amidation reaction, the salt of the compound represented by Formula VII is the product of the reaction between the compound represented by Formula VII and an acid, wherein the acid is an organic acid and / or an inorganic acid; (2) In the amidation reaction, the salt of the compound shown in Formula VII is the hydrochloride of the compound shown in Formula VII; (3) In the amidation reaction, the base is potassium phosphate; (4) In the amidation reaction, the solvent is water and / or an ether solvent; (5) In the amidation reaction, the molar ratio of the compound represented by Formula VII or its salt to the base is 1:(1.0-1.5); (6) In the amidation reaction, the molar ratio of the compound represented by Formula VII or its salt to the 3-chloropropionyl chloride is 1:(1.1-1.4); (7) In the amidation reaction, the volume mass ratio of the solvent to the compound represented by Formula VII or its salt is 1-18 mL / g; (8) In the amidation reaction, the temperature of the amidation reaction is -20-25°C; (9) In the amidation reaction, the reaction time of the amidation reaction is 0.5-6 hours; (10) The method for preparing the compound of formula VIII further comprises post-treatment, wherein the post-treatment comprises the following steps: after the amidation reaction is completed, extraction and desolvation; (11) It comprises a method for preparing a compound as represented by Formula VII or a salt thereof, wherein the method for preparing a compound as represented by Formula VII or a salt thereof comprises the following steps: subjecting a compound as represented by Formula VI to an amino group deprotection reaction in a solvent under the action of an acid to obtain a compound as represented by Formula VII or a salt thereof; 13. The method for preparing the compound of formula X according to claim 12, wherein: The method for preparing the compound represented by Formula VIII satisfies one or more of the following conditions: (1) In the amidation reaction, the salt of the compound represented by Formula VII is the product of the reaction of the compound represented by Formula VII with an acid, wherein the acid is selected from one or more of citric acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid; (2) In the amidation reaction, the salt of the compound represented by Formula VII is a compound represented by Formula VII-1, (3) In the amidation reaction, the solvent is selected from one or more of water, 2-methyltetrahydrofuran and tetrahydrofuran; (4) In the amidation reaction, the molar ratio of the compound represented by Formula VII or its salt to the base is 1:1 or 1:1.46; (5) In the amidation reaction, the molar ratio of the compound represented by Formula VII or its salt to the 3-chloropropionyl chloride is 1:1.2 or 1:1.35; (6) In the amidation reaction, the volume mass ratio of the solvent to the compound represented by Formula VII or its salt is 4-15 mL / g; (7) In the amidation reaction, the temperature of the amidation reaction is -5-5°C; (8) The method for preparing the compound of formula VIII further comprises post-treatment, which comprises the following steps: after the amidation reaction is completed, extraction and desolventization; when extraction is performed, the organic phase solvent in the extraction is 2-methyltetrahydrofuran and / or tetrahydrofuran.

14. The method for preparing the compound of formula X according to claim 13, wherein: In the method for preparing the compound represented by Formula VIII, in the amidation reaction, the volume mass ratio of the solvent to the compound represented by Formula VII or its salt is 12 mL / g or 14 mL / g.

15. The method for preparing the compound of formula X according to claim 12, wherein: The preparation method of the compound represented by Formula VII or its salt satisfies one or more of the following conditions: (1) In the amino deprotection reaction, the acid is hydrochloric acid and / or trifluoroacetic acid; (2) In the amino deprotection reaction, when the acid is hydrochloric acid, the reaction temperature of the amino deprotection reaction is 10-55°C; (3) In the amino deprotection reaction, when the acid is hydrochloric acid, the salt of the compound represented by Formula VII is the hydrochloride of the compound represented by Formula VII; (4) In the amino deprotection reaction, when the acid is trifluoroacetic acid, the reaction temperature of the amino deprotection reaction is 20-30°C; (5) In the amino deprotection reaction, the solvent is a halogenated hydrocarbon solvent and / or an alcohol solvent; (6) In the amino deprotection reaction, the reaction time of the amino deprotection reaction is 1-6 hours; (7) In the amino deprotection reaction, the volume mass ratio of the solvent to the compound represented by Formula VI is 1-10 mL / g; (8) In the amino deprotection reaction, the progress of the amino deprotection reaction is monitored by TLC, HPLC, GC or NMR; (9) The method for preparing the compound of formula VII or its salt further comprises post-treatment, wherein the post-treatment comprises the following steps: after the amino deprotection reaction is completed, acid-base neutralization is performed, slurrying is performed, solid-liquid separation is performed, and solid drying is performed.

