Preparation method for nitrogen-containing heterocyclic derivative, and intermediate of nitrogen-containing heterocyclic derivative

Abstract

The present invention relates to a preparation method for a nitrogen-containing heterocyclic derivative. The method of the present invention overcomes the defects in the prior art and greatly reduces the cost. The obtained product has good purity, a high yield, high process operability and high process safety. Therefore, the method is suitable for industrial application.

Description

Preparation method of nitrogen-containing heterocyclic derivative and intermediate thereof TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a preparation method of nitrogen-containing heterocyclic derivative, an intermediate thereof and application thereof. BACKGROUND

[0002] Rat sarcoma (RAS), encoded by proto-oncogenes HRAS, NRAS and KRAS, is divided into four proteins HRAS, NRAS, KRAS4A and KRAS4B, and is a GTP (guanosine triphosphate) binding protein. RAS is located in the inner surface of the cell membrane, and the upstream is a receptor tyrosine kinase (RTK), which activates the downstream PI3K, RAF and other signaling pathways, thereby regulating the functions of cell growth, survival, migration and differentiation.

[0003] RAS mainly has two states in the body: an inactivated state combined with GDP (guanosine diphosphate) and an activated state combined with GTP. Its activity is regulated by two proteins, guanine nucleotide exchange factor (GEF) promotes the release of GDP from RAS protein, activates RAS by binding GTP, and GTPase activating protein (GAP) activates the GTPase activity of RAS protein, hydrolyzes GTP combined in RAS protein into GDP, and inactivates RAS. Under normal circumstances, RAS protein is in an inactivated state, and after mutation, the conformation changes, RAS is in a sustained activated state, and the downstream signaling pathway is also continuously activated, thereby leading to the occurrence of various cancers.

[0004] As the first confirmed cancer gene, RAS is the mutation rate of the highest oncogene, accounting for an average of 25% in human cancers. The most common oncogenic mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutation mainly occurs in a series of cancers such as pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%). The most common mutation of KRAS is point mutation, which mainly occurs in G12, G13 and Q61 in the p-loop (aa 10-17) and Switch II region (aa 59-76), and G12 mutation is the most common (83%). In non-small cell lung cancer (NSCLC) and colorectal cancer, KRAS G12C is one of the most common mutations.

[0005] There are two main factors for the difficulty of developing KRAS inhibitors. First, the structure of RAS protein is smooth, and it is difficult for small molecules to bind to the surface of the protein. Second, the affinity of RAS GTPase to GTP is as high as picomolar (pM) level, and the endogenous GTP level is high, so it is difficult for small molecule drugs to block the combination of the two. Recent studies have found that after KRAS 12 glycine (Gly) is mutated to cysteine (Cys), the conformation changes and a new pocket is formed for covalent binding of small molecules, which irreversibly locks KRAS G12C in the non-activated state combined with GDP. At present, only two KRAS G12C inhibitor drugs Sotorasib and Adagrasib are marketed in Europe and the United States, and only three inhibitor drugs Glecirasib, Garsorasib and Fulzerasib are marketed in China, so there is still a great clinical demand for drugs targeting KRAS G12C mutation. KRAS G12C inhibitors with higher selectivity, better activity and better safety have the potential to treat a variety of cancers and have broad market prospects.

[0006] A nitrogen-containing heterocyclic derivative inhibitor, its preparation method and application are disclosed in PCT / CN2020 / 093285, wherein the patent uses pyridine amine derivatives and the like as raw materials to prepare nitrogen-containing heterocyclic derivatives. However, due to the complexity of the preparation steps and the low total yield, the commercial production cost is high. SUMMARY

[0007] In order to solve the problems existing in the prior art, the inventors have developed a method for preparing nitrogen-containing heteroaromatic derivatives in the long-term research and development process;

[0008] Specifically, the present application provides a compound represented by general formula (II):

[0009] R1 is selected from hydrogen or an amino protecting group; preferably hydrogen, acetyl, tert-butylsulfinyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; more preferably hydrogen or p-methoxybenzyl;

[0010] R2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 alkyl; preferably halogen; more preferably chlorine or bromine;

[0011] R3is absent or selected from halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkyl; preferably hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 alkyl; preferably fluorine, chlorine or bromine;

[0012] R4is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkyl; preferably hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 alkyl; more preferably selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy or cyclopropyl;

[0013] R5, R6and R7are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkyl; preferably hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl; more preferably selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy or cyclopropyl;

[0014] m is selected from 0, 1 or 2;

[0015] In certain embodiments of the present application, the structure of the compound of general formula (II) is selected from formula (II-1), formula (II-2) or formula (II-3):

[0016] Another object of the present application is to provide a method for preparing a compound of general formula (I), characterized in that it comprises the following preparation step:

[0017] reacting the compound of general formula (II) under halogen formate or acyl chloride conditions to obtain the compound of general formula (I); optionally, in the presence of a base ①;

[0018] Preferably, in the presence of an acyl chloride, the preparation step is:

[0019] the acyl chloride is selected from oxalyl chloride or dichlorosulfoxide;

[0020] Alternatively, preferably, in the presence of a halogen formate and a base ①, the preparation step is:

[0021] the halogen formate is selected from methyl chloroformate, ethyl chloroformate, isopropyl chloroformate or butyl chloroformate; preferably isopropyl chloroformate;

[0022] the base ① is selected from sodium hydroxide, potassium hydroxide, sodium hydride, aqueous ammonia, potassium tert-butoxide, sodium tert-butoxide, methylamine, dimethylamine, diethylamine, triethylamine, pyridine or imidazole; preferably sodium hydride.

[0023] In certain embodiments of the present application, in the method for preparing a compound of general formula (I):

[0024] the molar ratio between the compound of general formula (II) and the compound of general formula (A) is comprised between 1:2 and 5;

[0025] Preferably, the molar ratio between the compound of general formula (II-3) and the compound of general formula (A) is comprised between 1:2 and 5, preferably between 1:4 and 5;

[0026] The molar ratio of the compound of general formula (II-2) to the compound of general formula (A) is 1 :2-5, preferably 1 :2-3;

[0027] The reaction is carried out under nitrogen protection;

[0028] The reaction solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, anhydrous dimethyl sulfoxide or anhydrous N,N-dimethylformamide; preferably one or more of anhydrous N,N-dimethylformamide, anhydrous tetrahydrofuran or anhydrous 2-methyltetrahydrofuran;

[0029] Preferably, the solvent for the reaction of the compound of general formula (II-3) with the compound of general formula (A) is selected from one or more of anhydrous N,N-dimethylformamide, anhydrous tetrahydrofuran or anhydrous 2-methyltetrahydrofuran; preferably a mixed solvent of anhydrous tetrahydrofuran and anhydrous 2-methyltetrahydrofuran; more preferably the volume ratio of anhydrous tetrahydrofuran and anhydrous 2-methyltetrahydrofuran is 1:2-4;

[0030] The solvent for the reaction of the compound of general formula (II-2) with the compound of general formula (A) is selected from one or more of anhydrous N,N-dimethylformamide, anhydrous tetrahydrofuran or anhydrous 2-methyltetrahydrofuran; preferably a mixed solvent of anhydrous tetrahydrofuran and anhydrous N,N-dimethylformamide;

[0031] Preferably, the temperature for the reaction of the compound of general formula (II-3) with the compound of general formula (A) is selected from 50-100°C, preferably 70-80°C;

[0032] The temperature for the reaction of the compound of general formula (II-2) with the compound of general formula (A) is selected from 0-25°C, preferably room temperature;

[0033] Preferably, the product of the reaction of the compound of general formula (II-3) with the compound of general formula (A) is purified by recrystallization with a mixed solvent of ethyl acetate and n-heptane, and the volume ratio of ethyl acetate and n-heptane is 1:1-2;

[0034] The product of the reaction of the compound of general formula (II-2) with the compound of general formula (A) is purified by beating with methyl tert-butyl ether.

