Preparation method of pyrazine naphthyridine diketone compound and intermediate of pyrazine naphthyridine diketone compound

Abstract

The invention belongs to the technical field of medicines, and particularly provides a preparation method of a pyrazine naphthyridine diketone compound and an intermediate of the pyrazine naphthyridine diketone compound. The method uses simple, cheap and easily available starting raw materials, and is low in reaction cost, simple and convenient to operate and suitable for industrial application.

Description

Preparation method of pyrazino-naphthyridine-dione compound and intermediates thereof

[0001] This application claims priority to the prior application with patent application number 2023110285571 filed with the State Intellectual Property Office of China on August 15, 2023, and invention name “Method for preparing pyrazine-naphthyridine-dione compounds and intermediates thereof”. The full text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of pyrazinonaphthyridinedione compounds and intermediates thereof. Background Art

[0003] Lung cancer is the most common cancer worldwide, with nearly 80% of lung cancers occurring in non-small cell lung cancer (NSCLC). Mutations in the RAS gene have been identified in approximately 32% of lung cancers. Mutations in any of the three major RAS isoforms (HRAS, NRAS, or KRAS) can lead to tumorigenesis in humans. Reports indicate that KRAS is the most frequently mutated RAS gene, detected in 25-30% of tumors. The most common KRAS mutations are found at residues G12 and G13 in the P-loop and at residue Q61. The G12C mutation (glycine-12 to cysteine) is a frequent KRAS mutation. This mutation has been found in approximately 13% of cancers, approximately 43% of lung cancers, and nearly 100% of cases of MYH-associated polyposis (familial colorectal cancer syndrome). To enhance inhibitory activity against mutant KRAS while reducing inhibitory activity against wild-type KRAS, the development of novel KRAS mutant-selective inhibitors with enhanced activity, improved selectivity, and reduced toxicity is crucial.

[0004] PCT patent application WO2021083167A1 reports a series of inhibitors that selectively inhibit KRAS mutations, and reports a representative compound: (4aR,8R)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (compound of Formula I) and its preparation method, which has brought breakthrough progress in the research of KRAS inhibitors. Therefore, there is a need in the art to optimize the synthesis route of the compound of Formula I.

[0005] Summary of the Invention

[0006] In a first aspect of the present disclosure, a method for preparing compound D9 is provided, comprising the following steps:

[0007] Step D: Compound D6 undergoes a ring-closure reaction in the presence of a base, and then undergoes a resolution reaction with a chiral resolution agent to obtain compound D8;

[0008] Step E: Compound D8 is subjected to the removal of the chiral resolving agent to obtain compound D9;

[0009] Wherein, M is a chiral resolution agent;

[0010] R is a chiral auxiliary group.

[0011] The reaction conditions in step D and step E are consistent with the preparation method described in the first aspect below.

[0012] The present disclosure improves the selectivity of the target configuration by introducing a chiral auxiliary group, and separates to obtain compound D9 with a single R configuration.

[0013] In some embodiments, R is selected from

[0014] In some embodiments, the chiral resolving agent M is selected from one or more of D-(+)-di-p-methylbenzoyltartaric acid, N-acetyl-L-phenylalanine, L-(-)-dibenzoyltartaric acid, riboflavin, L-camphorsulfonic acid, glutamic acid, L-tartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid, D-glycine, D-mandelic acid, R-methoxy-trifluoromethylphenylacetic acid, L-aspartic acid, D-(+)-dibenzoyltartaric acid, L-pyroglutamic acid, and R-binaphthol phosphate;

[0015] Preferably, the chiral resolution agent M is selected from one or more of D-(+)-di-p-methylbenzoyltartaric acid, L-camphorsulfonic acid, L-tartaric acid, R-binaphthol phosphate and D-(+)-dibenzoyltartaric acid;

[0016] More preferably, the chiral resolution agent M is R-binaphthol phosphate.

[0017] In some embodiments, the compound D9 is used to prepare a compound of formula I:

[0018] or for preparing any one or a combination thereof selected from Compound D10, Compound D13, Compound D14, Compound D15, Compound D17, and Compound D18;

[0019] Compared with preparing the R and S racemates of the compound of formula I and then resolving the R-configured compound, synthesizing the R-configured compound of formula I using compound D9 as a raw material can effectively reduce the reaction cost and reduce the three wastes generated during the reaction.

[0020] Preferably, the compound D10, compound D13, compound D14, compound D15, compound D17 and compound D18 are used alone or in any combination thereof to prepare the compound of formula I.

[0021] In some embodiments, in the aforementioned preparation method, the preparation method of compound D10 comprises the following steps:

[0022] Step F: Compound D9 is subjected to nitration reaction to obtain compound D10;

[0023] The reaction conditions in step F are consistent with the preparation method described in the eighth aspect below.

[0024] In some embodiments, in the aforementioned preparation method, the preparation method of compound D13 comprises the following steps:

[0025] Step G: Substituting the hydroxyl group in compound D10 to obtain compound D13;

[0026] Preferably, the method for replacing the hydroxyl group in compound D10 is: compound D10 undergoes an esterification reaction with sulfonic anhydride or sulfonyl halide, and then undergoes a substitution reaction with compound D12 to obtain compound D13;

[0027] The reaction conditions in step G are consistent with the preparation method described in the seventh aspect below.

[0028] In some embodiments, in the aforementioned preparation method, the preparation method of compound D14 comprises the following steps:

[0029] Step H: Compound D13 is reacted in the presence of a reducing agent to obtain compound D14;

[0030] Preferably, the reducing agent is sodium dithionite.

[0031] Preferably, in the presence of a reducing agent, the compound D13 undergoes reduction and cyclization reaction to obtain compound D14.

[0032] The reaction conditions in step H are consistent with the preparation method described in the sixth aspect below.

[0033] In some embodiments, in the aforementioned preparation method, the preparation method of compound D15 comprises the following steps:

[0034] Step I: Compound D14 reacts with a methylating agent to obtain compound D15;

[0035] The reaction conditions in step I are consistent with the preparation method described in the fifth aspect below.

[0036] In some embodiments, in the aforementioned preparation method, the preparation method of compound D17 comprises the following steps:

[0037] Step J: Compound D15 is subjected to coupling reaction with compound D16 to obtain compound D17;

[0038] Wherein, X is a group that can undergo a coupling reaction with the chlorine substituent at the N-ortho position on the naphthyridine ring.

[0039] The reaction conditions in step J are consistent with the preparation method described in the fourth aspect below.

[0040] In some embodiments, in the aforementioned preparation method, the preparation method of compound D18 comprises the following steps:

[0041] Step K: Compound D17 is subjected to Boc removal to obtain compound D18;

[0042] The reaction conditions in step K are consistent with the preparation method described in the third aspect below.

[0043] In some embodiments, in the aforementioned preparation method, the preparation method of the compound of formula I comprises the following steps:

[0044] Step L: Compound D18 reacts with an acylating agent to obtain a compound of formula I;

[0045] The reaction conditions in step L are consistent with the preparation method described in the second aspect below.

[0046] In a second aspect, the present disclosure provides a method for preparing a compound of formula I, comprising:

[0047] Step L: Compound D18 reacts with an acylating agent to obtain a compound of formula I;

[0048] In one embodiment, the acylating agent is selected from acrylic anhydride or acryloyl chloride.

[0049] Preferably, the compound D18 is subjected to an acylation reaction with an acylating agent to obtain a compound of formula I.

[0050] In one embodiment, the mass ratio of the acylating agent to compound D18 is (0.1-1):1, for example, (0.1-0.5):1, or 0.2:1.

[0051] In one embodiment, the acylating agent is added to the reaction system dropwise at a temperature of -5 to 15°C.

[0052] In one embodiment, the solvent for the acylation reaction is dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, water, or a mixture thereof; preferably, the solvent is a mixed solvent of tetrahydrofuran or 2-methyltetrahydrofuran and water; the amount of the solvent used is 3 to 10 times the mass of compound D18.

[0053] In one embodiment, the temperature of the acylation reaction is -5 to 30°C, for example, 0 to 10°C; and the time of the acylation reaction is 0.5 to 10 hours.

[0054] In one embodiment, the preparation method may further include one or more of the following post-processing steps: after the reaction is completed, adding water and dichloromethane for extraction, concentrating, adding butanone for concentration, adding methyl tert-butyl ether for crystallization purification, and / or adding dichloromethane for slurrying, filtering, and drying.

[0055] In a third aspect, the present disclosure provides a method for preparing compound D18, comprising:

[0056] Step K: Compound D17 is subjected to Boc removal to obtain compound D18;

[0057] Preferably, compound D17 is subjected to acidic conditions to remove the Boc group to obtain compound D18.

[0058] In one embodiment, the acidic condition is an organic acid solution or an aqueous acid solution;

[0059] Preferably, the acidic condition is any one of hydrogen chloride-methanol solution, hydrogen chloride-ethanol solution, hydrogen chloride-isopropanol solution, hydrogen chloride-ethyl acetate solution, hydrogen chloride-dioxane, hydrogen chloride-aqueous solution or concentrated hydrochloric acid; more preferably, the acidic condition is hydrogen chloride-dioxane solution or hydrogen chloride-aqueous solution.

[0060] In one embodiment, the concentration of the organic acid solution or the aqueous acid solution may be 1 to 10 mol / L; preferably, the concentration is 4 mol / L.

[0061] In one embodiment, the feed equivalent ratio (molar ratio) of the organic acid solution or the aqueous acid solution to compound D17 is (5-10):1.

[0062] In one embodiment, the solvent for the Boc group removal reaction is one or more of an alcohol solvent, an ester solvent, an ether solvent, or water;

[0063] Preferably, the solvent is one or more of methanol, ethanol, isopropanol or water;

[0064] Preferably, the amount of the solvent used is 5 to 10 times the mass of compound D17.

[0065] In one embodiment, the temperature of the Boc removal reaction is -5 to 60°C, for example, -5 to 30°C, room temperature or 20 to 30°C; the time of the Boc removal reaction is 0.5 to 20h or 0.5 to 10h, for example, 0.5 to 1.5h or 1h.

[0066] In one embodiment, the preparation method may further include one or more of the following post-processing steps: after the reaction is completed, the reaction solution is concentrated, water and dichloromethane are added for extraction, the liquids are separated, N,N-dimethylformamide and methyl tert-butyl ether are added to the aqueous phase, the pH is adjusted with sodium carbonate aqueous solution, and / or n-heptane is added for stirring, filtered, and dried.

[0067] In a fourth aspect, the present disclosure provides a method for preparing compound D17, comprising:

[0068] Step J: Compound D15 is subjected to coupling reaction with compound D16 to obtain compound D17;

[0069] Wherein, X is a group that can undergo a coupling reaction with the chlorine substituent at the N-ortho position on the naphthyridine ring; preferably, it is a boronic acid group, a boronic ester group or potassium fluoroborate.

[0070] Preferably, compound D15 and compound D16 are subjected to a coupling reaction in the presence of a catalyst and a base to obtain compound D17.

[0071] In one embodiment, the feed equivalent ratio (molar ratio) of compound D16 to compound D15 is (1-3):1, for example, 1.5:1 or 1.4:1.

[0072] In one embodiment, the base in the coupling reaction can be an organic base or an inorganic base; the organic base is one or more of triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide; the inorganic base is one or more of sodium hydride, potassium phosphate, dipotassium hydrogen phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and lithium hydroxide.

[0073] In one embodiment, the base is dipotassium hydrogen phosphate, which helps to avoid racemization of the product.

[0074] In one embodiment, the equivalent ratio (molar ratio) of the base to compound D15 in the coupling reaction is (1-3):1, for example, 1.2:1, 2.4:1 or 3.1:1.

[0075] In one embodiment, the catalyst in the coupling reaction is a palladium catalyst; preferably, the catalyst is one or more of tetrakis(triphenylphosphine)palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium or tris(dibenzylideneacetone)dipalladium.

[0076] In one embodiment, the feed equivalent ratio (molar ratio) of the catalyst to compound D15 is (0.005-0.05):1, for example, it can be 0.025:1, 0.02:1 or 0.015:1.

[0077] In one embodiment, the solvent for the coupling reaction is tetrahydrofuran, dimethyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water or a mixture thereof; preferably, the reaction solvent is a mixed solvent of 1,4-dioxane and water.

[0078] In one embodiment, the amount of the reaction solvent is 10 to 30 times by volume, 20 to 30 or 25 to 30 times by mass of the compound D15, for example, 20 times by volume, 21 times by mass.

[0079] In one embodiment, the coupling reaction temperature is 50-100° C., for example, 75-85° C.; the coupling reaction time is 1-20 h or 1-10 h, for example, 2-4 h.

[0080] In one embodiment, the coupling reaction is carried out under the protection of an inert gas or nitrogen; the inert gas is selected from any one of helium and argon.

[0081] In one embodiment, the preparation method may further include one or more of the following post-processing steps: after the reaction is completed, the reaction solution is concentrated, 2-methyltetrahydrofuran and water are added for extraction, and then concentrated again, and / or ethanol and water are added for stirring, filtered, and dried.

[0082] In a fifth aspect, the present disclosure provides a method for preparing compound D15, comprising:

[0083] Step I: Compound D14 reacts with a methylating agent to obtain compound D15;

[0084] Preferably, compound D14 is reacted with a methylating agent in the presence of a base to obtain compound D15.

[0085] In one embodiment, the methylating agent is one or more of methyl iodide, dimethyl sulfate, and dimethyl carbonate; the feed equivalent ratio (molar ratio) of the methylating agent to compound D14 is (1-5):1; for example, it can be (1-2):1 or 1.5:1.

[0086] In one embodiment, the methylating agent is a combination of dimethyl sulfate and dimethyl carbonate.

[0087] In one embodiment, the base is one or more of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, lithium diisopropylamide, n-butyllithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate.

[0088] In one embodiment, the feed equivalent ratio (molar ratio) of the base to compound D14 is (1-5):1; for example, it can be (1-2):1.

[0089] In one embodiment, the solvent of the reaction is one or more of an ether solvent, a halogenated hydrocarbon solvent, an ester solvent, a nitrile solvent, an amide solvent, an alcohol solvent, and water; preferably, the solvent of the reaction is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, methyl formate, ethyl formate, ethyl acetate, isopropyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone (NMP), dimethyl sulfoxide, methanol, ethanol, isopropanol, and water; more preferably, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0090] In one embodiment, the amount of the reaction solvent is 5 to 15 times by volume or 5 to 15 times by mass of compound D14, for example, 10 times by volume.