16. The method for preparing the compound of formula X according to claim 15, wherein: The preparation method of the compound represented by Formula VII or its salt satisfies one or more of the following conditions: (1) In the amino deprotection reaction, when the acid is hydrochloric acid, the salt of the compound represented by Formula VII is the compound represented by Formula VII-1, (2) In the amino deprotection reaction, when the acid is trifluoroacetic acid, the reaction temperature of the amino deprotection reaction is 20-25°C; (3) In the amino deprotection reaction, the solvent is dichloromethane and / or methanol; (4) In the amino deprotection reaction, the reaction time of the amino deprotection reaction is 5-6 hours; (5) In the amino deprotection reaction, the volume mass ratio of the solvent to the compound represented by Formula VI is 2-8 mL / g; (6) In the amino deprotection reaction, the progress of the amino deprotection reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the amino deprotection reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula III is less than 1%.

17. The method for preparing the compound of formula X according to claim 16, wherein: The preparation method of the compound represented by Formula VII or its salt satisfies one or more of the following conditions: (1) In the amino deprotection reaction, the reaction time of the amino deprotection reaction is 2-3 hours; (2) In the amino deprotection reaction, the volume mass ratio of the solvent to the compound represented by Formula VI is 5 mL / g or 6 mL / g; (3) In the amino deprotection reaction, the progress of the amino deprotection reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the amino deprotection reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula III is less than 0.4%.

18. The method for preparing the compound of formula X according to any one of claims 15 to 17, wherein: The preparation method of the compound represented by Formula VII or its salt satisfies one or more of the following conditions: (1) In the post-treatment, when the acid and alkali are neutralized, the alkali used for the acid and alkali neutralization is an inorganic alkali; (2) During post-treatment, when beating, the beating solvent is one or more of a nitrile solvent, an alcohol solvent, and an ether solvent; (3) During post-processing, when beating, the beating temperature is 15-50°C; (4) During post-processing, when beating, the beating time is 1-24 hours; (5) In post-processing, when solid-liquid separation is performed, the solid-liquid separation method is filtration; (6) During post-treatment, when the solid is dried, the temperature of the solid is 45-50°C; (7) It includes a method for preparing a compound as shown in Formula VI, wherein the method for preparing a compound as shown in Formula VI comprises the following steps: in a solvent, a compound as shown in Formula V, a compound as shown in Formula V-1, a palladium catalyst, a base and a chiral phosphine ligand are subjected to a coupling reaction to obtain a compound as shown in Formula VI, 19. The method for preparing the compound of formula X according to claim 18, wherein: The preparation method of the compound represented by Formula VII or its salt satisfies one or more of the following conditions: (1) In the post-treatment, when acid-base neutralization is performed, the base used for the acid-base neutralization is carbonate and / or bicarbonate; (2) During post-treatment, when beating, the beating solvent is selected from one or more of acetonitrile, methanol and methyl tert-butyl ether; (3) During post-processing, when beating, the beating temperature is 20-30°C; (4) During post-processing, when beating, the beating time is 1-15 hours; (5) In the post-treatment, when the solid-liquid separation is performed, the solid-liquid separation method is filtration, and the solid after the solid-liquid separation is washed with methyl tert-butyl ether.