[0035] In certain embodiments of the present application, the method for preparing the compound of general formula (I) is characterized in that it further comprises a method for preparing the compound of general formula (II-3), comprising the following steps:

[0036] The compound represented by general formula (II-1) is reacted with a halogenating agent in the presence of a molecular sieve and under heating to obtain a compound represented by general formula (II-3);

[0037] The halogenating agent is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, iodine pentafluoride, stannous fluoride, cuprous fluoride, phosphorus trichloride, phosphorus pentachloride, dichloro hydantoin, chlorine, phosphorus oxychloride, dichloro sulfoxide, phosphorus tribromide, N-chlorosuccinimide, N-bromosuccinimide or tert-butyl hypochlorite; preferably phosphorus trichloride, phosphorus pentachloride, dichloro hydantoin, chlorine, phosphorus oxychloride, dichloro sulfoxide or N-chlorosuccinimide;

[0038] Optionally, the method for preparing the compound represented by general formula (II-1) further comprises the following steps:

[0039] The compound represented by general formula (III-1) is reacted with the compound represented by general formula (IV-1) in the presence of a base ② and under heating to obtain the compound represented by general formula (II-1);

[0040] The base ② is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium hydroxide, n-butyllithium, tert-butyllithium, lithium bis(trimethylsilyl)amide or phenyllithium; preferably lithium bis(trimethylsilyl)amide;

[0041] R L1 selected from halogen; preferably chlorine or bromine;

[0042] Optionally, the method for preparing the compound represented by general formula (IV-1) further comprises the following steps:

[0043] The compound represented by general formula (V-1) and the compound represented by general formula (VI-1) are reacted with an acid anhydride in the presence of a base ③ and under heating to obtain the compound represented by general formula (IV-1);

[0044] The acid anhydride is selected from acetic anhydride, propionic anhydride, aceto-propionic anhydride, trifluoroacetic anhydride, triflic anhydride or Boc anhydride; preferably Boc anhydride;

[0045] The base ③ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, aqueous ammonia, potassium tert-butoxide, sodium tert-butoxide, methylamine, dimethylamine, diethylamine, triethylamine, pyridine or imidazole; preferably pyridine.

[0046] In some embodiments of the present application, the method for preparing the compound represented by general formula (II-3) further comprises the following steps:

[0047] Preferably, the molar ratio of the compound represented by general formula (II-1) to the halogenating agent is 1:2-5, preferably 1:2-3.

[0048] Preferably, the molecular sieve is selected from 4A molecular sieve;

[0049] Preferably, the reaction temperature is selected from 40-100°C, preferably 45-50°C;

[0050] Preferably, the solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous dimethylsulfoxide, anhydrous N,N-dimethylacetamide, N-methylpyrrolidone or anhydrous N,N-dimethylformamide; preferably anhydrous N,N-dimethylformamide;

[0051] Preferably, the reaction is carried out under nitrogen protection;

[0052] Preferably, the product is purified by recrystallization with a mixed solvent of ethyl acetate and n-heptane, the volume ratio of which is 1:5-6;

[0053] In the method for preparing the compound represented by general formula (II-1):

[0054] Preferably, the molar ratio of the compound represented by general formula (III-1) to the compound represented by general formula (IV-1) is 1:1-5, preferably 1:1-2;

[0055] Preferably, the reaction temperature is selected from 50-100°C, preferably 60-70°C;

[0056] Preferably, the solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, anhydrous dimethylsulfoxide or anhydrous N,N-dimethylformamide; preferably anhydrous tetrahydrofuran;

[0057] Preferably, the reaction is carried out under nitrogen protection;

[0058] Preferably, the product is purified by recrystallization with a mixed solvent of ethyl acetate and n-heptane, the volume ratio of which is 1:5-6;

[0059] In the method for preparing the compound represented by general formula (IV-1):

[0060] Preferably, the molar ratio of the compound represented by general formula (V-1) to the compound represented by general formula (VI-1) to the acid anhydride is 1:1-5:1-5, preferably 1:1-2:1-2;

[0061] Preferably, the reaction temperature is selected from 20-50 °C, preferably 20-30 °C;

[0062] Preferably, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dry isopropyl ether, dry methyl tert-butyl ether, dry ethylene glycol dimethyl ether, dimethyl sulfoxide or N,N-dimethylformamide; preferably tetrahydrofuran or ethyl acetate;

[0063] Preferably, the reaction is carried out under nitrogen protection;

[0064] Preferably, the product is purified by recrystallization with a mixed solvent of ethyl acetate and n-heptane, the volume ratio of which is 1:10-15.

[0065] In certain embodiments of the present application, the method for preparing the compound of general formula (I) is characterized in that it further comprises a method for preparing the compound of general formula (II-2), comprising the following steps:

[0066] The compound of general formula (III-2), the compound of general formula (VII-1) and an acyl chloride reagent are reacted in the presence of a base ④ to obtain the compound of general formula (II);

[0067] The acyl chloride is selected from acetyl chloride, 4-chlorobutyryl chloride, sulfuryl chloride, oxalyl chloride, dichlorosulfoxide, di-tert-butyl dicarbonate, carbonyldiimidazole, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate or phosphorus oxychloride; preferably oxalyl chloride;

[0068] The base ④ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, aqueous ammonia, potassium tert-butoxide, sodium tert-butoxide, methylamine, dimethylamine, diethylamine, triethylamine, pyridine, DABCO, DBU, diisopropylethylamine or imidazole; preferably triethylamine;

[0069] Optionally, it further comprises a method for preparing the compound of general formula (III-2), characterized in that it further comprises the following steps:

[0070] The compound of general formula (IV-2) is reacted in the presence of CO atmosphere, a catalyst and a base ⑤ to obtain the compound of general formula (III-2);

[0071] R L2 selected from halogen; preferably chlorine or bromine;

[0072] The base ⑤ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, potassium carbonate or cesium carbonate; preferably potassium carbonate;

[0073] the palladium catalyst is selected from palladium on carbon, palladium acetate, palladium tetra-triphenylphosphine, palladium bis(triphenylphosphine)dichloride or palladium chloride; preferably palladium acetate;

[0074] Optionally, the application also includes a method for preparing a compound of general formula (IV-2), characterized in that it further comprises the following step:

[0075] reacting a compound of general formula (V-2) with a compound of general formula (VI-2) in the presence of a base (6) and under heating conditions to obtain a compound of general formula (IV-2);

[0076] the base (6) is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium hydroxide, n-butyllithium, tert-butyllithium, lithium bis(trimethylsilyl)amide or phenyllithium; preferably sodium bis(trimethylsilyl)amide; more preferably 2M sodium bis(trimethylsilyl)amide.

[0077] In certain embodiments of the application, the method for preparing a compound of general formula (II-2) comprises:

[0078] Preferably, the molar ratio of the compound of general formula (III-2) to the acyl chloride reagent is between 1 :2 and 5, preferably between 1 :2 and 3;

[0079] Preferably, the reaction temperature is selected from 0 to 50°C, preferably from 15 to 25°C;

[0080] Preferably, the solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous dimethylsulfoxide, anhydrous N,N-dimethylacetamide, N-methylpyrrolidone or anhydrous N,N-dimethylformamide; preferably anhydrous dichloromethane;

[0081] Preferably, the reaction is carried out under nitrogen protection;

[0082] Preferably, the product is purified by recrystallization in methyl tert-butyl ether;

[0083] In certain embodiments of the application, the method for preparing a compound of general formula (III-2) comprises:

[0084] Preferably, the molar ratio of the compound of general formula (IV-1) to the base (5) is between 1 :1 and 5, preferably between 1 :1 and 1.5;

[0085] Preferably, the reaction temperature is selected from 100 to 200°C, preferably from 100 to 150°C;

[0086] Preferably, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide or N,N-dimethylformamide; preferably dimethyl sulfoxide;

[0087] Preferably, the product is dissolved in ethyl acetate and dropped into acetic acid for crystallization purification, and the molar ratio of the compound of general formula (IV-1) to acetic acid is 1:1-5, preferably 1:2-5;

[0088] In the method for preparing the compound of general formula (IV-2), the compound of general formula (IV-1) is preferably dissolved in a solvent selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide or N,N-dimethylformamide; preferably dimethyl sulfoxide;

[0089] Preferably, the molar ratio of the compound of general formula (V-2) to the compound of general formula (VI-2) to the base (6) is 1:1-5:1-5, preferably 1:1-3:1-2.5;

[0090] Preferably, the reaction temperature is selected from 0-25°C, preferably after 1h of reaction at 0-10°C, the reaction temperature is raised to room temperature for 2h of reaction;

[0091] Preferably, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, dimethyl sulfoxide or N,N-dimethylformamide; preferably tetrahydrofuran;

[0092] Preferably, the reaction is carried out under nitrogen protection;

[0093] Preferably, the product is purified by beating with n-heptane.