[0091] In one embodiment, the reaction temperature is 0°C to 40°C; preferably, the reaction temperature is room temperature or 20 to 30°C; and the reaction time is 8 to 30 hours or 16 to 20 hours.

[0092] In one embodiment, the reaction temperature is below 0°C, for example, -10 to 0°C, to help improve the stability of the reaction.

[0093] In one embodiment, the preparation method may further include one or more of the following post-treatment steps: after the reaction is completed, adding water and stirring, filtering, and / or adding water and dichloromethane for extraction, and concentrating.

[0094] In one embodiment, the post-treatment step further comprises crystallizing the isolated compound D15, and the crystallization treatment is preferably performed by adding a crystallization solvent and cooling the crystallization.

[0095] In one embodiment, the crystallization solvent is one or more of n-heptane, dichloromethane, and methyl tert-butyl ether.

[0096] In one embodiment, the temperature drop crystallization is carried out at 20±5°C.

[0097] In a sixth aspect, the present disclosure provides a method for preparing compound D14, comprising:

[0098] Step H: Compound D13 is reacted in the presence of a reducing agent to obtain compound D14;

[0099] Preferably, the reducing agent is sodium dithionite.

[0100] Preferably, in the presence of a reducing agent, the compound D13 undergoes reduction and cyclization reaction to obtain compound D14;

[0101] In one embodiment, the preparation method of the compound D14 is that the compound D13 is first subjected to a reduction reaction in the presence of a reducing agent, and then subjected to a cyclization reaction to obtain the compound D14.

[0102] In one embodiment, the reducing agent is one or more of hydrogen, palladium carbon, platinum carbon, Raney nickel, zinc powder, iron powder, sodium dithionite or sodium sulfide and hydrazine hydrate; preferably, the reducing agent is sodium dithionite, palladium carbon or platinum carbon.

[0103] In one embodiment, the mass ratio of the reducing agent to compound D13 is (0.1-4):1, for example, 3.4:1.

[0104] In one embodiment, the reducing agent is an aqueous solution of hydrosulfur powder, and the aqueous solution is added to the reaction in a dropwise manner.

[0105] Optionally, the product of the reduction reaction can be directly subjected to a cyclization reaction without post-treatment.

[0106] In one embodiment, the reducing agent is hydrogen, and the reduction reaction is carried out in the presence of a catalyst. The catalyst is preferably a noble metal catalyst, more preferably a platinum catalyst, and more preferably a platinum-carbon catalyst.

[0107] In one embodiment, after the metal catalyst is removed by the reduction reaction, a cyclization reaction is performed in the presence of an acid catalyst, and the acid catalyst is preferably acetic acid.

[0108] In one embodiment, the reduction and cyclization reactions are carried out under nitrogen or inert gas protection conditions; the inert gas is one of argon and helium.

[0109] In one embodiment, the solvent for the reduction and cyclization reaction is one or more of an alcohol solvent, an ester solvent, and an ether solvent; preferably, the solvent for the reduction and cyclization reaction is one or more of methanol, ethanol, isopropanol, methyl formate, ethyl formate, ethyl acetate, isopropyl acetate, tetrahydrofuran, and 1,4-dioxane.

[0110] In one embodiment, the amount of the solvent used is 5 to 10 times the volume of the compound D13.

[0111] In one embodiment, the reaction temperature of the reduction reaction is 0-30°C, for example, 20-30°C; the reaction temperature of the cyclization reaction is 20-100°C or 50-100°C, for example, 75-85°C; the progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound disappears or no longer reacts.

[0112] In one embodiment, the preparation method may further include one or more of the following post-processing steps: after the cyclization reaction is completed, cooling, adding water and ethyl acetate for extraction, concentrating, and / or adding isopropyl acetate, stirring, filtering, and drying.

[0113] In one embodiment, the temperature drop crystallization is carried out at 0-10°C.

[0114] In a seventh aspect, the present disclosure provides a method for preparing compound D13, comprising:

[0115] Step G: Substituting the hydroxyl group in compound D10 to obtain compound D13;

[0116] Preferably, the method for replacing the hydroxyl group in compound D10 is: compound D10 undergoes an esterification reaction with sulfonic anhydride or sulfonyl halide, and then undergoes a substitution reaction with compound D12 to obtain compound D13.

[0117] Preferably, compound D10 undergoes an esterification reaction with sulfonic anhydride or sulfonyl halide in the presence of a base to obtain an intermediate compound D11, and the intermediate compound D11 then undergoes a substitution reaction with compound D12 to obtain compound D13;

[0118] Among them, the hydroxyl group is replaced to prepare an activated sulfonate compound, and the sulfonate is used as a leaving group, which makes the reaction easier to proceed, has fewer side reactions, and has high product purity.

[0119] In one embodiment, the sulfonic anhydride or sulfonyl halide in the esterification reaction is one or more of trifluoromethanesulfonic anhydride, trifluoroethanesulfonic anhydride, methanesulfonic anhydride, ethanesulfonic anhydride, benzenesulfonic anhydride, p-toluenesulfonic anhydride, trifluoroacetyltrifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride, ethylsulfonyl chloride, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride or 4-nitrobenzenesulfonyl chloride.

[0120] In one embodiment, the equivalent ratio (molar ratio) of the sulfonic anhydride or sulfonyl halide to compound D10 is (1-3):1, for example, 1.65:1, 1.5:1 or 1.4:1.

[0121] In one embodiment, the sulfonic anhydride or sulfonyl halide is added to the reaction dropwise.

[0122] In one embodiment, the base in the esterification reaction is one or more of triethylamine, diisopropylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

[0123] In one embodiment, the equivalent ratio (molar ratio) of the base to compound D10 is (1-5):1, for example, 3:1 or 4:1.

[0124] In one embodiment, the solvent for the esterification reaction is one or more of ethyl acetate, isopropyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, dimethyltetrahydrofuran, acetonitrile or N,N-dimethylformamide.

[0125] In one embodiment, the amount of the solvent is 5 to 15 times by volume or 5 to 15 times by mass, for example, 10 times by volume, of the mass of compound D10.

[0126] In one embodiment, the reaction temperature of the esterification reaction is -60 to 0°C, for example, -55 to -45°C, -30 to 0°C, or -20 to -30°C; the reaction time of the esterification reaction is preferably 10 to 120 min, for example, 20 min.

[0127] In one embodiment, the reaction temperature of the esterification reaction is lower than -30°C, further lower than -35°C, -40°C or -45°C, for example, -55 to -45°C or -45 to -35°C, which is beneficial for controlling the generation of impurities in the reaction or controlling the impurity content.

[0128] In one embodiment, the reaction solution of the esterification reaction does not need to be post-treated and can be directly subjected to the substitution reaction.

[0129] In one embodiment, in the substitution reaction, the equivalent ratio (molar ratio) of the compound D12 to the compound D10 is (1-2):1, for example, 1.3:1.

[0130] In one embodiment, compound D12 is added to the reaction dropwise.

[0131] In one embodiment, the reaction temperature of the substitution reaction is -30 to 0°C, such as -20 to 30°C; the reaction time of the substitution reaction is preferably 10 to 120 min, such as 30 min.

[0132] In one embodiment, the preparation method may further include one or more of the following post-treatment steps: after the substitution reaction is completed, adding water and stirring, separating the layers, concentrating the organic phase, and / or adding ethyl acetate and n-heptane and stirring, filtering and drying.

[0133] In some embodiments, the prepared organic solvent solution of D13 can also be directly used in the next reaction, and the organic solvent is preferably the solvent for the next reaction.

[0134] In an eighth aspect, the present disclosure provides a method for preparing compound D10, comprising:

[0135] Step F: Compound D9 is subjected to nitration reaction to obtain compound D10;

[0136] In one embodiment, the nitrating agent in the nitration reaction may be nitric acid, a nitrate, a mixture of nitric acid and other acids or anhydrides, or a mixture of nitrates and other acids or anhydrides; the other acids or anhydrides are preferably selected from one or more of sulfuric acid, concentrated sulfuric acid, glacial acetic acid, and acetic anhydride. The nitric acid is selected from dilute nitric acid, concentrated nitric acid, or fuming nitric acid.

[0137] Preferably, the nitrating agent is a mixed system of concentrated nitric acid-concentrated sulfuric acid, concentrated nitric acid-glacial acetic acid or concentrated nitric acid-acetic anhydride.

[0138] In one embodiment, the nitrate is selected from one or more of potassium nitrate, sodium nitrate, and sodium nitrite.

[0139] In one embodiment, the equivalent ratio (molar ratio) of the nitrating agent to compound D9 is (1-2):1, for example 1:1 or 2:1; the amount of the other acid or anhydride is 1-5 times the volume or 1-6 times the mass of compound D9.

[0140] In one embodiment, the temperature of the nitration reaction is 0-30°C; preferably, the reaction temperature is room temperature, such as 20-30°C.

[0141] In one embodiment, the nitration reaction time is 0.5 to 2 hours or 0.5 to 1 hour.

[0142] In one embodiment, the preparation method may further include post-treatment, which may be one or more of the following steps: after the reaction is completed, adding water, stirring, filtering, drying, and / or adding methanol, stirring, filtering, and drying.

[0143] In one embodiment, the preparation method may further include post-treatment, which may be one or more of the following steps: after the reaction is completed, adding water and stirring (and / or washing with water), cooling to 10-20° C., and / or stirring and filtering, washing the filter cake with water and / or acetonitrile solution, and drying.

[0144] In the first aspect of the present disclosure, a method for preparing compound D9 is also provided, comprising:

[0145] Step D: Compound D6 undergoes a ring-closure reaction in the presence of a base, and then undergoes a resolution reaction with a chiral resolution agent M to obtain compound D8;

[0146] as well as

[0147] The step of removing the chiral resolving agent M from compound D8 to obtain compound D9;

[0148] Preferably, compound D6 undergoes a ring-closure reaction in the presence of a base to obtain an intermediate compound D7; and the intermediate compound D7 undergoes a resolution reaction with a chiral resolution agent M to obtain compound D8.

[0149] In one embodiment, the base in the ring-closure reaction is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); the feed equivalent ratio (molar ratio) of the base to compound D6 is (1-10):1; preferably, it is (1-5):1, (1-3):1 or (1-2):1.

[0150] In one embodiment, the solvent for the ring-closure reaction is one or more of acetone, methanol, ethanol, isopropanol, tert-butanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran or toluene, or optionally further contains water.

[0151] In one embodiment, the amount of the solvent used is 5 to 10 times the volume of the compound D6.

[0152] In one embodiment, the temperature of the ring-closure reaction is below 40°C, and can further be 0-40°C or 0-30°C, such as 25-30°C, 20-30°C or 30-40°C;

[0153] In one embodiment, the reaction temperature is 10-50°C; preferably, room temperature.

[0154] In one embodiment, the ring-closure reaction time is preferably 30 to 72 hours, such as 48 to 72 hours.

[0155] In one embodiment, the chiral resolution agent M is selected from one or more of D-(+)-di-p-methylbenzoyltartaric acid, N-acetyl-L-phenylalanine, L-(-)-dibenzoyltartaric acid, riboflavin, L-camphorsulfonic acid, glutamic acid, L-tartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid, D-glycine, D-mandelic acid, R-methoxy-trifluoromethylphenylacetic acid, L-aspartic acid, D-(+)-dibenzoyltartaric acid, L-pyroglutamic acid and R-binaphthol phosphate; preferably, the chiral resolution agent M is selected from one or more of D-(+)-di-p-methylbenzoyltartaric acid, L-camphorsulfonic acid, L-tartaric acid, R-binaphthol phosphate and D-(+)-dibenzoyltartaric acid; more preferably, the chiral resolution agent M is R-binaphthol phosphate.

[0156] In one embodiment, the equivalent ratio (molar ratio) of the resolving agent M to the compound D6 is (0.25-5):1 (0.25-2):1, for example, it can be 0.25:1, 0.5:1, 1:1, 1.5:1 or 2:1; preferably, the equivalent ratio (molar ratio) is 1:1.

[0157] In one embodiment, the mass ratio of the resolving agent M to compound D6 is (0.5-1):1, for example, 0.67:1.

[0158] In the present disclosure, compound D8 may exist together with a resolving agent in the form of a co-crystal, a salt, and a corresponding solvate thereof.

[0159] In one embodiment, the solvent for the resolution reaction is one or more of an ether solvent, an alcohol solvent, a ketone solvent, a sulfoxide solvent, an ester solvent and an amide solvent, or optionally further contains water; preferably, the solvent is selected from one or more of 1,4-dioxane, methyltetrahydrofuran, methanol, ethanol, isopropanol, acetone, ketone, ethyl ketone, butanone, methyl isobutyl ketone, cyclohexanone, ethyl acetate, isopropyl acetate or N,N-dimethylformamide, or optionally further contains water.

[0160] In one embodiment, the amount of solvent used in the resolution reaction is 5 to 20 times the mass of compound D7.

[0161] In one embodiment, the temperature of the resolution reaction is -30 to 50°C; preferably, -25 to -15°C or 0 to 5°C or 0 to 50°C; the reaction progress can be monitored by HPLC, generally until the reaction is complete.

[0162] In one embodiment, the preparation method may further include the following post-processing steps: after the resolution reaction is completed, filtering and drying.

[0163] In one embodiment, compound D8 is subjected to acid neutralization reaction to remove the chiral resolution agent M to obtain compound D9.

[0164] In one embodiment, the acid used in the acid neutralization reaction is one or more of p-toluenesulfonic acid, p-nitrobenzoic acid, hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, and methanesulfonic acid.

[0165] In one embodiment, the feed equivalent ratio (molar ratio) of the acid to compound D8 is (1-5):1.

[0166] In one embodiment, the mass ratio of the acid to compound D8 is (1-5):1.

[0167] In one embodiment, the solvent for the acid neutralization reaction is one of an ether solvent and a nitrile solvent; preferably, the solvent is acetonitrile.

[0168] In one embodiment, the amount of the solvent used in the acid neutralization reaction is 1 to 10 times the volume or 1 to 10 times the mass of compound D8.

[0169] In one embodiment, the temperature of the acid neutralization reaction is 0-30°C, for example, 20-25°C; preferably, the reaction temperature is room temperature; the progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound disappears or no longer reacts.

[0170] In one embodiment, after the reaction is completed, it may further include one or more of the following post-treatment steps: filtering, adding water to concentrate, adjusting the pH (eg, 4.5 to 5) with sodium hydroxide solution, filtering, and drying.

[0171] In one embodiment, the preparation method may further include the following post-processing step: After the resolution reaction, the separated compound D9 is crystallized to obtain a product with good properties and easy drying. This reduces the problem of excessive water content, high viscosity, and difficulty in transferring or drying the product obtained from the crystallization system.