20. The method for preparing the compound of formula X according to claim 19, wherein: In the method for preparing the compound represented by Formula VII or a salt thereof, in the post-treatment, when acid-base neutralization is performed, the base used for acid-base neutralization is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

21. The method for preparing the compound of formula X according to claim 18, wherein: The method for preparing the compound of Formula VI satisfies one or more of the following conditions: (1) In the coupling reaction, the palladium catalyst is Pd2(dba)3; (2) In the coupling reaction, the base is CsF; (3) In the coupling reaction, the chiral phosphine ligand is BaryPhos; (4) In the coupling reaction, the molar ratio of the compound represented by Formula V to the compound represented by Formula V-1 is 1:(2-6); (5) In the coupling reaction, the molar ratio of the compound represented by Formula V to the base is 1:(2-6); (6) In the coupling reaction, the molar ratio of the compound represented by Formula V to the palladium catalyst is 1:(0.01-0.1); (7) In the coupling reaction, the molar ratio of the compound represented by Formula V to the chiral phosphine ligand is 1:(0.01-0.2); (8) In the coupling reaction, the volume mass ratio of the solvent to the compound represented by Formula V is 10-30 mL / g; (9) In the coupling reaction, the temperature of the coupling reaction is 60-65°C; (10) In the coupling reaction, the coupling reaction time is 12-16 hours; (11) The coupling reaction is carried out under anaerobic conditions; (12) In the coupling reaction, the progress of the coupling reaction is monitored by TLC, HPLC, GC or NMR; (13) The method for preparing the compound of formula VI further comprises post-treatment, which comprises the following steps: after the coupling reaction is completed, palladium removal, extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

22. The method for preparing the compound of formula X according to claim 21, wherein: The method for preparing the compound of Formula VI satisfies one or more of the following conditions: (1) In the coupling reaction, the molar ratio of the compound represented by Formula V to the compound represented by Formula V-1 is 1:4; (2) In the coupling reaction, the molar ratio of the compound represented by Formula V to the base is 1:4; (3) In the coupling reaction, the molar ratio of the compound represented by Formula V to the palladium catalyst is 1:0.015; (4) In the coupling reaction, the molar ratio of the compound represented by Formula V to the chiral phosphine ligand is 1:0.06; (5) In the coupling reaction, the volume mass ratio of the solvent to the compound represented by Formula V is 15-25 mL / g; (6) The coupling reaction is carried out under one or more of nitrogen, neon and argon; (7) In the coupling reaction, the progress of the coupling reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the coupling reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula V is less than 1%.

23. The method for preparing the compound of formula X according to claim 22, wherein: The method for preparing the compound of Formula VI satisfies one or more of the following conditions: (1) In the coupling reaction, the volume mass ratio of the solvent to the compound represented by Formula V is 20 mL / g; (2) In the coupling reaction, the progress of the coupling reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the coupling reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula V is less than 0.3%.

24. The method for preparing the compound of formula X according to any one of claims 21 to 23, wherein: The method for preparing the compound of Formula VI satisfies one or more of the following conditions: (1) In the post-treatment, the palladium removal is performed at least twice, and the palladium removal method is to add a cysteine ​​potassium carbonate aqueous solution to the organic phase after the coupling reaction, wherein the cysteine ​​potassium carbonate aqueous solution is prepared according to a weight ratio of cysteine: potassium carbonate: water = 1:1.14:15; (2) In the post-treatment, the organic phase solvent in the extraction is 2-methyltetrahydrofuran, and the aqueous phase is one or more of water, saline solution and potassium carbonate aqueous solution; (3) In the post-treatment, the solvent used in the recrystallization is water and / or an alcohol solvent; (4) The recrystallization temperature is 15-70°C; (5) During post-treatment, the recrystallization time is 1-24 hours; (6) In the post-processing, the solid-liquid separation method is filtration; (7) During post-treatment, the solid is dried at a temperature of 45-50°C; (8) It includes a method for preparing a compound as shown in Formula V, which comprises the following steps: in a solvent, at 20-30° C., subjecting a compound as shown in Formula IV, an organic phosphine, and an azodicarboxylate to a cyclization reaction to obtain a compound as shown in Formula V, wherein the organic phosphine is a trialkylphosphine or a triarylphosphine; 25. The method for preparing the compound of formula X according to claim 24, wherein: The method for preparing the compound of Formula VI satisfies one or more of the following conditions: (1) In the post-treatment, the solvent used in the recrystallization is water and / or methanol; (2) the recrystallization temperature is 25-70°C; (3) In the post-treatment, the recrystallization time is 1-15 hours.