[0094] In some embodiments of the present application, the use of the compound of general formula (II) or the compound of general formula (I) synthesized from the compound of general formula (II) in the preparation of a KRAS G12C inhibitor is characterized in that the structure of the KRAS G12C inhibitor is as shown in general formula (VI-A):

[0095] Preferably, the structure of the KRAS G12C inhibitor is as shown in general formula (VI):

[0096] R9is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C1-6 alkyl; preferably hydrogen or C 1-3 alkyl; more preferably hydrogen or methyl;

[0097] R 10 selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkyl; preferably hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 alkyl; more preferably hydrogen, fluorine, chlorine, amino, hydroxyl or methyl;

[0098] x is selected from 0, 1, 2, 3 or 4;

[0099] y is selected from 0, 1, 2, 3 or 4;

[0100] Preferably, the KRAS G12C inhibitor is selected from the following structure:

[0101] The present process route has obvious advantages over the previous route:

[0102] 1. Route 1 uses 2,6-dichloro hydrochloric acid as a starting material to synthesize the target product. The selective introduction of chlorine atoms at the 3 position of pyridine and the participation of the methyl sulfide group in the reaction are innovative, thereby replacing the use of expensive 2,3,6-trichloronicotinic acid as a raw material in the prior art.

[0103] 2. Route 2 uses 2,3,5,6-tetrachloropyridine as a starting material to synthesize the target product. The substitution reaction has good selectivity, the cost of tetrachloropyridine is low, there are many suppliers, and it is easy to purchase. Through ortho amino induction, selective carbonylation reaction is introduced to introduce carboxyl, thereby replacing the use of expensive 2,3,6-trichloronicotinic acid as a raw material in the prior art.

[0104] 3. The present route has simple preparation steps, high total yield, low cost, and is suitable for industrial large-scale production.

[0105] Detailed description of the invention

[0106] Unless otherwise stated, the following terms have the following meanings when used in the specification and claims.

[0107] "Alkyl" means a saturated aliphatic hydrocarbon group which is a straight chain or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof; an alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted on any available attachment point;

[0108] "Deuterated alkyl" means an alkyl group in which one or more hydrogens are replaced by deuterium, wherein alkyl is as defined above.

[0109] "Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.

[0110] Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0111] "Haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above; for example trifluoromethyl;

[0112] "Haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0113] "Hydroxyalkyl" means an alkyl group substituted with a hydroxyl group, wherein alkyl is as defined above.

[0114] "Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably containing from 3 to 12 carbon atoms, more preferably containing from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups;

[0115] "Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains from 3 to 20 ring atoms, of which one or more are heteroatoms selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2) but excluding ring members of the formula -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferably, the heterocyclyl group contains from 3 to 12 ring atoms, of which from 1 to 4 are heteroatoms; more preferably, the heterocyclyl group contains from 3 to 8 ring atoms; most preferably, the heterocyclyl group contains from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups; wherein the spiro, fused, and bridged heterocyclyl groups are optionally connected to other groups by a single bond or further annulated to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms of the ring;

[0116] "Aryl" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share pairs of adjacent carbon atoms) ring groups having a conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl; more preferably phenyl;

[0117] "Aryloxy" means -O-(aryl), wherein aryl is as defined above;

[0118] "Heteroaryl" means a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyridazinyl, pyrazinyl, oxadiazolyl, and the like;

[0119] "Heteroaryloxy" means -O-(heteroaryl), wherein heteroaryl is as defined above;

[0120] "Alkenyl" refers to an alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted with other relevant groups such as hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, or heteroaryloxy;

[0121] "Alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted with other relevant groups such as hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, or heteroaryloxy;

[0122] "Halogen" refers to fluorine, chlorine, bromine, or iodine;

[0123] In the present application, the plurality of, the plurality of, and the like means 1, 2, 3, 4, 5, 6, 7, and the like;

[0124] The hydrogen atoms in the present application can be replaced by its isotope deuterium, and any one or more hydrogen atoms in the compound of the present application can also be replaced by deuterium. DETAILED DESCRIPTION

[0125] The present application will be further described in detail below in conjunction with examples, but is not limited to the content of the examples.

[0126] The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR is measured by a Bruker AVANCE-400 nuclear magnetic instrument, and the measuring solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as internal standard.

[0127] The determination of liquid chromatography-mass spectrometry LC-MS uses Agilent 1260 Infinity Series mass spectrometer.

[0128] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, TLC uses a specification of 0.15mm-0.20mm, and thin layer chromatography separation and purification product uses a specification of 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0129] The HPLC detection method in the present application is as follows:

[0130] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized by using or according to the methods known in the art.

[0131] Unless otherwise specified, all reactions of the present application are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, and the solvent is a dry solvent.

[0132] Scheme 1:

[0133] Example 1-1

[0134] Preparation of N-(2-chloropyridin-3-yl)trimethylacetamide

[0135] A three-necked flask was charged with 3-amino-2-chloropyridine (50 g, 0.39 mol, 1 eq), dichloromethane (500 ml, 10 V), and triethylamine (74.7 g, 0.74 mol, 1.9 eq) was added after replacing N2. After addition, the system was stirred and cooled to 0-5 °C, and pivaloyl chloride (65.7 g, 0.56 mol, 1.4 eq) was added dropwise while maintaining the temperature of the system at no more than 10 °C. After the dropwise addition was completed, the system was allowed to react at room temperature for 2 h. TLC and HPLC were used to monitor the completion of the reaction. After the reaction was completed, the system was poured into 10 V saturated aqueous sodium bicarbonate solution, and after stirring for 20 min, the system was allowed to stand and separate into two phases. The aqueous phase was extracted with 2 x 250 ml (5 V) DCM, and after extraction, the organic phase was washed with 400 ml (8 V) saturated aqueous sodium chloride solution. After washing, the system was dried for 1 h with anhydrous sodium sulfate under stirring, and after filtration, the filter cake was washed with 2 x 50 ml (1 V) and the combined filtrate was vacuum dried. The dried reaction liquid was brushed with silica gel (3.5 x), and after drying, 94.2 g of yellow liquid was obtained with a crude yield of 113.9%.

[0136] LCMS: MS m / z (ESI): 213.0 [M+1] +

[0137] 1 H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.25 (dd, J = 4.7, 1.8 Hz, 1H), 7.97 (dd, J = 7.8, 1.8 Hz, 1H), 7.44 (dd, J = 7.9, 4.7 Hz, 1H), 1.26 (s, 9H).