[0172] In a preferred embodiment, the crystallization treatment is to add a crystallization solvent and then cool the crystallization.

[0173] In one embodiment, the crystallization solvent is n-heptane.

[0174] In one embodiment, the temperature drop crystallization is carried out at 10-20°C.

[0175] In a ninth aspect, the present disclosure provides a method for preparing compound D6, comprising:

[0176] Step C: Compound D4 and compound D5 undergo condensation reaction to obtain compound D6;

[0177] Wherein, R is selected from

[0178] In one embodiment, the preparation method of the compound D6 is that the compound D4 is acylated with an acylating agent, and then condensed with the compound D5 in the presence of a base and a catalyst to obtain the compound D6.

[0179] In one embodiment, the acylating agent in the acylation reaction is one or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, acetyl chloride, thionyl chloride, and pivaloyl chloride.

[0180] In one embodiment, the feed equivalent ratio (molar ratio) of the acylating agent to compound D4 is (1-5):1.

[0181] In one embodiment, the acylation reaction is carried out in the presence of a catalyst, which is a catalyst commonly used in the art, such as N,N-dimethylformamide or thionyl chloride.

[0182] In one embodiment, the solvent for the acylation reaction is one or more of dichloromethane, dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

[0183] In one embodiment, the amount of the solvent used is 5 to 10 times the volume or 5 to 10 times the mass of compound D4.

[0184] In one embodiment, the temperature of the acylation reaction is 40-100°C; preferably, 45-55°C or 50-100°C; the reaction progress can be monitored by HPLC, generally until the reaction is complete.

[0185] In one embodiment, the product of the acylation reaction is added with a solvent and directly subjected to the next reaction; the solvent is one or more of tetrahydrofuran and 2-methyltetrahydrofuran.

[0186] In one embodiment, the feed equivalent ratio (molar ratio) of compound D5 to compound D4 in the condensation reaction is (1-3):1, for example, it can be 1:1, 1.5:1, 2:1, 2.5:1 or 3:1; preferably, the feed equivalent ratio (molar ratio) is (1.5-2):1.

[0187] In one embodiment, the base in the condensation reaction is one or more of triethylamine, N,N-diisopropylethylamine, or DBU; the feed equivalent ratio (molar ratio) of the base to compound D4 is (1-10):1, for example, it can be 1:1, 2:1, 3:1, 4:1 or 5:1.

[0188] In one embodiment, the catalyst in the condensation reaction is one or more of magnesium chloride, magnesium bromide or magnesium iodide.

[0189] In one embodiment, the feed equivalent ratio (molar ratio) of the catalyst to compound D4 is (1-3):1.

[0190] In one embodiment, the solvent for the condensation reaction is one or more of dichloromethane, dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

[0191] In one embodiment, the temperature of the condensation reaction is 0-30°C or 0-10°C; the reaction progress can be monitored by HPLC, and the completion of the reaction is generally regarded as the end point.

[0192] In one embodiment, the method for preparing compound D5 comprises the following steps: performing an ester exchange reaction between compound SM1 and a chiral alcohol to obtain compound D5;

[0193] In one embodiment, in the transesterification reaction, the equivalent ratio (molar ratio) of the chiral alcohol to the compound SM1 is (0.9-3):1 or (1-3):1.

[0194] In one embodiment, the solvent for the transesterification reaction is one or more of an ether solvent, an aromatic hydrocarbon solvent, and an amide solvent; preferably, the solvent is one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, benzene, toluene, xylene, and N,N-dimethylformamide.

[0195] In one embodiment, the temperature of the transesterification reaction is 50-110° C. or 50-100° C.; the reaction progress can be monitored by HPLC, and the reaction is generally terminated when the reaction is complete.

[0196] In one embodiment, after the reaction is completed, it may further include post-treatment, and the post-treatment may be one or more steps of the following steps: after the reaction is completed, water, methyl tert-butyl ether, potassium carbonate, liquid separation, and / or methyl tert-butyl ether is added to the aqueous phase, hydrochloric acid is used to adjust the pH value, stirring, liquid separation, and organic phase concentration.

[0197] In some embodiments, the post-treatment further comprises crystallizing the separated compound D5; the solvent for the crystallization is preferably n-heptane, and the crystallization temperature is preferably -15 to 0°C.

[0198] In one embodiment, compound D5 is selected from the group consisting of:

[0199] In one embodiment, compound D6 is selected from the group consisting of:

[0200] In a tenth aspect, the present disclosure provides a method for preparing compound D4, comprising:

[0201] Step B: Compound D3 reacts with a chlorinating agent to obtain compound D4;

[0202] In one embodiment, the chlorination agent is selected from one or more of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or chlorine gas.

[0203] In one embodiment, the molar ratio of the chlorination reagent to compound D3 is (0.5-2):1, for example, 0.5:1, 1:1, 1.5:1 or 2:1.

[0204] Preferably, the molar ratio of the chlorination reagent to compound D3 is (0.5-1):1.

[0205] In one embodiment, the solvent for the chlorination reaction is selected from one or more of a nitrile solvent, an amide solvent, and an ether solvent;

[0206] Preferably, the solvent for the chlorination reaction is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran; or optionally further contains water.

[0207] In one embodiment, the amount of the solvent used is 5 to 15 times the volume of the compound D3.

[0208] In one embodiment, the reaction temperature of the chlorination reaction is 10-85°C, for example, 75-85°C, room temperature, or -5-5°C.

[0209] Preferably, the reaction temperature is room temperature. The reaction progress can be monitored by TLC, HPLC, etc., and the completion of the reaction is generally regarded as the end point.

[0210] In one embodiment, the chlorination reaction may be carried out under acid catalysis. The reaction is preferably carried out at room temperature, more preferably at 20 to 30°C or -5 to 5°C.

[0211] In one embodiment, the acid is selected from one or more of methanesulfonic acid, hydrochloric acid (eg, concentrated hydrochloric acid), trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.

[0212] Preferably, the acid is methanesulfonic acid or hydrochloric acid.

[0213] In one embodiment, in the chlorination reaction, the chlorination reagent is 1,3-dichloro-5,5-dimethylhydantoin or N-chlorosuccinimide; the molar ratio of the chlorination reagent to compound D3 is (0.5-1):1; the solvent for the chlorination reaction is acetonitrile or tetrahydrofuran; the reaction temperature is 10-80°C; the reaction progress can be monitored by TLC, HPLC, etc., and is generally stopped when the reaction is detected to be complete.

[0214] In one embodiment, the above reaction is carried out under the catalysis of methanesulfonic acid or hydrochloric acid.

[0215] In some embodiments, the chlorination reaction can be carried out in the presence of concentrated hydrochloric acid catalysis and water.

[0216] Preferably, the hydrochloric acid is a hydrochloric acid solution with a concentration of 20-35%. The acid catalyst can protonate dichlorohydantoin, increase its activity, and play an inducing and initiating role on chloride cations, which is conducive to the generation of positive ions and the electrophilic chlorination reaction of the aromatic ring.

[0217] In one embodiment, the preparation method may further include the following post-processing steps: after the reaction is completed, water is added, stirred, filtered, and dried.

[0218] In an eleventh aspect, the present disclosure provides a method for preparing compound D3, comprising the following steps:

[0219] Step A: Compound D1 reacts with compound D2 to obtain compound D3;

[0220] Preferably, compound D1 and compound D2 undergo a substitution reaction to obtain compound D3.

[0221] In one embodiment, the substitution reaction comprises the following steps: in a solvent, compound D1 is mixed with a base to obtain a reserve solution 1, and compound D2 is mixed with a base to obtain a reserve solution 2; reserve solution 1 and reserve solution 2 are contacted to react to obtain compound D3;

[0222] Alternatively, compound D1 is mixed with a base in a solvent, and compound D2 is added thereto to react and obtain compound D3.

[0223] In one embodiment, the feed equivalent ratio (molar ratio) of the compound D1 to the compound D2 is (0.5-2):1, for example, 1:1.

[0224] In one embodiment, the base in the substitution reaction is selected from one or more of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, lithium diisopropylamide, isopropylmagnesium chloride, n-butyllithium and tert-butyllithium; preferably, the base is lithium bistrimethylsilylamide, sodium bistrimethylsilylamide or a combination thereof.

[0225] In one embodiment, the equivalent ratio (molar ratio) of the base in the reserve solution 1 to the compound D1 is (0.5-2):1, for example, it can be 0.5:1, 1:1, 1.5:1 or 2:1; preferably, the equivalent ratio of the base in the reserve solution 1 to the compound D1 is (1-2):1.

[0226] In one embodiment, the feed equivalent ratio (molar ratio) of the base in the reserve solution 2 to the compound D2 is (1-2):1, for example, it can be 1:1, 1.5:1 or 2:1; preferably, the feed equivalent ratio (molar ratio) of the base in the reserve solution 2 to the compound D1 is (1-2):1.

[0227] In one embodiment, in the preparation method of the aforementioned compound D3, the feed equivalent ratio (molar ratio) of the base, compound D1 and D2 is (1.5-4):1:1, and can further be (2.5-4):1:1, for example, it can be 3:1:1 or 3.42:1:1.

[0228] In the present disclosure, the base is added to the reaction in a dropwise manner, and the temperature during the dropwise addition is 0-30°C, such as 0-5°C or 0-20°C.

[0229] In one embodiment, the solvent for the substitution reaction is an ether solvent; preferably, the solvent for the substitution reaction is selected from one or more of tetrahydrofuran and 2-methyltetrahydrofuran.

[0230] In one embodiment, the amount of the solvent used is 10 to 20 times the mass of compound D1.

[0231] In one embodiment, the reaction temperature of the substitution reaction is 0-50°C, for example, 0-5°C or 0-10°C; the reaction time of the substitution reaction is 0.5h-4h; the reaction progress can be monitored by HPLC, and the completion of the reaction is generally regarded as the end point.

[0232] In one embodiment, in the substitution reaction, the base in the reserve solution 1 is lithium bistrimethylsilylamide or sodium bistrimethylsilylamide, and the molar ratio of the base to compound D1 is (1-2):1.

[0233] In one embodiment, in the substitution reaction, the base in the reserve solution 2 is lithium bis(trimethylsilyl)amide, and the molar ratio of the base to compound D2 is (1-2):1.

[0234] In one embodiment, in the substitution reaction, the solvent for the substitution reaction is tetrahydrofuran; the amount of the reaction solvent used is 10 to 15 times the volume of the mass of compounds D1 and D2.

[0235] In one embodiment, in the substitution reaction, the reaction temperature is 0-10°C or 10-20°C.

[0236] In one embodiment, the substitution reaction comprises: mixing compound D1 with a base in a solvent, and then adding a reaction agent to obtain compound D3, and the reaction temperature is 10-20° C. The reaction operation is simple and energy consumption is low.

[0237] In one embodiment, in the substitution reaction, the reaction time is 0.5 to 2 h, and can further be 0.5 to 1 h or 1 to 2 h.

[0238] In one embodiment, the preparation method may further include one or more of the following post-treatment steps: after the reaction is completed, water is added to quench the reaction, concentrated, and / or hydrochloric acid solution is added to adjust the pH (adjust the pH to acidic, for example, the pH can be adjusted to 2-4, and further can be the pH used in the corresponding steps in the embodiments of the present disclosure), stirred, filtered, and dried.

[0239] In the present disclosure, the above-mentioned preferred conditions can be arbitrarily combined on the basis of conforming to the common sense in the art to obtain the preferred embodiments of the present disclosure.

[0240] The present disclosure provides a method for preparing a compound of formula I, comprising the following steps:

[0241] Step A: Compound D1 undergoes substitution reaction with compound D2 to obtain compound D3;

[0242] Step B: Compound D3 reacts with a chlorinating agent to obtain compound D4;

[0243] Step C: Compound D4 and compound D5 undergo condensation reaction to obtain compound D6;

[0244] Wherein, R is selected from

[0245] Step D: Compound D6 undergoes a ring-closure reaction in the presence of a base, and then undergoes a resolution reaction with a chiral resolution agent M to obtain compound D8;

[0246] Step E: Compound D8 is subjected to the removal of chiral resolving agent M to obtain compound D9;

[0247] Furthermore, the preparation method of the compound of formula I further comprises the following steps:

[0248] Step F: Compound D9 is subjected to nitration reaction to obtain compound D10;

[0249] Step G: Substituting the hydroxyl group in compound D10 to obtain compound D13;

[0250] Step H: Compound D13 is reacted in the presence of a reducing agent to obtain compound D14;

[0251] Step I: Compound D14 reacts with a methylating agent to obtain compound D15;

[0252] Step J: Compound D15 is subjected to coupling reaction with compound D16 to obtain compound D17;

[0253] wherein X is a group that can undergo a coupling reaction with the chlorine substituent at the N-ortho position on the naphthyridine ring; Step K: removing the Boc group from compound D17 to obtain compound D18;

[0254] Step L: Compound D18 reacts with an acylating agent to obtain a compound of formula I;

[0255] The acylating agent is selected from acrylic anhydride or acryloyl chloride.

[0256] The reaction conditions in each reaction step are consistent with the above-mentioned preparation method.

[0257] In one embodiment, the preparation method of the compound of formula I comprises the following steps:

[0258] Wherein, R and X are as defined above, and the reaction conditions in each reaction step are consistent with the above-mentioned preparation method. In one embodiment, the preparation method of the compound of formula I comprises the following steps:

[0259] Wherein, R and X are as defined above, and the reaction conditions in each reaction step are consistent with the aforementioned preparation method.

[0260] In a twelfth aspect of the present disclosure, there is provided the above-mentioned compounds D3, D5, D6, D8, D9, D10, D13, D14, D15, D17, D18 or pharmaceutically acceptable salts thereof:

[0261] Wherein, R is selected from

[0262] M is selected from D-(+)-di-p-methylbenzoyltartaric acid, N-acetyl-L-phenylalanine, L-(-)-dibenzoyltartaric acid, riboflavin, L-camphorsulfonic acid, glutamic acid, L-tartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid, D-glycine, D-mandelic acid, R-methoxy-trifluoromethylphenylacetic acid, L-aspartic acid, D-(+)-dibenzoyltartaric acid, L-pyroglutamic acid or R-binaphthol phosphate.

[0263] In a thirteenth aspect of the present disclosure, there is provided use of the above-mentioned compounds D3, D5, D6, D8, D9, D10, D13, D14, D15, D17, D18 or pharmaceutically acceptable salts thereof in the preparation of KRAS inhibitors.