26. The method for preparing the compound of formula X according to claim 25, wherein: In the preparation method of the compound represented by Formula VI, in the post-treatment, the solvents used in the recrystallization are water and methanol, and the volume ratio of methanol to water is 8:3.

5.

27. The method for preparing the compound of formula X according to claim 24, wherein: The method for preparing the compound of formula V satisfies one or more of the following conditions: (1) In the cyclization reaction, when the organic phosphine is a trialkylphosphine, the trialkylphosphine is trimethylphosphine or tributylphosphine; (2) In the cyclization reaction, when the organic phosphine is a triarylphosphine, the triarylphosphine is triphenylphosphine; (3) In the cyclization reaction, the azodicarboxylate is one or more of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and di-tert-butyl azodicarboxylate (DBAD); (4) In the cyclization reaction, the solvent is an aprotic solvent; (5) In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the organic phosphine is 1:(1.2-1.6); (6) In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the azodicarboxylate is 1:(1.2-1.6); (7) In the cyclization reaction, the volume mass ratio of the solvent to the compound represented by Formula IV is 1-15 mL / g; (8) In the cyclization reaction, the cyclization reaction time is 1-3 hours; (9) In the cyclization reaction, the cyclization reaction temperature is 20-30°C; (10) In the cyclization reaction, the progress of the cyclization reaction is monitored by TLC, HPLC, GC or NMR; (11) The preparation method of the compound represented by Formula IV further includes post-treatment, which comprises the following steps: extraction after the cyclization reaction, desolventization, recrystallization, solid-liquid separation, and solid drying.

28. The method for preparing the compound of formula X according to claim 27, wherein: The method for preparing the compound of formula V satisfies one or more of the following conditions: (1) In the cyclization reaction, the azodicarboxylate is diisopropyl azodicarboxylate; (2) In the cyclization reaction, the solvent is selected from one or more of benzene, toluene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, DMF and dichloromethane; (3) In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the organic phosphine is 1:1.5; (4) In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the azodicarboxylate is 1:1.5; (5) In the cyclization reaction, the volume mass ratio of the solvent to the compound represented by Formula IV is 5-12 mL / g; (6) In the cyclization reaction, the progress of the cyclization reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the cyclization reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula IV is less than 1%.

29. The method for preparing the compound of formula X according to claim 28, wherein: The method for preparing the compound of formula V satisfies one or more of the following conditions: (1) In the cyclization reaction, the solvent is ethyl acetate; (2) In the cyclization reaction, the volume mass ratio of the solvent to the compound represented by Formula IV is 12 mL / g or 10 mL / g; (3) In the cyclization reaction, the progress of the cyclization reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the cyclization reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula IV is less than 0.5%.