[0138] Example 1-2

[0139] Preparation of N-(2-isopropylpyridin-3-yl)trimethylacetamide

[0140] Into the system was placed N-(2-chloropyridin-3-yl)trime thylacetamide (50 g, 0.24 mol, 1.0 eq), tetrahydrofuran (250 ml, 5 V) and after thorough mixing and stirring, zinc chloride (48.2 g, 0.35 mol, 1.5 eq) was added. The system was warmed to 15 °C and nitrogen was bubbled through for 20 min until the system was a clear bright yellow solution. Pd(dppf)Cl2.DCM (1.93 g, 2.35 mmol, 0.01 eq) was added and the system turned dark red. Nitrogen was bubbled through and the system was maintained at 20-35 °C while isopropyl magnesium chloride solution (2 mol / L, 176 ml, 0.35 mol, 1.5 eq) was added dropwise. The system turned yellow slowly with solid precipitating during the addition. After the addition was complete, the system was maintained at 45-50 °C for 1.5 h and HPLC monitoring showed that the reaction was complete. The system was poured into saturated aqueous ammonium chloride solution (500 ml, 10 V) at 0-10 °C and the quenching was complete. The system was partitioned and the aqueous phase was extracted with 2 x 250 ml (5 V) ethyl acetate. The combined organic phase was washed with 400 ml saturated aqueous sodium chloride solution and the system was partitioned. The organic phase was dried over anhydrous sodium sulfate for 1 h, filtered and the filter cake was washed with 2 x 50 ml ethyl acetate. The combined filtrate was evaporated to dryness and the residue was dissolved in 250 ml ethyl acetate and heated to 65 °C. 830 ml n-heptane was added and the system was maintained at 55-65 °C for 3 h until black solid precipitated. The clear solution was removed while hot and the system was cooled to room temperature. The liquid was evaporated to dryness and the residue was dried under vacuum at 50 °C for 2 h to give a pink solid, 44.2 g, 99.21% purity, 85.3% yield.

[0141] LCMS: MS m / z (ESI): 221.1 [M+1] +

[0142] 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 8.39 (dd, J = 4.7, 1.7 Hz, 1H), 7.47 (dd, J = 7.9, 1.7 Hz, 1H), 7.20 (dd, J = 7.9, 4.7 Hz, 1H), 1.24 (s, 9H), 1.14 (d, J = 6.7 Hz, 6H).

[0143] Examples 1-3

[0144] Preparation of N-(2-isopropyl-4-(methylthio)pyridin-3-yl)trime thylacetamide

[0145] N-(2-isopropylpyridin-3-yl)trimethylacetamide (20.0 g, 90.84 mmol, 1.0 eq), tetrahydrofuran (160 ml, 8V) were mixed, replaced with nitrogen, and potassium tert-butoxide (25.5 g, 227.6 mmol, 2.5 eq) was added at room temperature while controlling the temperature at 20-30 °C. The system was replaced with nitrogen and cooled to -60 to -65 °C. A solid was precipitated, and 1.6 mol / L n-butyllithium (170 ml, 272.6 mmol, 3.0 eq) was added dropwise. The temperature of the system during the dropwise addition should not exceed -50 °C. After the addition was completed, the system was in a solid-liquid mixed state with a yellowish brown color. The reaction solution was transferred to a 500 ml separatory funnel under micro-negative pressure and nitrogen protection. The reaction solution was then added dropwise into dimethyl disulfide (85.4 g, 0.91 mol, 10 eq) under nitrogen protection and stirring at room temperature while controlling the temperature at 20-25 °C. The system gradually changed from clear to turbid and finally precipitated a solid. After stirring at room temperature for 16 h, the system was slowly poured into saturated aqueous ammonium chloride solution (200 ml, 10V) for quenching while controlling the temperature at 20-25 °C. After stirring for 15 min, 100 ml of water was added and stirred for 10 min. The filtrate was separated, and the solvent in the aqueous phase was rotary evaporated. The filter cake was washed with 200 ml (10V) of ethyl acetate, dried, and then rotary evaporated at 50 °C (6.56 g). The aqueous phase was extracted with 200 ml of ethyl acetate (10V) used to wash the filter cake, and the aqueous phase was further extracted with 100 ml of ethyl acetate (5V). All the organic phases were combined and washed with 160 ml (8V) of saturated aqueous sodium chloride solution. After washing, the organic phase was dried with anhydrous sodium sulfate for 1 h, and then filtered. The filter cake was washed with 2 x 50 ml (2.5V) of ethyl acetate. The filtrate was collected and rotary evaporated to obtain 44 g of a yellow solid, which was mixed with the filter cake retained during the extraction. The mixture was slurried with 10 ml of ethyl acetate and 190 ml of n-heptane for 30 min, and then the solvent was rotary evaporated. Another 10 ml of ethyl acetate and 190 ml of n-heptane were added, and the mixture was stirred at 50 °C for 1 h, and then stirred at room temperature for 2 h. The mixture was filtered, and the filter cake was washed with a mixture of 2 ml of ethyl acetate and 38 ml of n-heptane. After washing, the solid was collected and dried at 50 °C under vacuum for 40 min to obtain 25.6 g of a yellow solid with a yield of 105.8%.

[0146] LCMS: MS m / z (ESI): 267.1 [M+1] +

[0147] 1H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H), 3.08 (hept, J = 6.8 Hz, 1H), 2.39 (s, 3H), 1.24 (s, 9H), 1.11 (d, J = 6.8 Hz, 6H).

[0148] Example 1-4

[0149] Preparation of 2-isopropyl-4-(methylthio)pyridin-3-amine

[0150] Concentrated sulfuric acid 50 g (5x) was slowly poured into 40 ml (4V) water, after the system was reduced to room temperature with ice water bath, N-(2-isopropyl-4-(methylthio)pyridin-3-yl)trimethylacetamide (10 g, 28.90 mmol, 1 eq) was placed in the system, the oil temperature was set to 130 °C (the actual internal temperature rose to 110 °C), the reaction was carried out for 24 h, after the completion of the reaction was monitored by HPLC, the system was slowly poured into 0 °C water, 100 ml (10V) ethyl acetate was added, the pH was adjusted to 9-10 with 350 ml saturated aqueous sodium carbonate solution, stirred for 1 h, then separated, the organic phase had solid, the aqueous phase was extracted with 2x50 ml (5V) ethyl acetate, then combined and washed with 100 ml (10V) saturated aqueous sodium chloride solution, it was difficult to separate, 100 ml water was added and filtered, the filtrate was dried with anhydrous sodium sulfate for 2 h, then filtered, the filter cake was rinsed with 2x20 ml (2V) and the solution was rotary evaporated to give a black oil, which was dissolved in 30 ml ethyl acetate, then brushed silica gel (4x, 40 g), eluted with 100 ml petroleum ether, 750 ml petroleum ether / ethyl acetate = 3 / 1 mixed solution and 500 ml petroleum ether / ethyl acetate = 1 / 1 mixed solution, and then rotary evaporated to give dark brown oil 5.61 g, purity 97.48%, yield 82.0%.

[0151] LCMS: MS m / z (ESI): 183.1 [M+1] +

[0152] 1 H NMR (400 MHz, DMSO) δ 7.79 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 5.1 Hz, 1H), 4.79 (s, 2H), 3.22 (hept, J = 6.7 Hz, 1H), 2.45 (s, 3H), 1.16 (dd, J = 6.8, 2.2 Hz, 6H).

[0153] Example 1-5

[0154] Preparation of 2,6-dichloronicotinamide

[0155] Into a reaction flask was placed 2,6-dichloronicotinic acid (50.0 g, 1.0 eq) and ethyl acetate (900 ml, 18V) and stirred at room temperature until dissolved; Boc anhydride (113.67 g, 2.0 eq) was added to the reaction flask, pyridine (61.8 g, 3.0 eq) was added dropwise to the reaction flask, and the reaction was carried out at 20-30 °C for 4 h after replacing N2. HPLC detection showed complete conversion to the intermediate state; the reaction was cooled to 0-10 °C, and ammonia water (80 ml, 2 eq.) was added dropwise to the reaction flask, and stirred at 20-30 °C for 1-2 h, HPLC detection; after the reaction was completed, saturated sodium bicarbonate aqueous solution (500 ml, 10V) was added to the reaction flask at 15-25 °C, and stirred for 30 min before separating the layers, and the upper organic phase was collected; the aqueous phase was extracted with ethyl acetate (250 ml, 5V); the combined organic phase was washed with water (400 ml, 8V), and the upper organic phase was collected after separation; the organic phase was concentrated to 2V, n-heptane (250 ml) was added, and concentrated to obtain a yellow solid; ethyl acetate (50 ml) / n-heptane (500 ml) was added to the reaction flask, and the yellow solid was added to the reaction flask, which was stirred at 50 °C for 2 h, and then cooled to room temperature and stirred for 4 h; the filter cake was collected by filtration; and dried at 50 °C for another 6-8 h to obtain a white solid 56 g, purity 99.7%, content: 81.9%, molar yield: 92.2%.