[0264] The fourteenth aspect of the present disclosure provides the use of the above-mentioned compounds D3, D5, D6, D8, D9, D10, D13, D14, D15, D17, D18 or pharmaceutically acceptable salts thereof in the preparation of drugs for treating cancer.

[0265] Preferably, the cancer is a cancer associated with KRAS gene mutation.

[0266] In one embodiment, the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

[0267] In one embodiment, the cancer is non-small cell lung cancer.

[0268] In a fifteenth aspect of the present disclosure, there is provided use of the above-mentioned compound D3, D5, D6, D8, D9, D10, D13, D14, D15, D17 or D18 for preparing a compound of formula I.

[0269] Compared with the prior art, the present disclosure has the following advantages:

[0270] 1. The process product avoids the use of column chromatography purification operation, and the post-processing process is simple; by introducing the crystallization post-processing operation, the product purity is improved and the product separation is facilitated.

[0271] 2. Introducing asymmetric synthesis into process products can increase the proportion of target configurations; and advancing the separation, purification and refining of isomers from the final API step to the early intermediates, which can effectively reduce process volume and the generation of three wastes.

[0272] 3. The price of raw materials is greatly reduced, the yield is improved, and the overall route cost is reduced; the process is optimized to meet the needs of industrial scale-up, for example, the starting material 2,6-dichloronicotinic acid is cheap.

[0273] 4. The hydroxyl group is prepared into an activated sulfonate compound, which is then reacted with a piperazine compound. Compared with the original route, the reaction has high selectivity, is easier to carry out, and has fewer side reactions. It can effectively avoid the problem of impurities easily generated in the boron tribromide demethylation step in the process of Comparative Example 1, so that the quality of the raw material production process can be better controlled.

[0274] 5. The reaction is stable and the overall reaction process is controllable. DETAILED DESCRIPTION

[0275] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0276] As used herein and unless otherwise indicated, the term "about" or "approximately" means within plus or minus 10% of a given value or range. Where an integer is required, the term means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.

[0277] In the description herein, reference is made to "in one embodiment" or "in some embodiments," which describes a subset of possible embodiments, but it is understood that "in one embodiment" may be the same subset or different subsets of all possible embodiments, and may be combined with each other without conflict.

[0278] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0279] The "step C", "step D", "step E" and the like described herein are only for numbering purposes and do not limit the synthetic route to be strictly executed in the conventionally understood numbering order.

[0280] As used herein, the term "room temperature" includes temperatures of 4-30°C, generally refers to 15-30°C, preferably 20-30°C.

[0281] As used herein, the term "solution" refers to an aqueous solution unless otherwise specified.

[0282] As used herein, the term "clear" means to dissolve and become clear.

[0283] As used herein, the term "condensation reaction" refers to a reaction in which two or more organic molecules interact with each other to form a large molecule through covalent bonds, accompanied by the loss of small molecules (such as water, hydrogen chloride, alcohol, etc.).

[0284] As used herein, the term "substitution reaction" is defined according to the Compendium of Chemical Nomenclature of the International Union of Pure and Applied Chemistry (IUPAC) as "a one-step or stepwise reaction in which one atom or group in the molecule as a whole is replaced by another atom or group."

[0285] Michaelis' acid: 2,2-dimethyl-1,3-dioxane-4,6-dione.

[0286] The analytical methods involved in this disclosure may employ the following parameters:

[0287] HPLC analysis method 1: Chromatographic column: Waters sunfire C18, 4.6×150 mm, 3.5 μm; mobile phase: A: 10 mM ammonium acetate aqueous solution; B: acetonitrile; detection wavelength: 220 nm; flow rate: 1.0 mL / min; column temperature: 30°C; elution gradient: 0-30 min, A% (20-95), B% (5-80).

[0288] HPLC analysis method 2: Chromatographic column: Waters sunfire C18, 4.6×150 mm, 3.5 μm; mobile phase: A: 0.05% trifluoroacetic acid / water; B: 0.05% trifluoroacetic acid / acetonitrile; detection wavelength: 220 nm; flow rate: 1.0 mL / min; column temperature: 65°C; elution gradient: 0-32 min, A% (20-90), B% (10-80).

[0289] Chiral analysis method: Chromatographic column: CHIRALPAK IB 4.6*250 mm, 3 μm; mobile phase: 0.01% trifluoroacetic acid aqueous solution: methanol: ethanol (3:4:3); detection wavelength: 329 nm; flow rate: 0.35 mL / min; column temperature: 25°C; run time: 40 min.

[0290] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0291] Yield calculation method:

[0292] Yield = (amount of target product produced / theoretical amount of target product produced) * 100%;

[0293] Theoretical yield = the number of moles of raw materials added multiplied by the relative molecular mass of the target product.

[0294] Right now,

[0295] As used herein, the term "reaction is complete" means that the reactant consumption is greater than about 90%, preferably greater than 95%. In one embodiment, the reaction is complete using conventional methods in the art, such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), etc.

[0296] As used herein, the term "chiral resolving agent" refers to a compound used to resolve a racemate (a mixture containing two enantiomers) into a single enantiomer. These agents typically have a chiral center and can form a diastereomeric mixture with the racemate. These mixtures are separated by crystallization using differences in solubility and crystallization rate, thereby achieving chiral resolution. Chiral resolving agents can be chiral acids or chiral bases, which form salt bonds with the racemate to form diastereomeric salts, thereby achieving resolution.

[0297] As used herein, the term "post-treatment" refers to the process of extracting and / or isolating a reaction product from a mixture of reactants, products, and solvent. Examples include crystallization, filtration, extraction, washing, concentration, chromatography, optical purity testing, neutralization, addition of an adsorbent, and drying. Product isolation can be achieved by appropriately selecting the solvent and crystallization conditions. Different enantiomers may have different crystallization rates and solubilities, thereby enabling separation of chiral products. The product (preferably the chiral product) in the aqueous phase is extracted using an organic solvent to improve product purity and yield. After filtration or extraction, the product may need to be washed with water or other appropriate solvents to remove attached impurities. The washing solvent can also be another solvent that can dissolve impurities or the product (preferably the solvent used during the reaction to avoid the introduction of more impurities). The product is concentrated by evaporating the solvent in preparation for further purification or analysis. The optical purity of the chiral product is determined using instruments such as nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. If necessary, the product may need to be derivatized (e.g., pre-column derivatization before chromatographic analysis, optionally with aniline derivatization) and modified. If the product exists in the form of a salt, it may need to be neutralized with an appropriate base to obtain the chiral product in the form of a free base. Impurities, catalysts, and reaction by-products may be removed by adding specific adsorbents. For example, unreacted or fully reacted palladium catalyst may be removed by modifying a resin and by-products may be adsorbed by activated carbon. Finally, the product needs to be dried to remove residual solvent or water.

[0298] It is understood that in the reaction routes provided in the present disclosure, the intermediates can be prepared and isolated before use in the next reaction, or they can be directly dissolved in a solvent (preferably the solvent to be used in the next reaction) and used directly in the next reaction; it is understood that if the solvent used to dissolve the product is not a good solvent for the next reaction, it needs to be replaced with a good solvent before the reaction.

[0299] Generally speaking, reactants, catalysts, solvents, and reagents for providing an alkaline or acidic environment can be added all at once or in batches into the reaction system, as long as they are added before the next reaction step described in the present disclosure begins.

[0300] The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers (or may also be referred to as rotational isomers), etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation. The atropisomers of the compounds of the present invention may exist in the form of bolded bonds (e.g. ) or may be represented by other commonly used marking methods known in the art.

[0301] In this article, we use Indicates the absolute configuration of a stereocenter. Unless otherwise specified Including possible configuration, as long as the structure allows.

[0302] Unless otherwise specified, all reagents and raw materials used in the present disclosure are commercially available.

[0303] Example 1 Preparation of Compound D3

[0304] To reaction flask A, add compound D1 (20.5 g, 1.0 eq) and tetrahydrofuran (100 mL, 5 V), cool to 0-5°C, and add lithium bistrimethylsilylamide (1 M solution in tetrahydrofuran, 110 mL, 1 eq) dropwise. Maintain the temperature below 10°C. After completion of the addition, stir while incubating to obtain Reserve Solution 1. To reaction flask B, add compound D2 (16.5 g, 1.0 eq) and tetrahydrofuran (100 mL, 5 V). Cool to 0-5°C, and add lithium bistrimethylsilylamide (1 M solution in tetrahydrofuran, 210 mL, 2.0 eq) dropwise. After completion of the addition, stir while incubating at 0-5°C for 30 min to obtain Reserve Solution 2. Add Reserve Solution 2 dropwise to Reserve Solution 1. After completion of the addition, stir at 0-5°C until the reaction is complete. Maintain the temperature below 20°C and pour the reaction solution into 150 mL of water to quench the reaction. The solvent was dried in vortex to obtain a concentrate, which was then adjusted to pH with 4N hydrochloric acid solution until a large amount of solid precipitated. Filtering and drying the filter cake yielded 28.3 g of compound D3 with a purity of 100% and a yield of 86.68%. ES-API: [M+H] + =306.8. 1H NMR (400MHz, DMSO-d6) δ8.27(d,J=4.8Hz,1H),8.08(d,J=7.7Hz,1H),7.12(d,J=4.8Hz ,1H),6.58(d,J=7.7Hz,1H),3.21(p,J=6.7Hz,2H),2.12(s,3H),1.12(d,J=6.7Hz,6H).

[0305] Example 2 Preparation of Compound D3

[0306] The molar ratio of compound D1 to the base in reserve solution 1 is compound D1: lithium bistrimethylsilylamide = 1:2, the molar ratio of compound D2 to the base in reserve solution 2 is compound D2: lithium bistrimethylsilylamide = 1:1, and the molar ratio of compound D1 to compound D2 is compound D1: compound D2 = 1:1; the amount of tetrahydrofuran used to dissolve compound D1 and compound D2 is 15 times the volume of the mass of compound D1 and compound D2, the reaction temperature is 0-10 ° C, and the other operations are the same as in Example 1 to obtain compound D3 with a yield of 86.7%.

[0307] Example 3 Preparation of Compound D3

[0308] The molar ratio of compound D1 to the base in reserve solution 1 is 1:2 for compound D1: sodium bistrimethylsilylamide, the molar ratio of compound D2 to the base in reserve solution 2 is 1:1 for compound D2: lithium bistrimethylsilylamide, the molar ratio of compound D1 to compound D2 is compound D1: compound D2 = 1:1, the amount of tetrahydrofuran used to dissolve compound D1 and compound D2 is 15 times the volume of the mass of compound D1 and compound D2, the reaction temperature is 0-10 ° C, and the other operations are the same as in Example 1 to obtain compound D3 with a yield of 77.91%.

[0309] Example 4 Preparation of Compound D3

[0310] Add compound D1 and tetrahydrofuran to a reaction flask, stir to dissolve, then cool to 10-20°C. Add lithium bis(trimethylsilyl)amide. Once complete, add a tetrahydrofuran solution of compound D2. Stir and react at 10-20°C for 1-2 hours. After sampling to check for reaction completion, quench the reaction by dropwise addition of water. Add water to the reaction solution, concentrate under reduced pressure, and adjust the pH to 2-3 with 4M hydrochloric acid to precipitate a solid. Filter the solid, wash with water, and dry the filter cake to yield compound D3 as a white solid in a 94% yield.

[0311] The molar ratio of compound D1, compound D2 and lithium bis(trimethylsilyl)amide is 1:1:3.42.

[0312] Example 5 Preparation of Compound D3

[0313] Referring to the method of Example 1, tetrahydrofuran (4435 g) and compound D2 (782.4 g, 5.20 mol) were added to reaction flask 1, the temperature was lowered to 0-5°C, 1M lithium bistrimethylsilylamide tetrahydrofuran solution (6719 g, 7.81 mol) was added dropwise to reaction flask 1, and the reaction solution in reaction flask 1 was stirred at 0-5°C for 30-60 min; tetrahydrofuran (8870 g) was added to reaction flask 2, and the mixture was heated to 40°C. Compound D1 (1000 g, 5.20 mol) was cooled to 10-20°C, and a 1M solution of lithium bistrimethylsilylamide in tetrahydrofuran (6719 g, 7.81 mol) was added dropwise to reaction flask 2. The reaction mixture in reaction flask 2 was stirred at 10-20°C for 30-60 min. The temperature was then maintained at 10-20°C, and the reaction mixture in reaction flask 1 was added to reaction flask 2. The mixture was then heated to 25-30°C and stirred for 30-60 min. Water (20,000 g) and activated carbon (400 g) were added to reaction flask 2, stirred for 0.5-1.5 h, filtered, and the filter cake rinsed with water. 4M aqueous hydrochloric acid was added dropwise to the filtrate to adjust the pH to 2-3, filtered, and the filter cake rinsed with water. The filter cake was dried to obtain 140 g of compound D3 as a yellow solid in an 88% yield.

[0314] Example 6 Preparation of Compound D4

[0315] Compound D3 (28.14 g, 1.0 eq), acetonitrile (200 mL, 7 V), and methanesulfonic acid (36.20 g, 4.0 eq) were added to a reaction flask at room temperature. The temperature was lowered to 0-10°C and kept warm until ready to use. 1,3-Dichloro-5,5-dimethylhydantoin (9.07 g, 0.5 eq) was dissolved in acetonitrile (100 mL, 3 V) and added dropwise to the reaction mixture, maintaining the temperature below 25°C. After the addition was complete, the reaction mixture was brought to room temperature and concentrated to dryness. 100 mL of water was added for slurrying, the solid was collected by filtration, and dried to yield 31.20 g of compound D4 with a purity of 100% and a yield of 77.96%. ES-API: [M+H] + =340.2. 1 H NMR (500MHz, DMSO-d6) δ9.74(s,1H),8.35(d,J=4.8Hz,1H),8.28(s,1H),7.18(d,J=4.9Hz,1H),2.13(s,3H),1.12(d,J=6.8Hz,6H).

[0316] Example 7 Preparation of Compound D4

[0317] Refer to the preparation of Example 4, wherein compound D3 (1.0 eq), acetonitrile (8V), temperature 20-25 ° C, add concentrated hydrochloric acid (3.2 L, 4.0 eq), the system gradually clarifies, and after the addition, keep warm at 20-25 ° C for use. 1,3-dichloro-5,5-dimethylhydantoin in acetonitrile solution is added dropwise to the reaction solution prepared above. The temperature is controlled at 20-30 ° C during the addition. After the addition is completed, sample and detect the reaction until D3 disappears. Adjust the pH to 2-2.5 with 2M sodium hydroxide, keep warm at 20-25 ° C, and stir for 1 hour. Filter, collect the solid and dry to obtain compound D4 with a purity of 97.42% and a yield of 91.3%.