30. The method for preparing the compound of formula X according to any one of claims 27 to 29, wherein: The method for preparing the compound of formula V satisfies one or more of the following conditions: (1) In the post-treatment, the organic phase solvent in the extraction is ethyl acetate, and the aqueous phase is water, sodium chloride aqueous solution or ammonium chloride aqueous solution; (2) In the post-treatment, the solvent used in the recrystallization is an alcohol solvent; (3) During post-treatment, the recrystallization temperature is 15-66°C; (4) During post-treatment, the recrystallization time is 1-24 hours; (5) In the post-processing, the solid-liquid separation method is filtration; (6) During post-treatment, the solid is dried at a temperature of 45-55°C; (7) It comprises a method for preparing a compound as shown in Formula IV, wherein the method for preparing a compound as shown in Formula IV comprises the following steps: in a solvent, subjecting a compound as shown in Formula III, a fluoride and acetic acid to a deprotection reaction of the hydroxyl group to obtain a compound as shown in Formula IV, wherein the fluoride is potassium fluoride and / or tetrabutylammonium fluoride; 31. The method for preparing the compound of formula X according to claim 30, wherein: The method for preparing the compound of formula V satisfies one or more of the following conditions: (1) In the post-treatment, the solvent used in the recrystallization is methanol; (2) In the post-treatment, the recrystallization time is 1-15 hours.

32. The method for preparing the compound of formula X according to claim 30, wherein: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the fluoride is 1:(1.05-1.3); (2) In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the acetic acid is 1:(2-5); (3) In the deprotection reaction of the hydroxyl group, the deprotection reaction time is 2-4 hours; (4) In the deprotection reaction of the hydroxyl group, the deprotection reaction temperature is 20-40°C; (5) The volume mass ratio of the solvent to the compound represented by Formula III is 1-15 mL / g; (6) In the deprotection reaction of the hydroxyl group, the progress of the deprotection reaction of the hydroxyl group is monitored by TLC, HPLC, GC or NMR; (7) The method for preparing the compound of formula IV further comprises post-treatment, which comprises the following steps: after the deprotection reaction of the hydroxyl group is completed, extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

33. The method for preparing the compound of formula X according to claim 32, wherein: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the fluoride is 1:(1.1-1.2); (2) In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the acetic acid is 1:(2-3); (3) In the deprotection reaction of the hydroxyl group, the deprotection reaction temperature is 28-33°C; (4) The volume mass ratio of the solvent to the compound represented by Formula III is 2-12 mL / g; (5) In the deprotection reaction of the hydroxyl group, the progress of the deprotection reaction of the hydroxyl group is monitored by TLC, HPLC, GC or NMR. When the progress of the deprotection reaction of the hydroxyl group is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula III is less than 1%.

34. The method for preparing the compound of formula X according to claim 33, wherein: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the fluoride is 1:1.2; (2) In the deprotection reaction of the hydroxyl group, the molar ratio of the compound represented by Formula III to the acetic acid is 1:3; (3) The volume mass ratio of the solvent to the compound represented by Formula III is 8 mL / g; (4) In the deprotection reaction of the hydroxyl group, the progress of the deprotection reaction of the hydroxyl group is monitored by TLC, HPLC, GC or NMR. When the progress of the deprotection reaction of the hydroxyl group is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula III is less than 0.35%.

35. The method for preparing the compound of formula X according to any one of claims 32 to 34, wherein: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) In the post-treatment, the organic phase solvent in the extraction is dichloromethane and / or tetrahydrofuran, and the aqueous phase is water, sodium bicarbonate aqueous solution or sodium chloride aqueous solution; (2) In the post-treatment, the solvent used in the recrystallization is an ether solvent; (3) During post-treatment, the recrystallization temperature is 15-70°C; (4) During post-treatment, the recrystallization time is 1-12 hours; (5) In the post-processing, the solid-liquid separation method is filtration; (6) During post-treatment, the solid is dried at a temperature of 45-55°C; (7) It includes a method for preparing a compound as shown in Formula III, which comprises the following steps: in a solvent, in the presence of a base, subjecting a compound as shown in Formula I to a substitution reaction with a compound as shown in Formula II to obtain a compound as shown in Formula III, wherein the base is an alkoxide; 36. The method for preparing the compound of formula X according to claim 35, wherein: The method for preparing the compound of formula IV satisfies one or more of the following conditions: (1) In the post-treatment, the solvent used in the recrystallization is tetrahydrofuran; (2) In the post-treatment, the recrystallization time is 1-4 hours.