[0156] LCMS: MS m / z (ESI): 191.1 [M+1] +

[0157] 1 H NMR (400 MHz, DMSO) δ 8.08 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H).

[0158] Examples 1-6

[0159] Preparation of 6-chloro-2-((2-isopropyl-4-(methylthio)pyridin-3-yl)amino)nicotinamide

[0160] Into a three-necked flask, 2-isopropyl-4-(methylthio)pyridin-3-amine (40.0 g, 1.0 eq) and 2,6-dichloronicotinamide (49.4 g, 1.1 eq) were added, and anhydrous tetrahydrofuran (400 ml, 10 V) was added to the flask, which was stirred at room temperature until the solution was clear; after replacing N2 three times, R1 was cooled to -5-5 °C, and LiHMDS (660 ml, 16.5 V, 3 eq.) was slowly added dropwise to the flask, which was warmed to 60-70 °C and stirred for 4-6 h after the dropwise addition was completed, and HPLC detection was performed; after the reaction was cooled to 15-25 °C, saturated aqueous ammonium chloride solution (400 ml, 10 V) was slowly added to the flask, which was stirred at room temperature for 30 min, and the upper organic phase was collected after standing and partitioning; the aqueous phase was extracted with ethyl acetate (400 ml, 10 V), and the organic phases were combined; the organic phase was extracted with water (320 ml, 8 V), and the upper organic phase was collected; the organic phase was concentrated to dryness; ethyl acetate (40 ml, 1 V) was added to the flask, which was warmed to 65 °C and stirred for 30 min, and n-heptane (240 ml, 6 V) was slowly added dropwise to the flask; after stirring at 65 °C for 1-2 h, the temperature was lowered to room temperature and stirring was continued overnight; the filter cake was collected by filtration and dried at 50 °C for 6-8 h to obtain 68.6 g of a white solid, with a purity of 90.6%, a content of 81.6%, and a molar yield of 81.3%.

[0161] LCMS: MS m / z (ESI): 337.1 [M+1] +

[0162] 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.14 (d, J = 5.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 3.12 - 2.94 (m, J = 6.7, 6.3 Hz, 1H), 2.40 (s, 3H), 1.12 (d, 3H), 1.09 (d, J = 6.7 Hz, 3H).

[0163] Examples 1-7

[0164] Preparation of 5,6-dichloro-2-((2-isopropyl-4-(methylsulfinyl)pyridin-3- yl)amino)nicotinamide

[0165] Into a reaction flask, 6-chloro-2-((2-isopropyl-4-(methylthio)pyridin-3- yl)amino)nicotinamide (30.0 g, 1.0 eq) and anhydrous N,N-dimethylformamide (120 ml, 4V) were charged; activated 4A powdered molecular sieves (24 g, 0.8X) were charged into the reaction flask, NCS (24.3 g, 2.05 eq) was charged into the reaction flask 1; after purging with N2for three times, the reaction was warmed to 45-50 °C and stirred for 4-6 h, HPLC was used for monitoring; after the reaction was completed, it was cooled to room temperature, filtered, the filter cake was rinsed with DMF (3V), and the filtrate was collected; into reaction flask 2, water (1350 ml, 45V) was charged, the filtrate in reaction flask 1 was added dropwise into reaction flask 2 slowly, stirred for 1-2 h, filtered, the filter cake was rinsed with 2-3V water, and the filter cake was collected; the filter cake was stirred in EA (26 ml) / n-heptane (155 ml) at 50 °C for 2 h, then stirred overnight at room temperature, filtered, the filter cake was collected, and dried at 50 °C for 6-8 h to obtain 26.4 g of light yellow solid, with a purity of 91.4%, a content of 88.9%, and a molar yield of 83.4%.

[0166] LCMS: MS m / z (ESI): 387.0 [M+1] +

[0167] 1 H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 5.0 Hz, 1H), 3.11 (p, J = 6.7 Hz, 1H), 2.71 (s, 3H), 1.17 (d, J = 6.7 Hz, 3H), 1.11 (d, J = 6.7 Hz, 3H).

[0168] 13 C NMR (101 MHz, DMSO) δ 179.85, 168.16, 164.71, 154.97, 154.88, 149.02, 148.53, 140.59, 128.03, 116.60, 116.17, 110.82, 30.30, 29.99, 22.34, 22.00.

[0169] Examples 1-8

[0170] 6,7-dichloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3-d]pyrimidine- 2,4(1H,3H)-dione

[0171] Preparation of 6,7-dichloro-1-(2-isopropyl-4-(methylthio)pyridin-3-yl)pyrido[2,3- d]pyrimidine-2,4(1H,3H)-dione

[0172] Into a reaction flask was placed 5,6-dichloro-2-((2-isopropyl-4- (methylsulfinyl)pyridin-3-yl)amino)nicotinamide (8 g, 1.0 eq), dry dimethyltetrahydrofuran (40 ml, 5V) and dry tetrahydrofuran (80 ml, 10V), replaced with N2 three times, cooled to 0 °C under N2 atmosphere, oxalyl chloride (7 ml, 4.0 eq) was added slowly dropwise into the reaction flask, the reaction was warmed to 70 °C and stirred for 2-4 h, HPLC detection; after the reaction was completed, the reaction solution was cooled to room temperature, n-heptane (160 ml, 20V) was added slowly, stirred at room temperature for 2-4 h, then filtered, the filter cake was rinsed with n-heptane; the filter cake, ethyl acetate (40 ml, 5V) and n-heptane (40 ml, 5V) were added into a reaction flask, warmed to 60 °C and stirred for 1-2 h, then cooled to room temperature and stirred for 4-6 h, filtered, and the filter cake was collected; dried at 45-50 °C for 6-8 h to obtain 8.9 g of yellow solid, purity 99.7%, content: 81.9%, molar yield: 88.7%.

[0173] LCMS: MS m / z (ESI): 397.1 [M+1] +

[0174] 1 H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 8.62 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H), 7.27 (d, J = 5.3 Hz, 1H), 2.97 (p, J = 6.6 Hz, 1H), 2.43 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H).

[0175] 13 C NMR (101 MHz, DMSO) δ 164.51, 160.32, 151.93, 150.00, 149.87, 149.83, 149.15, 139.83, 125.61, 124.66, 117.89, 112.52, 29.86, 22.50, 22.25, 13.45.