[0318] Example 8 Preparation of Compound D4

[0319] To a reaction flask, add compound D3 (9.52 g, 0.031 mol), acetonitrile (63.2 g), water (30 g), and concentrated hydrochloric acid (6.5 g). Slowly add a solution of 1,3-dichloro-5,5-dimethylhydantoin (3.68 g, 0.019 mol) in acetonitrile (15.8 g) dropwise at 10-30°C. Stir the mixture at 20-30°C for 2-6 hours. After completion, adjust the pH to 2-3 with 2M sodium hydroxide solution. Stir for 2-6 hours, filter, and rinse with water (20 g). Dry the filter cake to yield 10.03 g of compound D4 as a white solid (90% yield).

[0320] Example 9 Preparation of Compound D4

[0321] Referring to the preparation method of Example 7, compound D3, acetonitrile, and concentrated hydrochloric acid were added to the reaction flask. After addition, the temperature was cooled to -5 to 5°C. An acetonitrile solution of 1,3-dichloro-5,5-dimethylhydantoin, an acetonitrile solution of 1,3-dichloro-5,5-dimethylhydantoin, water, and an acetonitrile solution of 1,3-dichloro-5,5-dimethylhydantoin were added to the reaction system in three separate steps. The molar ratio of compound D3 to 1,3-dichloro-5,5-dimethylhydantoin was 1.68:1; the molar ratio of the 1,3-dichloro-5,5-dimethylhydantoin added in the three additions was 1:1:1; and the molar ratio of concentrated hydrochloric acid to compound D3 was 9:1. Other procedures were followed as in Example 7 to obtain compound D4 as a yellow solid in a 93% yield.

[0322] Example 10 Preparation of Compound D5

[0323] (1-1) Preparation of Compound D5-1

[0324] Add Michaelis' acid (50 g), L-menthol (50 g) and toluene (250 mL) to the reaction flask. Stir and react at 100°C for 1-2 hours. Cool the reaction solution to room temperature, add water (500 mL), methyl tert-butyl ether (500 mL) and potassium carbonate (66.3 g) to the reaction solution and stir for 0.5 hour. Separate the liquid phase, add methyl tert-butyl ether (300 mL) to the aqueous phase. Slowly add 6M hydrochloric acid dropwise to the above system and adjust the pH to 3-5. Stir for 0.5 hour and let stand to separate. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound D5-1, 79 g of oily product, purity: 95.28%, yield: 97.1%.

[0325] (1-2) Preparation of Compound D5-1

[0326] Add L-menthol (10 g, 64 mmol), Michaelis' acid (10 g, 69.1 mmol), and toluene (43.6 g) to a reaction flask and stir at 90-100°C for 6-10 h. After sampling to confirm the reaction is complete, add water (100 g), potassium carbonate (11.5 g), and methyl tert-butyl ether (37 g) to the reaction system and stir to separate the layers. Discard the organic phase, wash the aqueous phase once more with methyl tert-butyl ether (37 g), discard the organic phase, add methyl tert-butyl ether (44.4 g) to the aqueous phase, and slowly add 6M hydrochloric acid solution dropwise with stirring to adjust the pH to 3-4. After stirring and separating the layers, collect the organic phase. The reaction mixture was concentrated under reduced pressure to 2-3 V, and n-heptane (35 g) was added. The reaction mixture was again concentrated under reduced pressure to 2-3 V, and n-heptane (14 g) was added. Compound D5-1 seed crystals (0.1 g) were added at 25-35°C. The temperature was slowly lowered to -15-0°C, and the mixture was stirred for 2-6 h. The mixture was filtered, and the filter cake was rinsed with n-heptane (10 g). The mixture was dried to obtain 12.4 g of compound D5-1 as a white solid (yield: 80%).

[0327] (2) Preparation of compound D5-2

[0328] L-menthol was replaced with S-phenylethanol, and other operations were carried out the same as in Example 10 (1-1) to obtain compound D5-2.

[0329] (3) Preparation of compound D5-3

[0330] L-menthol was replaced with (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol, and other operations were carried out the same as in Example 10(1-1) to obtain compound D5-3.

[0331] Example 11 Preparation of Compound D6-1

[0332] Add compound D4 (50 g, 1.0 eq) and dichloroethane (250 mL) to reaction flask A. Add thionyl chloride (50 mL, 4.7 eq) dropwise and allow to react at 80°C until complete. Concentrate the reaction mixture to dryness and add tetrahydrofuran (500 mL, 10 V) to obtain reaction solution A.

[0333] Under ice-water bath, add acetonitrile (500 mL) to reaction flask B, add compound D5-1 (71 g, 1.0 eq), add magnesium chloride (42 g, 3.0 eq) and triethylamine (89 g, 3.0 eq) in sequence, and stir at room temperature after addition to obtain reaction solution B.

[0334] Under an ice-water bath, reaction solution A was added to reaction solution B. After the reaction was complete, water (500 mL) and ethyl acetate (500 mL) were added to the reaction solution. The pH of the aqueous phase was adjusted to 5-6, and the layers were separated. The organic phase was washed with saturated sodium bicarbonate solution (500 mL) and then with 10% sodium chloride solution (500 mL). Concentration afforded 71 g of crude compound D6-1 with a purity of 97.07% and a yield of 94.8%.

[0335] Example 12 Preparation of Compound D6-1

[0336] Compound D4 (200 g, 588 mmol), toluene (1740 g) and DMF (0.2 g) were added to the reaction flask. Dichlorothionyl (140 g, 2.00 eq, 0.70 w / w) was added at 20-30°C. After stirring for 2-6 h, the temperature was raised to 50-60°C and the stirring was continued until the reaction was complete. The temperature was then lowered to 20-30°C, filtered, and washed with toluene to obtain the acyl chloride intermediate for use.

[0337] To a reaction flask, add D5-1 (285 g, 2.00 eq), acetonitrile (1572 g), and dichloromethane (2253 g) sequentially with stirring. Add magnesium chloride (168 g, 3.00 eq) at 20-30°C, followed by the dropwise addition of triethylamine (357 g, 1.79 w / w). Stir for 2-4 hours. Add the aforementioned acid chloride intermediate to the system and allow the reaction to proceed at 20-30°C until complete. Concentrate under reduced pressure to 11-13°C, and slowly add water (2000 g) dropwise to quench the reaction. Add isopropyl acetate (1744 g), and adjust the pH to 3-4 with 4M hydrochloric acid. The layers were separated by stirring, and the organic phase was collected and washed once with water (2000 g), once with 5% sodium bicarbonate solution (2000 g), and once with water (2000 g). The organic phase was concentrated under reduced pressure to 5-7 V, and the isopropyl acetate solution of the obtained product D6-1 was collected and used directly in the next reaction.

[0338] Example 13 Preparation of Compound D6-1

[0339] Add dichloroethane (313 g), compound D4 (50 g, 147 mmol) and thionyl chloride (52.5 g, 441 mmol) to reaction flask A, keep stirring at 45-55°C for 2-3 h, then concentrate under reduced pressure to 2-3V, add dichloroethane (500 g), and concentrate under reduced pressure again to 2-3V, add tetrahydrofuran (444 g), and set aside;

[0340] A solution of compound D5-1 (53.4 g, 220 mmol) in acetonitrile (150 g) and acetonitrile (275 g) were added to reaction flask B, cooled to 0-10°C, and magnesium chloride (42.0 g, 441 mmol) and triethylamine (89.3 g, 882 mmol) were added portionwise. Stir at 0-10°C for 30-60 min. The reaction solution in reaction flask A was then added dropwise to reaction flask B, controlled at 0-10°C. The temperature was raised to 30-40°C, and stirred for 0.5-2 h. The temperature was then lowered to 20-30°C, water (500g) and ethyl acetate (451g) were added, and then 4M aqueous hydrochloric acid solution was added dropwise to adjust the pH to 3-5. The liquid was separated, and the organic phase was washed three times with 10% sodium bicarbonate solution (500g), and then washed with 10% sodium chloride solution (500g), concentrated under reduced pressure to 1-2V, and methanol (120g) was added. The mixture was concentrated under reduced pressure to 1-2V, and methanol (605g) was added to obtain a brown-red D6 methanol solution with a yield of 95%.

[0341] Example 14 Preparation of Compound D8

[0342] To 20 g of crude compound D6-1, methanol (200 mL, 10 V) and sodium carbonate (8.15 g, 2.0 eq) were added. The mixture was stirred at 25-30°C until the reaction was complete, then filtered and the filter cake rinsed with methanol. The combined filtrates were concentrated to dryness, and methanol (6 V) and R-binaphthol phosphate (R-BNDHP, 13.38 g, 1.0 eq) were added. The temperature was lowered to 0-5°C, and isopropyl acetate (12 V) was added dropwise. The mixture was kept warm. The solid was collected by filtration and dried to yield 17.8 g of compound D8. The three-step yield was 52.80%, and the R / S ratio was 99.14:0.86. 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.56(d,J=5.1Hz,1H),8.47(s,1H),8.15(d,J=8.8Hz,2H),8.08(dd,J=8.4,1.3Hz,2H),7 .60-7.46(m,4H),7.47-7.30(m,3H),7.24(d,J=8.5Hz,2H),6.06(s,1H),4.86(m,J=6.3Hz,1H),1.96(s,3H),1.12-0.96(m,6H).

[0343] Example 15 Preparation of Compound D8

[0344] Acetone and water (9.5:1, V / V) were added to the above concentrate to replace methanol. The reaction temperature was room temperature. Other operations were carried out as in Example 14 to obtain compound D8 with a purity of 97.33%, a yield of 43.55%, and R / S = 89.33 / 10.67.

[0345] Example 16 Preparation of Compound D8

[0346] Compound D5-1 was replaced by compound D5-2, and other operations were carried out the same as in Example 11 and Example 14 to obtain compound D8, R / S=65.44:34.56.

[0347] Example 17 Preparation of Compound D8

[0348] Compound D5-1 was replaced by compound D5-3, and other operations were carried out the same as in Example 11 and Example 14 to obtain compound D8, R / S=54.02:45.98.

[0349] Example 18 Preparation of Compound D8

[0350] Add a solution of compound D6-1 (10 g, 1.0 eq) in isopropyl acetate to a reaction flask, concentrate under reduced pressure to 1-2V, add methanol (40.0 g), concentrate under reduced pressure to 1-2V, add methanol (80.0 g), and stir until dissolved. Control the temperature at 25±5°C, add 300-mesh sodium carbonate (6.1 g, 3.0 eq), stir until the reaction is complete, filter, and add concentrated hydrochloric acid (36%) dropwise to the filtrate to adjust the pH to 3-5. Concentrate under reduced pressure to 2-2.5V, add methanol (16.0 g, 1.6 w / w). Add 20% sodium hydroxide dropwise to adjust the pH to 4.5-5.0. Control the temperature at 0-5°C, and add R-binaphthol phosphate (6.7 g, 0.67 w / w) and isopropyl acetate (52.3 g, 5.23 w / w) in sequence. Stir for 24 hours. Sampling and filtration testing revealed the S-isomer impurity in the filter cake to be <5.0%. The temperature was maintained at -15±5°C and stirring was continued for 2–4 hours. The filter cake was filtered and rinsed with isopropyl acetate (17.5 g, 1.75 w / w) and then with water (30 g, 3.0 w / w). Drying afforded 7.47 g of compound D8, a three-step yield of 55.1%.

[0351] Example 19 Preparation of Compound D8

[0352] A methanol solution of compound D6-1 (100 g, 192 mmol) and sodium carbonate (61.0 g, 576 mmol) were added to a reaction flask. The mixture was stirred at 20-30°C for 48-72 hours, filtered, and the filter cake was rinsed with methanol (79 g). Concentrated hydrochloric acid (60 g) was added dropwise to the filtrate to adjust the pH to 3-5. The filtrate was then concentrated to 2-3°C under reduced pressure, methanol (158 g) was added, and 20% sodium hydroxide solution (10.0 g) was added dropwise to adjust the pH to 4.5-5. The temperature was lowered to -5-5°C, and R-binaphthol phosphate (66.9 g, 192 mmol) and isopropyl acetate (524 g) were added. The mixture was stirred at 20-30°C for 24-48 hours, then cooled to -25--15°C and stirred for 2-4 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl acetate (175 g) and water (300 g). The filter cake and water (1000 g) were stirred at 20-30° C. for 4-6 h, filtered, and dried to obtain 71.2 g of compound D8 as a white solid, with a yield of 52%.

[0353] Example 20 Preparation of Compound D9

[0354] At room temperature, add compound D8 (1.60 kg, 1.0 eq) to a reaction kettle, followed by acetonitrile (8 L, 5 V) and stirring. Add methanesulfonic acid (2.11 kg, 5.0 eq) dropwise to the system, maintain at 20-25°C, and stir until complete. Filter, and rinse the filter cake once with acetonitrile (1 V). Add water (5 V) to the filtrate and concentrate under reduced pressure to remove the acetonitrile. Adjust the pH of the aqueous phase to 5-6 with 6 M sodium hydroxide solution and stir at room temperature for 1 hour. Filter, rinse the filter cake once with water (2 V), and dry to obtain 810 g of compound D9 with a purity of 76.6% and a yield of 90.39%. 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.9Hz,1H),8.46(s,1H),7.27(d,J=4.8Hz,1H ),6.02(s,1H),4.04(q,J=7.1Hz,1H),1.90(s,3H),1.01(dd,J=24.7,6.7Hz,6H).

[0355] Example 21 Preparation of Compound D9

[0356] At room temperature, add acetonitrile (159.89 g, 9.40 w / w) and methanesulfonic acid (35.26 g, 2.08 w / w) to the reaction flask. Control the temperature at 20-30°C and add D8 (17 g, 42.5% content) in portions. Stir until the reaction is complete. Filter. Concentrate the filtrate under reduced pressure to 6-7 V. Control the temperature at 20-30°C. Add water (10 V) and adjust the pH to 4.5-5.2 with 10% sodium hydroxide solution. Add 2-methyltetrahydrofuran (10 V) to the above system, separate the layers, and wash the organic phase with 5% sodium chloride solution (4 V). After concentrating the organic phase under reduced pressure, add isopropyl acetate (8 V) and concentrate again under reduced pressure to 5-6 V. Control the temperature at 50-60°C. Add n-heptane (8 V) and stir. Filter and dry the filter cake to obtain 15.3 g of compound D9. Yield: 90%.