37. The method for preparing the compound of formula X according to claim 36, wherein: In the preparation method of the compound shown in Formula IV, in the post-treatment, the recrystallization time is 1-2 hours.

38. The method for preparing the compound of formula X according to claim 35, wherein: The method for preparing the compound of formula III satisfies one or more of the following conditions: (1) In the substitution reaction, the alkoxide is a compound in which the hydrogen in the alcohol molecule is replaced by a metal; (2) In the substitution reaction, the solvent is one or more of an ether solvent, an alcohol solvent, and a nitrile solvent; (3) In the substitution reaction, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:(1.05-1.3); (4) In the substitution reaction, the molar ratio of the compound represented by formula I to the alkoxide is 1:(1.5-3.5); (5) In the substitution reaction, the volume mass ratio of the solvent to the compound represented by Formula I is 1-15 mL / g; (6) In the substitution reaction, the reaction time of the substitution reaction is 15-24 hours; (7) In the substitution reaction, the reaction temperature of the substitution reaction is 20-35°C; (8) In the substitution reaction, the progress of the substitution reaction is monitored by TLC, HPLC, GC or NMR; (9) The method for preparing the compound of formula III further comprises post-treatment, which comprises the following steps: after the substitution reaction is completed, quenching, extraction, desolventization, recrystallization, solid-liquid separation, and solid drying.

39. The method for preparing the compound of formula X according to claim 38, wherein The method for preparing the compound of formula III satisfies one or more of the following conditions: (1) In the substitution reaction, the alkoxide is a lithium salt of an alcohol and / or a potassium salt of an alcohol; (2) In the substitution reaction, the solvent is an ether solvent; (3) In the substitution reaction, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:(1.1-1.2); (4) In the substitution reaction, the molar ratio of the compound represented by formula I to the alkoxide is 1:(2-3); (5) In the substitution reaction, the volume mass ratio of the solvent to the compound represented by Formula I is 5-12 mL / g; (6) In the substitution reaction, the progress of the substitution reaction is monitored by TLC, HPLC, GC or NMR. When the progress of the substitution reaction is monitored by HPLC, the reaction endpoint is when the percentage content of the compound represented by Formula I is less than 1%.

40. The method for preparing the compound of formula X according to claim 39, wherein: The method for preparing the compound of formula III satisfies one or more of the following conditions: (1) In the substitution reaction, the alkoxide is lithium tert-butoxide and / or potassium tert-butoxide; (2) In the substitution reaction, the solvent is 2-methyltetrahydrofuran; (3) In the substitution reaction, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:1.2; (4) In the substitution reaction, the molar ratio of the compound represented by Formula I to the alkoxide is 1:2.5 or 1:3; (5) In the substitution reaction, the volume mass ratio of the solvent to the compound represented by formula I is 12 mL / g.

41. The method for preparing the compound of formula X according to claim 38, wherein The method for preparing the compound of formula III satisfies one or more of the following conditions: (1) In the post-treatment, when quenching, the reagent for quenching the alkoxide is dihydrogen phosphate or its aqueous solution; the system temperature is controlled at 20-30°C; (2) in the post-treatment, when recrystallization is performed, the solvent used in the recrystallization is a nitrile solvent and / or water; (3) During post-treatment, when recrystallization is performed, the recrystallization temperature is 15-70°C; (4) During post-treatment, when recrystallization is performed, the recrystallization time is 1-24 hours; (5) In post-processing, when solid-liquid separation is performed, the solid-liquid separation method is filtration; the separated solid is washed with a mixed solvent of acetonitrile and water to remove impurities; (6) During post-treatment, when the solid is dried, the temperature of the solid drying is 50-60°C.