[0176] Scheme 2:

[0177] Example 2-1

[0178] Preparation of 3,5,6-trichloro-N-(2-isopropyl-4-methylsulfanylpyridin-3-yl)pyridin-2- amine

[0179] A three-necked flask was charged with 2,3,5,6-tetrachloropyridine (49 g, 0.27 mol, 1 eq), 2-isopropyl-4-methylsulfanylpyridin-3-amine (175 g, 0.81 mol, 3 eq), THF (1 L, 20 V), stirred well and purged with N2 for three times, then the system was cooled to 0-5 °C, 2M NaHMDS in THF (336 ml, 0.67 mol, 2.5 eq) was added dropwise, the temperature of the system was maintained below 10 °C, after the addition was completed, the system was reacted at 0-10 °C for 1 h, then the temperature was raised to room temperature and reacted for 2 h. TLC, HPLC monitoring showed that the reaction was completed, then saturated aqueous ammonium chloride solution (500 ml, 10 V) was added dropwise to the system, stirred well for 20 min, then the system was allowed to stand and separated, the aqueous phase was extracted with 500 ml (10 V) EA, after extraction, the organic phase was washed with 500 ml (10 V) saturated aqueous sodium chloride solution, after washing, the organic phase was dried over anhydrous sodium sulfate for 1 h, then the filtrate was vacuum filtered, the filter cake was washed with 2 x 50 ml (1 V), the filtrate was vacuum dried, the reaction solution after drying was purified by slurry with 750 ml (15 V) n-heptane for 16 h, then filtered, the filter cake was washed with 2 x 150 ml (3 V), then the solvent was dried, the collected solid was dried in a vacuum drying oven at 45 °C for 6 h, and 89.8 g of light pink solid was obtained (yield 92.8%)

[0180] LCMS: MS m / z (ESI): 362.1 [M+1] +

[0181] 1 H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.14 (d, J = 1.1 Hz, 1H), 7.15 (d, J = 5.3 Hz, 1H), 3.05 (hept, J = 6.8 Hz, 1H), 2.39 (s, 3H), 1.15 (d, J = 6.7 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H).

[0182] Example 2-2

[0183] Preparation of 5,6-dichloro-2-((2-isopropyl-4-methylsulfanylpyridin-3- yl)amino)nicotinic acid

[0184] A 100-ml high-pressure reactor was charged with 3,5,6-trichloro-N-(2-isopropyl-4- methylthiopyridin-3-yl)pyridin-2-amine (10 g, 27.6 mmol, 1.0 eq), palladium acetate (31 mg, 0.14 mmol, 0.005 eq), DCPP-2HBF4(0.17 g, 0.28 mmol, 0.01 eq), anhydrous potassium carbonate (5.8 g, 42.0 mmol, 1.5 eq), water (2.5 g, 0.14 mol, 5 eq), and DMSO (100 ml, 10 V) in sequence. The high-pressure reactor was tightly screwed, and the gas inlet and outlet valves were closed. The gas inlet line was connected to the carbon monoxide cylinder, and the outlet was connected to a vacuum device. The main valve of the cylinder was opened, and the pressure of the gas was adjusted to 0.2-0.3 MPa. The vacuum device was opened, and the outlet valve of the reactor was opened. After 8-10 seconds, the outlet valve was closed, the inlet valve was opened, and the pressure of the system was adjusted to 0.1-0.2 MPa. After 6-8 seconds, the inlet valve was closed. This replacement process was repeated three times, and the pressure of the system was adjusted to 0.5 MPa. The reactor was placed in an oil bath, and the temperature was set to 150 °C (the internal temperature was about 125 °C). The stirring speed was about 400 r / min. After 28-30 h, the heating and stirring were stopped. The reactor was taken out of the oil bath and cooled to room temperature. The outlet valve was opened, and the gas was released. The reactor was opened, and the reaction was monitored by HPLC. When the reaction was completed, the system was maintained at 15-25 °C and poured into saturated ammonium chloride aqueous solution (100 ml, 10 V). After stirring for 10 min, EA (100 ml, 10 V) and sodium chloride (20 g, 2x) were added to the system, and stirring was performed for 20 min. The mixture was filtered, and the filter cake was eluted with EA (50 ml, 5 V). The upper organic phase was collected, and the aqueous phase was extracted with EA (3x100 ml, 10 V). The combined organic phase was washed with saturated sodium chloride aqueous solution (100 ml, 10 V) and allowed to stand for 5 min. The upper organic phase was collected and washed with saturated sodium chloride aqueous solution (100 ml, 10 V). The upper organic phase was collected and added with anhydrous sodium sulfate (40 g, 4x). After stirring and drying for 1 h, the mixture was filtered, and the filter cake was eluted with EA (20 ml, 2 V). The organic phase was concentrated to a glue-like solid, which was dissolved in 30 ml of EA. Acetic acid (3.5 g, 58.3 mmol, 2.1 eq) was added dropwise to the system under stirring at room temperature. After the solid was precipitated, the mixture was stirred for 16 h, filtered, and the filter cake was eluted with EA (20 ml, 2 V). The solid was collected and dried in a vacuum drying box at 50 °C for 1 h to obtain 10.3 g of a yellow solid (acetate salt), which had a purity of 99.28%, a free base content of 72.9%, and a yield of 82.5%.

[0185] LCMS: MS m / z (ESI): 373.8 [M+1] +

[0186] 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.15 (s, 1H), 7.12 (d, J = 5.3 Hz, 1H), 3.03 (h, J = 6.7 Hz, 1H), 2.38 (s, 3H), 1.91 (s, 3H), 1.22-1.06 (m, 6H).

[0187] Example 2-3

[0188] Preparation of 5,6-dichloro-2-((2-isopropyl-4-methylsulfanylpyridin-3-yl)amino)-N- (4-methoxybenzyl)nicotinamide

[0189] After 5,6-dichloro-2-((2-isopropyl-4-methylsulfanylpyridin-3-yl)amino)nicotinic acid (26.7 g, 71.7 mmol, 1.0 eq), DCM (267 mL, 10 V) were mixed and stirred uniformly, they were protected by nitrogen replacement three times, DMF (0.39 mL, 5.02 mmol, 0.07 eq.) was added, the temperature was lowered to 0-5 °C, and oxalyl chloride (71.7 mL, 0.14 mol, 2.0 eq) was added dropwise. After the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was allowed to proceed for 1 h. After the completion of the reaction was monitored by HPLC, the reaction liquid was rotary evaporated at 35 °C, and then dried under vacuum using an oil pump until the weight was constant. The solid was mixed with anhydrous DCM (267 mL, 10 V), and stirring was started. Nitrogen replacement was performed three times, the temperature was lowered to 0-5 °C, and 4-methoxybenzylamine (19.7 g, 0.14 mol, 2.0 eq) and triethylamine (14.5 g, 0.14 mol, 2.0 eq) were added dropwise. After the dropwise addition was completed, the temperature was raised to 15-25 °C, and the reaction was allowed to proceed for 2 h. After the completion of the reaction was monitored by HPLC, DCM (267 mL, 10 V) and 7% aqueous citric acid solution (267 mL, 10 V) were added to the system at 15-25 °C with stirring for 20 min, and then the liquid was separated. The lower organic phase was collected, saturated aqueous sodium bicarbonate solution (267 mL, 10 V) was added to the organic phase with stirring, the mixture was separated, and the lower organic phase was collected. The organic phase was washed with saturated aqueous sodium chloride solution (267 mL, 10 V), the liquid was separated, and the organic phase was collected. Anhydrous sodium sulfate (40 g, 0.8x) was added to the organic phase, and stirring was performed for 2 h. The mixture was filtered, DCM (50 mL, 2 V) was added to the filter cake, the solvent was rotary evaporated from the filtrate, MTBE (134 mL, 5 V) was added to the obtained solid, the temperature was raised to 60 °C, and the mixture was stirred under reflux for 1 h. After the temperature was lowered to room temperature, the mixture was stirred for 3 h, filtered, and the filter cake was washed with n-heptane (50 mL, 2 V). The solvent was removed by suction, and the solid was collected. The solid was dried under vacuum at 45 °C for 6 h until the weight was constant, and 26.2 g of a white solid was obtained. The purity was 96.39%, the content was 88.7%, and the yield was 90.4%.

[0190] LCMS: MS m / z (ESI): 491.1 [M+1] +

[0191] 1 H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.34 (t, J = 5.8 Hz, 1H), 8.44 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.14 (d, J = 5.3 Hz, 1H), 6.96 - 6.88 (m, 2H), 4.43 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H), 3.01 (h, J = 6.8 Hz, 1H), 2.40 (s, 3H), 1.20 - 1.06 (m, 6H).