[0357] Example 22 Preparation of Compound D10

[0358] Add acetic acid (1200 mL, 3V) to the reaction flask and cool to 20-25°C. Slowly add 95% fuming nitric acid (146 g, 1.0 eq mmol) dropwise, maintaining the temperature at 20-30°C. After the addition is complete, maintain the internal temperature at 17-28°C and add compound D9 (400 g, 1.0 eq) in batches. Stir until the reaction is complete. Add water (34V, 13.6 L) to the system, stir for 2 hours, then cool to 10-15°C and filter. Rinse the filter cake with water (800 mL, 2V). After drying, add methanol (2000 mL, 5V) and slurry for 1 hour. Filter and dry to obtain 367 g of compound D10 with a purity of 98.57% and a yield of 100%. 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=5.7Hz,1H),8.45(s,1H),7.83(s,1H),2.94(p,J=6.9Hz,1H),2.17(s,3H),1.17(dd,J=29.4,6.9Hz,6H).

[0359] Example 23 Preparation of Compound D10

[0360] Acetic acid (54 g) was added to reaction flask A, the temperature was controlled at 20-30°C, and fuming nitric acid (7 g) was slowly added dropwise. Compound D9 (20 g) and acetic acid (64 g) were added to reaction flask B and stirred to dissolve. The temperature was controlled at 20-30°C, and the solution in reaction flask B was slowly added dropwise to reaction flask A. After the addition was complete, the reaction was stirred at 20-30°C until complete. Water (400 g) was added dropwise, and the mixture was stirred at 20-30°C for 1-2 hours, and filtered. The filter cake was stirred with water (200 g) and acetonitrile (80 g), filtered, and the filter cake was rinsed with a mixed solvent of acetonitrile (16 g) and water (40 g). Drying gave 21.30 g of compound D10 as a yellow powdery solid with a yield of 94.6% and a purity of 99.5%.

[0361] Example 24 Preparation of Compound D10

[0362] D8 (225 g) containing compound D9 (100 g, 275 mmol) and acetonitrile (1179 g) were added to reaction flask A. Methanesulfonic acid (212 g, 2196 mmol) was added to reaction flask A with stirring. The mixture was kept at 20-30°C with stirring for 4-8 hours, filtered, and the filter cake was rinsed with acetonitrile (236 g). The filtrate was transferred to reaction flask B and concentrated under reduced pressure until no fractions were discharged. Acetic acid (158 g) was added to reaction flask B and the mixture was further concentrated under reduced pressure until no fractions were discharged, yielding a pale yellow D9 solution. Acetic acid (149 g) and 95% fuming nitric acid (34.8 g, 552 mmol) were added to reaction flask C and mixed thoroughly. The contents of reaction flasks B and C were nitrated using a fluid reactor. After nitration, the temperature was controlled at 20-30°C and the reaction mixture was added dropwise to water (3760 g) with stirring. 30% sodium hydroxide solution was then added dropwise until the pH reached 3-4, and the mixture was stirred at this temperature for 2-3 hours. Filtered, the filter cake was rinsed with water (200 g). The dried crude product was slurried with methanol (1120 g) at 20-30°C for 8-12 hours, filtered, and the filter cake was rinsed with methanol (149 g). Drying afforded 98.9 g of compound D10 as a yellow solid in an 88% yield.

[0363] Example 25 Preparation of Compound D13

[0364] Add compound D10 (330 g, 1 eq) and dichloromethane (3.3 L, 10 V) to the reaction vessel and start stirring. Add N-methylmorpholine (245 g, 3 eq), and the system will become clear. Cool to an internal temperature of -20 to -30°C, then add trifluoromethanesulfonic anhydride (375 g, 1.65 eq) dropwise. Maintain the temperature at -20 to -30°C and stir until the reaction is complete.

[0365] Control the temperature between -20 and -30°C and add a solution of compound D12 (256 g, 1.3 eq) in dichloromethane (2 V). After the addition is complete, stir and react until complete. Add water (5 V) and stir to separate the layers. Wash the organic phase once with a saturated aqueous sodium bicarbonate solution (5 V) and then with an aqueous sodium chloride solution (5 V). Collect the organic phase and spin dry it. Add ethyl acetate (2 V) and then n-heptane (20 V) with stirring. Stir at 20-30°C for 2-3 hours. Filter, rinse the filter cake with n-heptane (1 V), and dry to obtain 501.2 g of compound D13 with a purity of 94.88% and a yield of 95.18%. 1 H NMR(400MHz, DMSO-d6)δ8.56(d,J=4.8Hz,2H),7.37-7.28(m,1H),4.52(s,1H),4.31(d,J=13.5Hz,1H),4.12- 3.85(m,3H),3.67(s,3H),3.52(s,2H),3.12(s,1H),1.98(s,3H),1.43(s,9H),1.03(dd,J=13.4,6.7Hz,6H).

[0366] Example 26 Preparation of Compound D13

[0367] Compound D10 (100 g) and dichloromethane (1320 g) were added to a reaction flask. N-methylmorpholine (98.87 g) was added with stirring. The temperature was maintained at -55 to -45°C. Trifluoromethanesulfonic anhydride (103.42 g) was added dropwise. After the addition was complete, the mixture was stirred and incubated until the reaction was complete. A solution of compound D12 (80 g) in dichloromethane (300 g) was added dropwise while maintaining the internal temperature at -55 to -45°C. After the addition is completed, the mixture is stirred at room temperature until the reaction is complete, and the temperature is raised to 0±5°C. Water (500 g) is added, and hydrochloric acid is added dropwise to adjust the pH to 2-3. The mixture is stirred for 1-2 h, and the liquid is separated. The organic phase is washed twice with aqueous hydrochloric acid solution (2 g concentrated hydrochloric acid, 498 g water), and then washed twice with 5% sodium bicarbonate (500 g) solution and once with water (500 g). The mixture is filtered, and the filter cake is rinsed with dichloromethane (300 g) to obtain a dichloromethane solution of compound D13, which is directly used in the next reaction.

[0368] Example 27 Preparation of Compound D13

[0369] D10 (100 g, 244 mmol), dichloromethane (1125 g), and N-methylmorpholine (74.2 g, 733 mmol) were added to a reaction flask. The temperature was lowered to -45 to -35°C, trifluoromethanesulfonic anhydride (96.5 g, 342 mmol) was added dropwise, and the mixture was stirred at this temperature for 1 to 1.5 hours. A solution of compound D12 (77.6 g, 318 mmol) in dichloromethane (265 g) was then added dropwise to the reaction flask. The temperature was kept at -45 to -35°C, and the mixture was stirred at this temperature for 1 to 1.5 hours. The mixture was heated to 15 to 25°C, and water (500 g) was added. The mixture was stirred and separated into layers. The organic phase was washed twice with 0.1N hydrochloric acid solution (500 g), washed with 9% sodium bicarbonate aqueous solution (500 g), and washed with 26% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure to 3.0-4.0 V, ethyl acetate (450 g) was added, and n-heptane (1360 g) was added dropwise at 40-50°C. The mixture was stirred at 20-30°C for 3.0-4.0 h. The mixture was filtered, and the filter cake was rinsed with n-heptane (136 g) and dried to obtain 139.8 g of compound D13 as a brown solid (yield: 90%).

[0370] Example 28 Preparation of Compound D14

[0371] Add compound D13 (500 g, 1 eq) and 1,4-dioxane (5 L, 10 V) to a reaction kettle and stir to dissolve. Dissolve hydrosulfite (465 g, 3.4 eq) in water (3 V) and stir to clarify. Control the temperature at 20-30°C and add the hydrosulfite solution dropwise to the reaction kettle. After addition is complete, replace the atmosphere with argon. Heat to 75-85°C and allow to react until satisfactory. Cool the reaction mixture to 20-30°C, add water (10 V) and ethyl acetate (15 V). Separate the layers, concentrate the organic phase under reduced pressure, and add isopropyl acetate (5 V). Continue concentrating, add isopropyl acetate (2 V) to the concentrated crude product, and stir at 0-10°C for 2 h. Filter, and rinse the filter cake with isopropyl acetate (0.5 V). Dry to obtain 400.97 g of compound D14 with a purity of 97.37% and a yield of 89.33%. 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.56(d,J=4.9Hz,1H),8.45(s,1H),7.32(dd,J=4.8,0.9Hz,1H),4.94-4.37(m,2H),4.04(q, J=7.1Hz,1H),3.87(d,J=29.7Hz,2H),2.76(s,1H),2.60(m,J=6.6Hz,2H),1.85(s,3H),1.45(s,9H),1.05(dd,J=27.7,6.6Hz,6H).

[0372] Example 29 Preparation of Compound D14

[0373] Add a dichloromethane solution of compound D13 (actual amount of D13: 155 g), 1% platinum on carbon (10.85 g), and isopropyl acetate (527 g) to a hydrogenation flask. Replace the atmosphere with nitrogen and then hydrogen, adjusting the pressure to 0.1-0.3 MPa. Control the temperature at 20-30°C and stir until the reaction is complete. Filter, transfer the filtrate to a reaction flask, add acetic acid (31 g), raise the temperature to 20-30°C, and stir until the reaction is complete. Then, add 5% aqueous sodium bicarbonate (775 g) dropwise. After the addition is complete, stir for 1-2 hours, allow to stand and separate, wash the organic phase once with water (500 g), and concentrate under reduced pressure to 3-4 V. Add isopropyl acetate (697.5 g) and concentrate twice to 3-4 V. Stir for 1-2 hours. Slowly add n-heptane (418.5 g) dropwise. After the addition is complete, control the temperature at 80±5°C and stir for 1-2 hours. The mixture was slowly cooled to 0-10°C and stirred for 5 h. Filtered and the filter cake was rinsed with a mixture of n-heptane (155 g) and isopropyl acetate (155 g). Drying afforded 106.08 g of compound D14 as a yellow solid with a purity of 99.9% and a yield of 80.0%.

[0374] Example 30 Preparation of Compound D15

[0375] Add compound D14 (400 g, 1.0 eq) and N,N-dimethylformamide (4 L, 10 V) to a reaction kettle. While stirring, add potassium carbonate (193.0 g, 2.0 eq) to the reaction kettle and stir evenly. Maintain the temperature at 20-30°C and stir for 2 h. Slowly add dimethyl sulfate (132 g, 1.5 eq) dropwise to the reaction kettle while maintaining the temperature at 20-30°C. After addition, maintain the temperature at 20-30°C and add water (20 V) dropwise to the reaction kettle. After the addition is complete, maintain the temperature at 20-30°C and stir for 2 h. Filter and rinse the filter cake with water (2 V). Dissolve the filter cake in dichloromethane (10 V) and extract once with water (10 V). After separation, wash the aqueous layer once more with dichloromethane (10 V). The organic phases were combined and concentrated to obtain 415 g of compound D15 with a purity of 97.36% and a yield of 92.09%. 1H NMR (400MHz, DMSO-d6) δ8.53(d,J=4.9Hz,1H),8.50(s,1H),7.30(dd,J=4.9,0.9Hz,1H),4.65(d,J=13.3Hz,1H),3.85(d,J=40.6Hz,2H ),3.30(s,3H),3.44-3.34(dd,2H),3.13(s,1H),2.71(dt,J=14.7,7.3Hz,2H),1.80(s,3H),1.44(s,9H),1.06(dd,J=19.8,6.7Hz,6H).

[0376] Example 31 Preparation of Compound D15

[0377] To a reaction flask, add compound D14 (60 g), potassium carbonate (42 g), NMP (255 g), and DMSO (270 g) in sequence, stirring at -10-0°C. Add dimethyl sulfate (19.8 g) dropwise at -10-0°C until addition is complete and the reaction is stirred until complete. Slowly add the reaction system dropwise to water (810 g). Maintain the temperature at 20-30°C and stir for 1-3 hours. Filter and rinse the filter cake with water (300 g). The filter cake was transferred to a reaction flask, and dichloromethane (780 g), water (570 g) and sodium chloride (30 g) were added. After stirring and dissolving, the mixture was allowed to stand for 2 to 5 minutes and the organic phase was collected. The aqueous phase was extracted once with dichloromethane (180 g). The organic phases were combined, washed once with water (300 g), and concentrated under reduced pressure to 2 to 3 V. Dichloromethane (420 g) was added and concentrated under reduced pressure to 2 to 3 V. Methyl tert-butyl ether (300 g) was added and concentrated under reduced pressure to 2 to 3 V. n-heptane (120 g) was added. The temperature was raised to 50 to 60 ° C and stirred for 3 to 5 h. The temperature was slowly lowered to 20 ± 5 ° C and filtered. The filter cake was dried to obtain 54.1 g of compound D15 as a yellow solid with a purity of 99.7% and a yield of 95.8%.

[0378] Example 32 Preparation of Compound D15

[0379] Add compound D13 (50 g, 79 mmol) and 1,4-dioxane (515 g) to reaction flask A and stir to dissolve. Add water (150 g) and sodium dithionite (46.6 g, 267 mmol) to reaction flask B and stir to dissolve. Add the contents of reaction flask B to reaction flask A and stir at 75-85°C for 16-20 hours. Cool to 20-30°C, add water (500 g) and ethyl acetate (675 g), stir, separate the layers, and concentrate the organic phase under reduced pressure to 1.5-2.5 V. Concentrate the mixture three times with ethyl acetate (90 g) to 1.5-2.5 V. Add N,N-dimethylformamide (428.6 g) and concentrate under reduced pressure to 9.5-11.0 V. Add potassium carbonate (29 g, 210 mmol), then dropwise add dimethyl sulfate (19.85 g, 160 mmol), and stir at 20-30°C for 16-20 h. Continue adding potassium carbonate (7.18 g, 52 mmol), then dropwise add dimethyl sulfate (4.96 g, 39 mmol), and stir at 20-30°C for 5-7 h. Add water (902 g) to the reaction flask, stir at 20-30°C for 2-3 h, filter, and rinse the filter cake with water (90 g). Dichloromethane (600 g) and water (451 g) were added to the filter cake, stirred until dissolved, and then the liquid was separated to separate the organic phase. The aqueous phase was washed twice with dichloromethane (600 g). The combined organic phases were concentrated to 1.5-2.2 V, and n-heptane (614 g) was added dropwise at 25-35 ° C. The mixture was stirred for 1-2 h, slowly cooled to 0-5 ° C. and stirred for 1.5-2.5 h. Filtered, the filter cake was rinsed with n-heptane (61.4 g), and dried to obtain 37 g of compound D15, a brown solid product, with a 2-step yield of 80%.