42. The method for preparing the compound of formula X according to claim 41, wherein The method for preparing the compound of formula III satisfies one or more of the following conditions: (1) In the post-treatment, when quenching, the reagent for quenching the alkoxide is KH2PO4 or a 10% KH2PO4 aqueous solution; (2) In the post-treatment, when recrystallization is performed, the solvents used in the recrystallization are acetonitrile and water; (3) In the post-treatment, when recrystallization is performed, the recrystallization time is 1-15 hours.

43. The method for preparing the compound of formula X according to claim 42, wherein: In the preparation method of the compound shown in Formula III, in the post-treatment, when recrystallizing, the solvents used in the recrystallization are acetonitrile and water, and the volume ratio of acetonitrile to water is 3:

1.

44. A method for preparing a compound of formula IX, characterized in that: This includes any of the following options: Option 1 includes the following steps: In a solvent, in the presence of an inorganic base and a phase transfer catalyst, the compound represented by formula VIII is subjected to an elimination reaction to obtain a compound represented by formula IX; Scheme 2 comprises the following steps: in a solvent, in the presence of an organic base, subjecting the compound represented by Formula VIII to an elimination reaction to obtain a compound represented by Formula IX; The reaction conditions and operations are the same as those described in the method for preparing the compound represented by formula IX according to any one of claims 5 to 43.

45. A method for preparing a compound as represented by formula VIII, characterized in that: It includes the following steps: In a solvent, under the action of a base, the compound represented by Formula VII or its salt is subjected to an amidation reaction with 3-chloropropionyl chloride to obtain a compound represented by Formula VIII. The reaction conditions and operations are the same as those described in the method for preparing the compound represented by formula VIII according to any one of claims 10 to 43.

46. ​​A method for preparing a compound of formula VII or a salt thereof, characterized in that: It includes the following steps: In a solvent, under the action of an acid, the compound represented by Formula VI is subjected to amino deprotection reaction to obtain a compound represented by Formula VII or a salt thereof. Wherein each reaction condition and operation are as described in any one of claims 12-43 as the method for preparing the compound represented by formula VII or its salt; In the amino deprotection reaction, the volume mass ratio of the solvent to the compound represented by Formula VI is 1-10 mL / g.

47. A method for preparing a compound as represented by formula VI, characterized in that: It includes the following steps: In a solvent, a compound represented by formula V, a compound represented by formula V-1, a palladium catalyst, a base and a chiral phosphine ligand are subjected to a coupling reaction to obtain a compound represented by formula VI. The reaction conditions and operations are the same as those described in the method for preparing the compound represented by formula VI according to any one of claims 18 to 43.

48. A method for preparing a compound as shown in formula V, characterized in that: It includes the following steps: In a solvent, at 20-30° C., a compound represented by Formula IV, an organic phosphine and an azodicarboxylate are subjected to a cyclization reaction to obtain a compound represented by Formula V, wherein the organic phosphine is a trialkylphosphine or a triarylphosphine. Wherein each reaction condition and operation are as described in the method for preparing the compound represented by formula V according to any one of claims 24 to 43; In the cyclization reaction, the molar ratio of the compound represented by Formula IV to the organic phosphine is 1:(1.2-1.6).

49. A method for preparing a compound as shown in formula IV, characterized in that: It includes the following steps: In a solvent, a compound as shown in formula III, a fluoride and acetic acid are subjected to a hydroxyl deprotection reaction to obtain a compound as shown in formula IV, wherein the fluoride is potassium fluoride and / or tetrabutylammonium fluoride. The reaction conditions and operations are the same as those described in the method for preparing the compound represented by formula IV according to any one of claims 30 to 43.

50. A method for preparing a compound as shown in formula III, characterized in that: It includes the following steps: In a solvent, under the action of a base, a compound represented by Formula I is subjected to a substitution reaction with a compound represented by Formula II to obtain a compound represented by Formula III, wherein the base is an alkoxide. The reaction conditions and operations are the same as those described in the method for preparing the compound represented by formula III according to any one of claims 35 to 43.

51. A compound represented by formula X:

52. A compound selected from any of the following structures:

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