[0192] Example 2-4

[0193] Preparation of 6,7-dichloro-l-(2-isopropyl-4-methylsulfanylpyridin-3-yl)-3-(4- methoxybenzyl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione

[0194] NaH (4.68 g, 0.117 mol, 2.3 eq. 60% purity) was added into a three-necked flask, purged with N2for three times, stirred at room temperature after adding anhydrous THF / DMF (125 mL, 10 / 1 v / v, 5V), 5,6-dichloro-2-((2-isopropyl-4-methylsulfanylpyridin-3-yl)amino)-N-(4- methoxybenzyl)nicotinamide (25 g, 50.87 mmol, 1.0 eq.) in THF / DMF (125 mL, 5V) was added dropwise, after the addition was completed, the reaction was continued to stir at room temperature for 1 h, then isopropyl chloroformate (12.47 g, 0.10 mol, 2.0 eq) was added, after the addition was completed, the ice water bath was removed, the reaction was continued to stir at room temperature for 0.5 h, then 125 uL water was added, after bubbles were generated, the reaction was continued to stir for 0.5 h, HPLC monitoring showed that the raw material was completely consumed, then the reaction solution was slowly poured into a half-saturated ammonium chloride solution (250 mL, 10V, 2 volumes of saturated NH4Cl diluted with 1 volume of water) to quench the reaction, the organic phase was diluted with EA (150 mL, 6V) after separation, the aqueous phase was extracted with EA (100 mL, 6V), the combined organic phase was washed with saturated sodium chloride aqueous solution (100 mL, 6V) after separation, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to obtain a light yellow solid, the solid was slurried with MTBE (175 mL, 7V) for 16 h, then filtered, the filter cake was eluted with MTBE / PE (25 mL x 2, 5 / 1), then the solid was collected and dried in a vacuum drying oven at 50°C for 2 h to obtain 22.7 g of white solid, purity 96.91%, yield 86.2%.

[0195] LCMS: MS m / z (ESI): 517.1 [M+1] +

[0196] 1 H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 7.35 - 7.25 (m, 3H), 6.92 - 6.84 (m, 2H), 5.09 (s, 2H), 3.72 (s, 3H), 2.94 (h, J = 6.6 Hz, 1H), 2.42 (s, 3H), 1.13 - 1.01 (m, 6H).

Claims

1. A compound represented by general formula (II): R1 is selected from hydrogen or an amino protecting group; preferably hydrogen, acetyl, tert-butylsulfinyl, benzyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, triphenylmethyl or phthalyl; more preferably hydrogen or p-methoxybenzyl. R2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 Alkyl; preferably halogen; more preferably chlorine or bromine; R3 is absent or selected from halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 Alkyl groups; preferably hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl group; preferably fluorine, chlorine, or bromine; R4 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 Alkyl groups; preferably hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, or cyclopropyl; R5, R6, and R7 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 Alkyl groups; preferably hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, or cyclopropyl; m is selected from 0, 1, or 2.

2. The compound of general formula (II) according to claim 1, characterized in that, The structure of the compound is further shown as in formula (II-1), formula (II-2), or formula (II-3):

3. The compound of general formula (II) according to any one of claims 1-2, characterized in that, The structure of the compound is as follows:

4. A method for preparing the compound represented by general formula (I), characterized in that, The preparation steps include the following: The compound of general formula (II) is reacted under haloformate or acyl chloride conditions to give the compound of general formula (I); optionally, the reaction is carried out in the presence of a base ①. Preferably, under acyl chloride conditions, the preparation steps are as follows: The acyl chloride is selected from oxalyl chloride or thionyl chloride; Alternatively, preferably, in the presence of haloformate and base ①, the preparation step is as follows: The haloformate is selected from methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, or butyl chloroformate; isopropyl chloroformate is preferred. The alkali ① is selected from sodium hydroxide, potassium hydroxide, sodium hydride, ammonia, potassium tert-butoxide, sodium tert-butoxide, methylamine, dimethylamine, diethylamine, triethylamine, pyridine, or imidazole; sodium hydride is preferred.

5. The method for preparing the compound of general formula (I) according to claim 4, characterized in that, In the method for preparing the compound represented by general formula (I): The molar ratio of the compound represented by general formula (II) to the compound represented by general formula (A) is 1:2 to 5; Preferably, the molar ratio of the compound represented by general formula (II-3) to the compound represented by general formula (A) is 1:2 to 5, more preferably 1:4 to 5; The molar ratio of the compound represented by general formula (II-2) to the compound represented by general formula (A) is 1:2 to 5, preferably 1:2 to 3; The reaction was carried out under nitrogen protection; The reaction solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, anhydrous dimethyl sulfoxide, or anhydrous N,N-dimethylformamide; preferably one or more of anhydrous N,N-dimethylformamide, anhydrous tetrahydrofuran, or anhydrous 2-methyltetrahydrofuran. Preferably, the solvent for reacting the compound of general formula (II-3) with the compound of general formula (A) is selected from one or more of anhydrous N,N-dimethylformamide, anhydrous tetrahydrofuran, or anhydrous 2-methyltetrahydrofuran; preferably, a mixed solvent of anhydrous tetrahydrofuran and anhydrous 2-methyltetrahydrofuran; more preferably, the volume ratio of anhydrous tetrahydrofuran to anhydrous 2-methyltetrahydrofuran is 1:2 to 4. The solvent for reacting the compound of general formula (II-2) with the compound of general formula (A) is selected from one or more of anhydrous N,N-dimethylformamide, anhydrous tetrahydrofuran or anhydrous 2-methyltetrahydrofuran; preferably a mixed solvent of anhydrous tetrahydrofuran and anhydrous N,N-dimethylformamide. Preferably, the reaction temperature of the compound of general formula (II-3) with the compound of general formula (A) is selected from 50 to 100°C, and more preferably 70 to 80°C; The reaction temperature of the compound of general formula (II-2) with the compound of general formula (A) is selected from 0 to 25°C, preferably room temperature; Preferably, the product of the reaction between the compound of general formula (II-3) and the compound of general formula (A) is purified by recrystallization in a mixed solvent of ethyl acetate and n-heptane, wherein the volume ratio of ethyl acetate to n-heptane is 1:1 to 2. The product of the reaction between the compound of general formula (II-2) and the compound of general formula (A) is purified by slurrying with methyl tert-butyl ether.

6. The method for preparing the compound of general formula (I) according to any one of claims 4 or 5, characterized in that, It also includes a method for preparing the compound of general formula (II-3), comprising the following steps: The compound of general formula (II-1) reacts with a halogenating agent in the presence of a molecular sieve and under heating conditions to give the compound of general formula (II-3); The halogenating agent is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, iodine pentafluoride, stannous fluoride, cuprous fluoride, phosphorus trichloride, phosphorus pentachloride, dichlorohydantoin, chlorine, phosphorus oxychloride, sulfonium chloride, phosphorus tribromide, N-chlorosuccinimide, N-bromosuccinimide, or tert-butyl hypochlorite; preferably phosphorus trichloride, phosphorus pentachloride, dichlorohydantoin, chlorine, phosphorus oxychloride, sulfonium chloride, or N-chlorosuccinimide. Optionally, it also includes a method for preparing the compound of general formula (II-1), characterized by further comprising the following steps: The compound of general formula (III-1) reacts with the compound of general formula (IV-1) in the presence of base ② and under heating conditions to give the compound of general formula (II-1); Wherein, the alkali ② is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, sodium di(trimethylsilyl)amino, potassium tert-butoxide, lithium hydroxide, n-butyllithium, tert-butyllithium, lithium di(trimethylsilyl)amino or phenyllithium; preferably lithium di(trimethylsilyl)amino; R L1 Selected from halogens; preferably chlorine or bromine; Optionally, it also includes a method for preparing the compound represented by general formula (IV-1), characterized by further comprising the following steps: The compound of general formula (V-1) and the compound of general formula (VI-1) react with acid anhydrides in the presence of base ③ and under heating conditions to give the compound of general formula (IV-1); The acid anhydride is selected from acetic anhydride, propionic anhydride, acetopropionic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, or Boc anhydride; preferably Boc anhydride. The base ③ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, ammonia, potassium tert-butoxide, sodium tert-butoxide, methylamine, dimethylamine, diethylamine, triethylamine, pyridine, or imidazole; preferably pyridine.