[0380] Example 33 Preparation of Compound D17

[0381] To a reaction kettle, add compound D15 (415 g, 1.0 eq), 1,4-dioxane (6.56 L, 16 V), and water (1.6 L, 4 V). The atmosphere was purged with argon. Potassium carbonate (117.0 g, 1.2 eq) and tetrakis(triphenylphosphine palladium) (20.0 g, 0.025 eq) were added, and the atmosphere was purged with argon. After the addition was complete, the temperature was raised to 75-85°C, and a dioxane aqueous solution of compound D16 (165.0 g, 1.5 eq dissolved in 1,4-dioxane (1.64 L, 4 V) and water (0.4 L, 1 V)) was added dropwise. After the addition was complete, the reaction mixture was allowed to react at 75-85°C until the reaction was satisfactory. The temperature was lowered to 20-30°C, the reaction mixture was concentrated under reduced pressure, and 2-methyltetrahydrofuran (10 V) and water (10 V) were added. Separate the liquids, retain the organic phase, and wash the aqueous phase once with 2-methyltetrahydrofuran (5V). Combine the organic phases and concentrate under reduced pressure. Add ethanol (4V) to the concentrated material, raise the temperature to 40°C, and add water (4V). After addition is complete, maintain the temperature at 40-45°C and stir for 1 hour. Cool naturally to 25°C, then continue to cool to 0-10°C, maintain the temperature and stir for 1 hour. Filter and dry to obtain 366.9 g of compound D17 with a purity of 97.63% and a yield of 85.88%. 1 H NMR (400MHz, DMSO-d6) δ10.02(d,J=6.0Hz,1H),8.44(d,J=5.1Hz,2H),7.23(q,J =8.3Hz,2H),6.70(d,J=8.3Hz,1H),6.68-6.61(m,1H),4.69(d,J=13.3Hz,1H),4. 04(q,J=7.1Hz,1H),3.90(d,J=31.2Hz,2H),3.49(d,J=12.0Hz,2H),3.35(s,3H) ,3.30(s,2H),1.80(d,J=10.1Hz,3H),1.47(s,9H),1.04(dd,J=55.3,6.2Hz,6H).

[0382] Example 34 Preparation of Compound D17

[0383] Compound D15 (40 g), dipotassium hydrogen phosphate (28.4 g), 1,4-dioxane (660 g), and water (160 g) were added to reaction flask A, and the mixture was stirred. The internal temperature was controlled at 25±5°C. Nitrogen was bubbled into the reaction solution to replace the mixture, and the temperature was raised to 90±5°C. Tetrakis(triphenylphosphine)palladium (1.18 g) was added.

[0384] D16 (16 g), 1,4-dioxane (164 g), and water (40 g) were added to reaction flask B. The internal temperature was controlled at 25±5°C, and the mixture was stirred and replaced with nitrogen bubbling.

[0385] Control the reaction flask temperature at 90±5°C. Add the solution in reaction flask B dropwise to reaction flask A. After complete addition, stir and react until complete, cool to below 50°C, allow to stand and separate, and concentrate the organic phase under reduced pressure to 6-7°C. Cool to 25±5°C, and slowly add a mixed solution of ethanol (120g) and water (304g) dropwise to the concentrated system. After the addition is complete, continue stirring for 2-4 hours, and filter. Wash the filter cake with water (200g). Add dichloromethane (240g) and water (200g) to the filter cake, stir until dissolved, and allow to separate. Collect the organic phase, extract the aqueous phase once with dichloromethane (120g), combine the organic phases, and wash once with water (200g). Add modified resin (2g) to the organic phase, stir at 20-30°C for 4-6 hours, filter, rinse with dichloromethane (40g), and concentrate the organic phase under reduced pressure to 3-4°C. Dichloromethane (240 g) was added again and the mixture was concentrated under reduced pressure to 3-4°C. Methyl tert-butyl ether (40 g) was added dropwise to the concentrated system, and the internal temperature was controlled at 30-36°C and stirred for 2 h. Methyl tert-butyl ether (240 g) was added dropwise for 3-4 h. After the addition was complete, n-heptane (240 g) was added dropwise for 3-4 h. The temperature was slowly lowered to 20-30°C and stirred for more than 9 h. The mixture was filtered, and the filter cake was rinsed with n-heptane (120 g). The filter cake was dried to obtain 41.50 g of compound D17 as an off-white powdery solid with a purity of 99.2% and a yield of 91.9%.

[0386] Example 35 Preparation of Compound D17

[0387] Compound D15 (500 g, 851 mmol), 1,4-dioxane (8272 g), and water (2000 g) were added to reaction flask A, the atmosphere was replaced with nitrogen, and the temperature was raised to 75-85°C before the addition of dipotassium hydrogen phosphate (355.8 g, 2042 mmol) and tetrakis(triphenylphosphine)palladium (19.7 g, 17 mmol). 1,4-dioxane (2060 g), water (500 g), and compound D16 (185.8 g, 1192 mmol) were added to reaction flask B, the atmosphere was replaced with nitrogen, and the mixture was stirred until dissolved. Control the temperature of reaction flask A at 75-85°C, add the solution in reaction flask B dropwise to reaction flask A three times, keep warm and stir for 30-60min after each addition, keep warm and stir at 75-85°C for 8-16h after completion of the addition, cool to 35-45°C, add acetic acid to adjust the pH to 5.5-6.5, then concentrate under reduced pressure to 4.5-5.5V, add 2-methyltetrahydrofuran (4315g) and 20% sodium chloride solution (3750g), stir, separate the organic phase, wash the aqueous phase with 2-methyltetrahydrofuran (2157g), combine the organic phases, add activated carbon (50g), keep warm and stir at 45-55°C for 30-60min, filter, and rinse the filter cake with 2-methyltetrahydrofuran (863g). The filtrate was combined, modified resin (50 g) was added, and the mixture was stirred at 45-55°C for 2.5-3.5 h, filtered, and the filter cake was rinsed with 2-methyltetrahydrofuran. The combined filtrate was concentrated under reduced pressure to 1.5-2.0 V, and concentrated twice with ethanol (1578 g) to 1.5-2.0 V. Ethanol (1184 g) was added, and the temperature was raised to 35-45°C. Water (2000 g) was added dropwise, and the mixture was stirred at 35-45°C for 1-2 h. The temperature was lowered to 0-10°C and stirred for 1-2 h. The mixture was filtered, and the filter cake was rinsed with ethanol (200 g). The mixture was dried to obtain 508 g of compound D17 as a brown solid with a yield of 90%.

[0388] Example 36 Preparation of Compound D18

[0389] Add compound D17 (360.0 g, 1.0 eq) and methanol (2.8 kg, 8 W) to a reactor. Add a 4 M solution of hydrogen chloride in dioxane (1.4 L, 10.0 eq) dropwise with stirring. Stir until dissolved. After reaction is complete, concentrate under reduced pressure. Add water (10 W) and dichloromethane (13 W). Separate the mixture, and wash the aqueous layer once with dichloromethane (6.5 W). Collect the aqueous layer, filter it through celite, and add N,N-dimethylformamide (1.1 W) and methyl tert-butyl ether (1.5 W). Adjust the pH to 7-8 by adding a 10% aqueous sodium carbonate solution dropwise at a temperature of 10-20°C. Add the solution over a 3-4 hour period. After the addition is complete, slowly add n-heptane (2.0 W) dropwise while maintaining the temperature at 10-20°C. Stir the mixture for 16-20 hours. The filter cake was filtered and rinsed once with water (2W). The filter cake was dried to obtain 309.05 g of compound D18 with a purity of 98.93% and a yield of 100%. 1 H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.44(d,J=4.9Hz,1H),8.41(s,1H),7.31-7 .14(m,2H),6.70(d,J=8.3Hz,1H),6.66(t,J=8.8Hz,1H),3.61(dd,J=8.2,4.8Hz,2 H),3.37(s,3H),3.02(dd,J=13.5,4.4Hz,2H),2.91(d,J=13.5Hz,1H),2.75(q,J=6 .8Hz,1H),2.63(dd,J=12.5,9.6Hz,2H),1.80(d,J=9.8Hz,3H),1.21-0.84(m,6H).

[0390] Example 37 Preparation of Compound D18

[0391] D17 (25 g), modified resin (1.25 g), and water (125 g) were added to reaction flask A, and stirring was started. The temperature was raised to 50-60°C, and concentrated hydrochloric acid (11.5 g) was added dropwise. The temperature was controlled at 50-60°C, and the reaction was stirred until the reaction was complete. The temperature was then lowered to 20-30°C, filtered, and the filter cake was washed with water (25 g). The filtrate was transferred to reaction flask A. 2-Methyltetrahydrofuran (100 g) was added, stirred, and allowed to stand for stratification. The organic phase was discarded, and the aqueous phase was washed once with methyl tert-butyl ether (100 g) and transferred to reaction flask A.

[0392] To reaction flask B, add water (100 g), potassium bicarbonate (15 g), DMF (35 g), and MTBE (37.5 g). Control the temperature at 10-20°C and slowly add the organic phase from reaction flask A dropwise to the system in reaction flask B over 2-4 hours. After the addition is complete, add n-heptane (50 g) dropwise to reaction flask B, cool to 10-20°C, filter, and rinse the filter cake with water (75 g). The filter cake is dried to yield 26.10 g of compound D18 with a purity of 99.3% and a yield of 100%, which is used directly in the next reaction.

[0393] Example 38 Preparation of Compound D18

[0394] Compound D17 (500 g, 754 mmol) and methanol (3955 g) were added to reaction flask A, and 4 M hydrogen chloride / 1,4-dioxane solution (1949 g, 7540 mmol) was added dropwise with stirring. The mixture was kept warm at 20-30°C and stirred for 1-2 h, and then concentrated under reduced pressure to 3V. Water (2500 g) was added to reaction flask A, and then concentrated under reduced pressure to 6V. Water (2500 g) and dichloromethane (6625 g) were added to reaction flask A, stirred and separated, the organic phase was discarded, and the aqueous phase was washed with dichloromethane (3250 g). The reaction mixture was filtered through diatomaceous earth three times, and the filter cake was washed with water (1500 g). The filtrate was transferred to reaction flask B and allowed to stand. The organic phase was separated and N,N-dimethylformamide (550 g), methyl tert-butyl ether (750 g) and n-heptane (1000 g) were added to reaction flask B. A 10% aqueous sodium carbonate solution (2500 g) was added dropwise to reaction flask B to adjust the pH to 7-8. The mixture was stirred at 10-20°C for 16-20 h and filtered. The filter cake was rinsed with water (1000 g) and then with n-heptane (700 g). The filter cake was dried to obtain 403.3 g of compound D18 as a yellow solid in a yield of 95%.

[0395] Example 39 Preparation of Compound of Formula I

[0396] Add compound D18 (300.0 g, 1.0 eq), tetrahydrofuran (1200 g, 4 W), and water (675 g, 2.25 W) to a reactor. While stirring and controlling the temperature at 0-10°C, add acryloyl chloride (60.0 g, 0.2 W) dropwise to the reactor and allow the reaction to complete. Add water (6 W) to the reaction mixture and extract twice with dichloromethane (15 W). The combined organic phases are washed once with a 5% aqueous sodium bicarbonate solution (6 W) and extracted once with water (6 W). The organic phase is concentrated under reduced pressure, and butanone is added to the concentrated crude product. Concentrate until the residual tetrahydrofuran and dichloromethane remain acceptable. After testing, maintain butanone (2.0 W) in the system and heat to 60-70°C with stirring for 0.5-1 hour. Cool to 35-40°C and stir for 1-2 hours. Control the temperature at 35-40°C and add methyl tert-butyl ether (0.8W). Maintain the temperature at 35-40°C with stirring for 2 hours. Continue to add methyl tert-butyl ether (4W) dropwise. After completion of the addition, maintain the temperature at 35-40°C with stirring for 2 hours. Cool to 15-20°C and maintain with stirring for 16-20 hours. Filter and rinse the filter cake with methyl tert-butyl ether. Dry the filter cake to obtain 275.18 g of compound I with a purity of 99.54% and a yield of 84.96%.

[0397] Add the compound of Formula I (270.0 g, 1.0 eq) obtained in the above step and dichloromethane (1430.0 g, 5.3 W) to a reaction kettle. After addition, stir at 35-45°C for 6-10 h. Cool to 0-8°C and stir at 0-8°C for 16-20 h. Filter, and rinse the filter cake once with dichloromethane (1.3 W) at 0-8°C. Dry the filter cake to yield 248.46 g of the compound of Formula I with a purity of 99.65% and a yield of 94.74%.

[0398] Example 40 Preparation of Compound of Formula I

[0399] Add D18 (20 g), THF (80 g), and water (38.9 g) to the reaction flask, start stirring, and cool to 5±5°C. Slowly add acryloyl chloride (4 g) dropwise. After the addition is complete, allow to react at 5±5°C until complete. Add water (120 g) to the reaction mixture and stir for 2 h. Add dichloromethane (300 g), stir, and allow to stand to separate. Separate the organic phase, and extract the aqueous phase once with dilute hydrochloric acid (200 g water + 3.4 g concentrated hydrochloric acid), once with sodium bicarbonate solution (114 g water + 6 g sodium bicarbonate), and once with water (120 g). Concentrate the organic phase twice with butanone (88 g) to 3.5-4.5 V. Heat to 60-70°C and stir for 1-2 h. Cool to 30-38°C, add seed crystals of the compound of Formula I (0.02 g), and stir for 1-2 hours. Maintain the temperature at 30-38°C and add methyl tert-butyl ether (16 g) dropwise over 5-6 hours. After the addition is complete, maintain the temperature at 30-38°C and stir for 2-4 hours. Cool to 15-25°C, stir at 5-25°C for 3-10 hours, filter, and wash the filter cake with methyl tert-butyl ether. Filter and dry to obtain 18.24 g of the crude compound of Formula I (yield: 83.2%).

[0400] Add crude compound of Formula I (50 g), dichloromethane (2500 g), and activated carbon (0.5 g) to a reaction flask and stir at 35-45°C for 2-4 hours. Cool to 20-30°C and filter. Rinse the filter cake with dichloromethane. Concentrate the filtrate under reduced pressure to 4-5°C. After concentration, heat to 35-45°C, maintain at 35-45°C, and stir for 6-10 hours. Cool to 2-10°C, maintain at 2-10°C, and stir for 6-10 hours. Filter and wash the filter cake with pre-cooled (0-8°C) dichloromethane (66.5 g). Dry the wet product to yield 45 g of compound of Formula I, yield: 90%.

[0401] Comparative Example 1 Preparation of Compound of Formula I

[0402] Step 1: Suspend 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) in a mixture of 1,4-dioxane (120 mL) and water (120 mL). Slowly add concentrated sulfuric acid (120 mL). Stir at 120°C for 36 hours. Pour the cooled reaction mixture into 200 mL of ice water, adjust the pH to 2-3 with sodium carbonate, and extract with ethyl acetate (1000 mL x 2). Combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and vacuum-dry the filtrate to obtain 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridine-2(1H)-one (24 g, yield: 85.7%) as a light brown solid. ES-API:[M+H] + =364.1.

[0403] Step 2: 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16 g, 8.705 mmol) was dissolved in acetic acid (15 mL). Sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added sequentially. The reaction was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL of ice water. The precipitated solid was filtered, and the filter cake was washed with 20 mL of ice water and dried under vacuum to obtain the product, 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, yield: 92%), as a yellow solid. ES-API: [M+H] + =409.1.

[0404] Step 3: To a 100 mL three-necked round-bottom flask, add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.5 g, 8.570 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8 g, 34.10 mmol), tetrakistriphenylphosphine palladium (1.15 g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL of water, and 40 mL of dioxane. Under nitrogen, stir at 100°C for 2-3 hours. After completion of the reaction, cool the reaction mixture to room temperature, add 80 mL of water and 100 mL of methyl tert-butyl ether, and extract once. The aqueous phase was adjusted to pH 3-5 with 1M hydrochloric acid solution and extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum to obtain the product, 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.5 g, crude), as a light yellow solid. ES-API: [M+H] + =499.1.

[0405] Step 4: 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (4.6 g, 8.57 mmol) was dissolved in acetonitrile (30 mL). Phosphorus oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropylethylamine (10.5 g, 81.24 mmol) were added sequentially. The reaction mixture was gradually heated to 80°C and stirred for 30 minutes. The reaction solution was concentrated, 30 mL of cold acetonitrile was added, and the mixture was added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath. The mixture was extracted with ethyl acetate (200 mL x 2). The ethyl acetate phases were combined and washed once with 200 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic phase was dried and concentrated. The crude product was then purified by flash silica gel column chromatography (EtOAc / PE: 0-50%) to give 4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (3.05 g, yield: 76%) as a yellow solid. ES-API: [M+H] + =517.2.

[0406] Step 5: 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL). 1-(tert-butyl)-3-methyl(R)-piperazine-1,3-dicarboxylate (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol) were added sequentially. The reaction mixture was stirred at 120°C for 2 hours. 80 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed three times with 80 mL of saturated brine. The ethyl acetate phase was dried and concentrated, and the crude product was purified on a flash silica gel column (EtOAc / PE: 0-80%) to obtain 1-(tert-butyl) 3-methyl (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, yield: 77%) as a yellow solid. ES-API: [M+H] + =725.2.

[0407] Step 6: 1-(tert-Butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), iron powder (835 mg, 14.91 mmol) was added, and the reaction was stirred at 80 °C for 30 minutes. The reaction mixture was concentrated, and 200 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate were added sequentially. The suspension was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was separated and washed sequentially with 100 mL of saturated sodium bicarbonate and 150 mL of saturated brine. The mixture was dried and concentrated to give (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (2.70 g, crude) as a yellow solid. ES-API: [M+H]+ = 663.2.

[0408] Step 7: To a 150 mL sealed tube, tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (2.7 g, 3.728 mmol), 30 mL of acetone, anhydrous potassium carbonate (2.2 g, 15.94 mmol), and iodomethane (5.4 g, 38.03 mmol) were added in sequence. The tube was sealed and the reaction was stirred at 55°C for 18 hours. The reaction mixture was added with 150 mL of ethyl acetate, washed three times with 100 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-80%) to obtain (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (2.2 g, yield: 87%) as a yellow solid. ES-API: [M+H] + =677.2.

[0409] Step 8: Tert-butyl (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (517 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to give the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (530 mg, crude product), which was used directly in the next reaction. ES-API: [M+H] + =577.2.

[0410] Step 9: (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (530 mg, 0.7549 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (3.0 mL, 21.62 mmol) was added. The reaction mixture was cooled to 0°C and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise. The reaction was stirred at 0°C for 15 minutes. 80 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of saturated aqueous NaHCO₃ and 80 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (EtOAc / PE: 0-60%) to obtain (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, yield: 59%) as a yellow solid. ES-API: [M+H] + =631.2.

[0411] Step 10: In an ice-water bath, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (280 mg, 0.444 mmol) was added to dry dichloromethane (6.0 mL), and then boron tribromide (5.0 mL, 5.0 mmol) was added. The mixture was warmed to room temperature and reacted overnight. Under ice-water bath conditions, the reaction solution was added dropwise to a saturated sodium bicarbonate solution, extracted twice with dichloromethane (80 mL), dried, and concentrated. The crude product was purified by flash silica gel column chromatography (EtOAc / PE: 0-60%) to give (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione (233 mg, yield: 85%).

[0412] Step 11: The compound (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione was separated by preparative chiral HPLC (column type: IA: 10 μm, 30*250 mm, mobile phase: hexane:EtOH=60:40, flow rate: 25 ml / min, column temperature) to obtain: an atropisomer compound of formula I (76.8 mg, peak 1, retention time 2.531 min, yield: 34%). 1 H NMR (500MHz, DMSO-d6) δ10.03(d,J=18.4Hz,1H),8.52(d,J=7.3Hz,1H),8.43(d,J=4.7Hz,1H),7.23(d,J=9.6Hz,2H) ,7.08(dd,J=16.6,10.5Hz,1H),6.74-6.62(m,2H),6.15(d,J=16.8Hz,1H),5.75(d,J=10.7Hz,1H),4.73(d,J=14.2H z,1H),4.46(d,J=12.9Hz,1H),4.00(s,1H),3.61(d,J=10.0Hz,1H),3.51(s,1H),3.34(s,3H),3.22(s,1H),2.64(t, J=11.5Hz,1H),2.48-2.42(m,1H),1.98(d,J=5.1Hz,3H),1.03(t,J=6.9Hz,3H),0.86(t,J=7.9Hz,3H).ES-API:[M+H] + =617.2; and another atropisomer compound (70 mg, peak 2, retention time 3.683 min, yield: 31%). 1H NMR (500MHz, CDCl3) δ8.64-8.59(m,1H),8.35(s,1H),8.07(s,1H),7.27-7.20(m,2H),7.14-7.02(m, 1H),6.75-6.63(m,2H),6.39(dd,J=17.0,2.0Hz,1H),5.88-5.77(m,1H),4.91(d,J=14.0Hz,1H),4.8 3(d,J=13.0Hz,1H),3.72-3.58(m,2H),3.50(s,3H),3.43(d,J=12.0Hz,1H),3.16(t,J=13.0Hz,1H), 2.91(t,J=12.0Hz,1H),2.82-2.73(m,1H),1.93(s,3H),1.24(d,J=7.0Hz,3H),1.12(d,J=7.0Hz,3H). ES-API:[M+H] + = 617.2. The isomers were detected by analytical chiral HPLC (column type: IA: 5 μm, 4.6*150 mm, mobile phase: hexane:EtOH=60:40, flow rate: 1 ml / min, column temperature=30°C).

[0413] The preparation method uses 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a starting material, which is difficult to purchase on a large scale. The products of steps 4, 5, 7, 9, and 10 need to be purified using silica gel column chromatography. In addition, the final product is chiral and needs to be separated by chirality, resulting in high material consumption. The preparation method is a small-scale laboratory preparation and is not suitable for large-scale industrial production.

[0414] In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing compound D9, comprising the following steps: Step D: Compound D6 is subjected to a ring-closing reaction in the presence of a base, and then subjected to a resolution reaction with a chiral resolution agent to obtain compound D8; Step E: Compound D8 is freed from the chiral resolution agent to obtain compound D9; Wherein, M is a chiral resolution agent; R is a chiral auxiliary group.

2. The preparation method according to claim 1, wherein R is a chiral auxiliary group, preferably selected from and / or the chiral resolution agent M is selected from one or more of D-(+)-di-p-methylbenzoyltartaric acid, N-acetyl-L-phenylalanine, L-(-)-dibenzoyltartaric acid, riboflavin, L-camphorsulfonic acid, glutamic acid, L-tartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid, D-glycine, D-mandelic acid, R-methoxy-trifluoromethylphenylacetic acid, L-aspartic acid, D-(+)-dibenzoyltartaric acid, L-pyroglutamic acid and R-binaphthol phosphate; Preferably, the chiral resolution agent M is selected from one or more of D-(+)-di-p-methylbenzoyltartaric acid, L-camphorsulfonic acid, L-tartaric acid, R-binaphthol phosphate and D-(+)-dibenzoyltartaric acid; More preferably, the chiral resolution agent M is R-binaphthol phosphate.

3. The preparation method according to claim 1 or 2, wherein The compound D9 is used to prepare a compound of formula I: or used for preparing any one or a combination thereof selected from Compound D10, Compound D13, Compound D14, Compound D15, Compound D17 and Compound D18; Preferably, the compound D10, compound D13, compound D14, compound D15, compound D17 and compound D18 are used alone or in any combination thereof to prepare the compound of formula I.

4. The preparation method according to claim 3, wherein The preparation method of the compound D10 comprises the following steps: Step F: Compound D9 is subjected to nitration reaction to obtain compound D10; And / or the preparation method of the compound D13 comprises the following steps: Step G: Substituting the hydroxyl group in compound D10 to obtain compound D13; Preferably, the method for replacing the hydroxyl group in compound D10 is: compound D10 undergoes an esterification reaction with sulfonic anhydride or sulfonyl halide, and then undergoes a substitution reaction with compound D12 to obtain compound D13; And / or the preparation method of the compound D14 comprises the following steps: Step H: Compound D13 is reacted in the presence of a reducing agent to obtain compound D14; Preferably, the reducing agent is sodium dithionite; Preferably, in the presence of a reducing agent, the compound D13 undergoes reduction and cyclization reaction to obtain compound D14; And / or the preparation method of the compound D15 comprises the following steps: Step I: Compound D14 reacts with a methylating agent to obtain compound D15; And / or the preparation method of the compound D17 comprises the following steps: Step J: Compound D15 and compound D16 undergo coupling reaction to obtain compound D17; Wherein, X is a group that can undergo coupling reaction with the chlorine substituent at the N-ortho position on the naphthyridine ring; And / or the preparation method of the compound D18 comprises the following steps: Step K: Compound D17 is debonded to obtain compound D18; And / or the preparation method of the compound of formula I comprises the following steps: Step L: Compound D18 is reacted with an acylating agent to obtain a compound of formula I; 5. The preparation method according to any one of claims 1 to 4, wherein: The preparation method of the compound D6 comprises the following steps: Step C: Compound D4 and compound D5 undergo condensation reaction to obtain compound D6; Wherein, R is a chiral auxiliary group; preferably selected from 6. The preparation method according to claim 5, wherein: The preparation method of the compound D4 comprises the following steps: Step B: Compound D3 reacts with a chlorinating agent to obtain compound D4; Preferably, the chlorination agent is selected from one or more of N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or chlorine; Preferably, the molar ratio of the chlorination reagent to compound D3 is (0.5-2):

1.

7. The preparation method according to claim 6, wherein: The preparation method of the compound D3 comprises the following steps: Step A: Compound D1 undergoes a substitution reaction with compound D2 to obtain compound D3; 8. The preparation method according to claim 7, wherein: The feed equivalent ratio of the compound D1 to the compound D2 is (0.5-2):1; Preferably, the substitution reaction The method comprises the following steps: in a solvent, compound D1 is mixed with a base to obtain a reserve solution 1, and compound D2 is mixed with a base to obtain a reserve solution 2; the reserve solution 1 is contacted with the reserve solution 2 to react to obtain compound D3; Alternatively, compound D1 is mixed with a base in a solvent, and compound D2 is added to react to obtain compound D3; Preferably, the base is selected from one or more of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, lithium diisopropylamide, isopropylmagnesium chloride, n-butyllithium and tert-butyllithium; Preferably, the solvent is an ether solvent; Preferably, the feed equivalent ratio of the base, compound D1 and D2 is (1.5-4):1:

1.

9. The preparation method according to claim 5, wherein: The preparation method of the compound D5 comprises the following steps: Compound SM1 undergoes an ester exchange reaction with a chiral alcohol to obtain compound D5; Wherein, R is a chiral auxiliary group; preferably selected from Preferably, the feed equivalent ratio of the chiral alcohol to the compound SM1 is (1-3):

1.

10. The preparation method according to claim 3, wherein: The preparation method of the compound of formula I comprises the following steps: Step A: Compound D1 undergoes a substitution reaction with compound D2 to obtain compound D3; Further, step B: compound D3 reacts with a chlorinating agent to obtain compound D4; Further, step C: compound D4 and compound D5 are subjected to condensation reaction to obtain compound D6; Wherein, R is a chiral auxiliary group; preferably selected from Further, step D: compound D6 undergoes a ring-closing reaction in the presence of a base, and then undergoes a resolution reaction with a chiral resolution agent M to obtain compound D8; Further, step E: compound D8 is freed from chiral resolving agent M to obtain compound D9; Further, step F: compound D9 is subjected to nitration reaction to obtain compound D10; Further, step G: replacing the hydroxyl group in compound D10 to obtain compound D13; Further, step H: compound D13 reacts in the presence of a reducing agent to obtain compound D14; Further, step I: compound D14 reacts with a methylating agent to obtain compound D15; Further, step J: compound D15 and compound D16 are subjected to coupling reaction to obtain compound D17; Wherein, X is a group that can undergo coupling reaction with the chlorine substituent at the N-ortho position on the naphthyridine ring; Further, step K: compound D17 is freed from the Boc group to obtain compound D18; Further, step L: compound D18 reacts with an acylating agent to obtain a compound of formula I; The acylating agent is selected from acrylic anhydride or acryloyl chloride.

11. The following compound or a pharmaceutically acceptable salt thereof: in, R is a chiral auxiliary group; preferably selected from M is selected from D-(+)-di-p-methylbenzoyltartaric acid, N-acetyl-L-phenylalanine, L-(-)-dibenzoyltartaric acid, riboflavin, L-camphorsulfonic acid, glutamic acid, L-tartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid, D-glycine, D-mandelic acid, R-methoxy-trifluoromethylphenylacetic acid, L-aspartic acid, D-(+)-dibenzoyltartaric acid, L-pyroglutamic acid or R-binaphthol phosphate.

12. Use of the compound according to claim 11 or a pharmaceutically acceptable salt thereof in the preparation of a KRAS inhibitor.

13. Use of the compound according to claim 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer; Preferably, the cancer is a cancer associated with KRAS gene mutation.