7. The method for preparing the compound of general formula (I) according to claim 6, characterized in that, In the method for preparing the compound represented by general formula (II-3): Preferably, the molar ratio of the compound represented by general formula (II-1) to the halogenating agent is 1:2 to 5, more preferably 1:2 to 3; Preferably, the molecular sieve is selected from 4A molecular sieve; Preferably, the reaction temperature is selected from 40 to 100°C, and more preferably 45 to 50°C; Preferably, the solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous dimethyl sulfoxide, anhydrous N,N-dimethylacetamide, N-methylpyrrolidone, or anhydrous N,N-dimethylformamide; preferably anhydrous N,N-dimethylformamide. Preferably, the reaction is carried out under nitrogen protection; Preferably, the product is purified by recrystallization in a mixed solvent of ethyl acetate and n-heptane, wherein the volume ratio of ethyl acetate to n-heptane is 1:5-6. In the method for preparing the compound represented by general formula (II-1): Preferably, the molar ratio of the compound represented by general formula (III-1) to the compound represented by general formula (IV-1) is 1:1 to 5, more preferably 1:1 to 2; Preferably, the reaction temperature is selected from 50 to 100°C, and more preferably 60 to 70°C; Preferably, the solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, anhydrous dimethyl sulfoxide, or anhydrous N,N-dimethylformamide; preferably anhydrous tetrahydrofuran. Preferably, the reaction is carried out under nitrogen protection; Preferably, the product is purified by recrystallization in a mixed solvent of ethyl acetate and n-heptane, wherein the volume ratio of ethyl acetate to n-heptane is 1:5-6. In the method for preparing the compound represented by general formula (IV-1): Preferably, the molar ratio of the compound represented by general formula (V-1), the compound represented by general formula (VI-1) to the acid anhydride is 1:1 to 5:1 to 5, more preferably 1:1 to 2:1 to 2; Preferably, the reaction temperature is selected from 20 to 50°C, and more preferably from 20 to 30°C; Preferably, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, dimethyl sulfoxide, or N,N-dimethylformamide; tetrahydrofuran or ethyl acetate are preferred. Preferably, the reaction is carried out under nitrogen protection; Preferably, the product is purified by recrystallization in a mixed solvent of ethyl acetate and n-heptane, wherein the volume ratio of ethyl acetate to n-heptane is 1:10-15.

8. The method for preparing the compound of general formula (I) according to any one of claims 4 or 5, characterized in that, It also includes a method for preparing the compound of general formula (II-2), comprising the following steps: The compound of general formula (III-2) and the compound of general formula (VII-1) react with an acyl chloride reagent in the presence of base ④ to give the compound of general formula (II); The acyl chloride is selected from acetyl chloride, 4-chlorobutyryl chloride, sulfonyl chloride, oxalyl chloride, thionyl chloride, ditert-butyl dicarbonate, carbonyl diimidazole, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, or phosphorus oxychloride; preferably oxalyl chloride. The alkali ④ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, ammonia, potassium tert-butoxide, sodium tert-butoxide, methylamine, dimethylamine, diethylamine, triethylamine, pyridine, DABCO, DBU, diisopropylethylamine or imidazole; preferably triethylamine; Optionally, it also includes a method for preparing the compound represented by general formula (III-2), characterized in that it further comprises the following steps: The compound of general formula (IV-2) reacts under a CO atmosphere in the presence of a catalyst and base ⑤ to give the compound of general formula (III-2); R L2 Selected from halogens; preferably chlorine or bromine; The alkali ⑤ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, sodium di(trimethylsilyl)aminosodium, potassium tert-butoxide, potassium carbonate, or cesium carbonate; potassium carbonate is preferred. The palladium catalyst is selected from palladium on carbon, palladium acetate, tetra-triphenylphosphine palladium, bis(triphenylphosphine)dichloride palladium or palladium chloride; palladium acetate is preferred. Optionally, it also includes a method for preparing the compound represented by general formula (IV-2), characterized by further comprising the following steps: The compound of general formula (V-2) reacts with the compound of general formula (VI-2) in the presence of base ⑥ and under heating conditions to give the compound of general formula (IV-2); The alkali ⑥ is selected from sodium hydroxide, potassium hydroxide, sodium hydride, sodium n-propoxide, sodium tert-butoxide, sodium di(trimethylsilyl)amino, potassium tert-butoxide, lithium hydroxide, n-butyllithium, tert-butyllithium, lithium di(trimethylsilyl)amino or phenyllithium; preferably sodium di(trimethylsilyl)amino; more preferably 2M sodium di(trimethylsilyl)amino.

9. The method for preparing the compound of general formula (I) according to claim 8, characterized in that, In the method for preparing the compound represented by general formula (II-2): Preferably, the molar ratio of the compound of general formula (III-2) to the acyl chloride reagent is 1:2 to 5, more preferably 1:2 to 3; Preferably, the reaction temperature is selected from 0 to 50°C, and more preferably from 15 to 25°C; Preferably, the solvent is selected from one or more of anhydrous ethyl acetate, anhydrous dichloromethane, anhydrous toluene, anhydrous xylene, anhydrous tetrahydrofuran, anhydrous 2-methyltetrahydrofuran, anhydrous 1,4-dioxane, anhydrous dimethyl sulfoxide, anhydrous N,N-dimethylacetamide, N-methylpyrrolidone, or anhydrous N,N-dimethylformamide; preferably anhydrous dichloromethane. Preferably, the reaction is carried out under nitrogen protection; Preferably, the product is purified by recrystallization using methyl tert-butyl ether; In the method for preparing the compound represented by general formula (III-2): Preferably, the molar ratio of the compound represented by general formula (IV-1) to the base ⑤ is 1:1 to 5, more preferably 1:1 to 1.5; Preferably, the reaction temperature is selected from 100 to 200°C, and more preferably from 100 to 150°C; Preferably, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide, or N,N-dimethylformamide; preferably dimethyl sulfoxide. Preferably, the product is dissolved in ethyl acetate and purified by crystallization with acetic acid, wherein the molar ratio of the compound of general formula (IV-1) to acetic acid is 1:1 to 5, preferably 1:2 to 5; In the method for preparing the compound represented by general formula (IV-2): Preferably, the molar ratio of the compound represented by general formula (V-2), the compound represented by general formula (VI-2) to the base ⑥ is 1:1 to 5:1 to 5, more preferably 1:1 to 3:1 to 2.5; Preferably, the reaction temperature is selected from 0 to 25°C, and more preferably, the reaction is carried out at 0 to 10°C for 1 hour, followed by a reaction at room temperature for 2 hours. Preferably, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether, anhydrous ethylene glycol dimethyl ether, dimethyl sulfoxide, or N,N-dimethylformamide; tetrahydrofuran is preferred. Preferably, the reaction is carried out under nitrogen protection; Preferably, the product is purified by pulping with n-heptane.

10. The compound of general formula (II) according to any one of claims 1-3, or the compound of general formula (I) synthesized from the compound of general formula (II) according to claims 1-9, or the use of the method thereof in the preparation of KRAS G12C inhibitors, characterized in that, The structure of the KRAS G12C inhibitor is shown in general formula (VI-A): Preferably, the structure of the KRAS G12C inhibitor is shown in general formula (VI): R9 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 Alkyl; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen or methyl; R 10 Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 Alkyl groups; preferably hydrogen, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, amino, hydroxyl or methyl; x is selected from 0, 1, 2, 3 or 4; y is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, or 2; Preferably, the KRAS G12C inhibitor is selected from the following structures:

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