Preparation method of pyridopyrimidinone compound

Abstract

The invention relates to a preparation method of a pyridopyrimidone compound, which comprises the following reactions: # imgabs0, wherein R1, R2 and R3 are independently selected from F or Cl, R4 is selected from methyl, ethyl, propyl and isopropyl, and X is O or S; comprising the following steps: (1) carrying out acylation reaction on a compound A and an acylation reagent in an organic solvent to obtain a compound B; (2) reacting the compound B with O-alkyl isourea salt or S-alkyl isothiourea salt under the condition of organic alkali to obtain a compound C; and (3) carrying out cyclization on the compound C in an organic solvent under an alkaline condition to obtain a compound D. The method is short in process route, mild in condition, simple to operate, high in yield and simple in post-treatment; a plurality of brand-new intermediates are obtained in the synthesis process, and the intermediates are stable in property, good in reproducibility, high in yield and easy to realize industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing a pyridopyrimidone compound, and belongs to the field of drug intermediate synthesis. Background Art

[0002] RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignant tumors are related to mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, among which KRAS mutations are the most common, accounting for about 85%. KRAS mutations are common in solid tumors, and high-frequency mutations exist in the three major fatal human cancers: lung cancer (17%), colorectal cancer (33%) and pancreatic cancer (61%). Among the KRAS gene mutations, 97% are mutations in the 12th or 13th amino acid residues, among which G12D is an important mutation. KRAS G12D inhibitors have good development prospects.

[0003] Pyridopyrimidinone compounds are important intermediates for the synthesis of KRAS G12D inhibitors; the structure is shown below:

[0004]

[0005] Wherein R1, R2, R3 are each independently selected from F or Cl, R4 is selected from methyl, ethyl, propyl, isopropyl, and X is O or S.

[0006] Hengrui Medicine's patent CN118221699A discloses that 4-amino-2,6-dichloropyridine is used as the starting material, and fluorination, substitution-rearrangement, hydrolysis, amidation, and ring closure are used to prepare a pyridopyrimidone compound; the total yield of the five steps is low at only 6.3%, and this method is not conducive to industrial scale-up. The preparation method is as follows:

[0007]

[0008] Lingda Bio's patent CN117800976A discloses that 4-amino-2,6-dichloropyridine is used as the starting material, and fluorination, substitution, rearrangement, hydrolysis, esterification, substitution, and ring closure are used to prepare a pyridopyrimidone compound; the total yield of the 7 steps is only 8.4%. The method route is long and is not conducive to industrial scale-up. The preparation method is as follows:

[0009]

[0010] In the patent CN115557974A of Shanghai Dino Pharmaceutical Technology, 4-amino-2,6-dichloropyridine is used as the starting material, and pyridopyrimidone compounds are obtained through fluorination, iodination, carbonyl insertion, amidation, and ring closure. The total yield is only 18.4%, which is not conducive to industrial scale-up. The preparation method is as follows:

[0011]

[0012] In the patent WO2023030385A1 of Jinfang Pharmaceutical Technology (Shanghai) Co., Ltd., 2,6-dichloro-5-fluoronicotinic acid is used as the starting material, and thioester is obtained through bromination, amidation, and ring closure. The total yield is only 13.4%, and the yield of the two-step amidation is only 29.8%. This method is not conducive to industrial scale-up. Its preparation method is as follows:

[0013] Summary of the invention

[0014] In view of the defects of the prior art, the present invention provides a method for preparing a pyridopyrimidone compound. The intermediate prepared by the method is simple, efficient and high in yield, which greatly reduces the cost and is conducive to large-scale commercial production.

[0015] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0016] The first aspect of the present invention provides a method for preparing compound C, the reaction is as follows:

[0017]

[0018] Wherein R1, R2, R3 are each independently selected from F or Cl, R4 is selected from methyl, ethyl, propyl, isopropyl, and X is O or S;

[0019] The steps include:

[0020] Step (1): Compound A and an acylating agent are reacted in an organic solvent to obtain compound B;

[0021] Step (2): Compound B reacts with O-alkyl isourea salt or S-alkyl isothiourea salt under organic base conditions to obtain compound C.

[0022] As a further improvement of the present invention, including but not limited to, the acylation reaction in step (1) comprises: compound A and an acylation agent are subjected to an acylation reaction in an organic solvent in the presence of a catalyst to obtain compound B.

[0023] As a further improvement of the present invention, including but not limited to, the catalyst for the acylation reaction in step (1) is selected from DMF.

[0024] As a further improvement of the present invention, including but not limited to, the acylating agent in step (1) is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride, preferably oxalyl chloride.

[0025] As a further improvement of the present invention, including but not limited to, the molar ratio of compound A to catalyst in step (1) is 1:(0.01-0.1), preferably 1:(0.03-0.06).

[0026] As a further improvement of the present invention, including but not limited to, the molar ratio of compound A to acylating agent in step (1) is 1:(1.1-2.5), preferably 1:(1.3-1.6).

[0027] As a further improvement of the present invention, including but not limited to, the organic solvent in step (1) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, dimethyl sulfoxide, preferably dichloromethane.

[0028] As a further improvement of the present invention, including but not limited to, the volume amount of the organic solvent in step (1), mL, is 3 to 20 times, preferably 3 to 15 times, the mass amount of compound A, g.

[0029] As a further improvement of the present invention, including but not limited to, the reaction temperature of the acylation reaction in step (1) is 20 to 55°C, preferably 25 to 50°C.

[0030] As a further improvement of the present invention, including but not limited to, the reaction time of the acylation reaction in step (1) is 0.2 to 3 hours, preferably 0.5 to 1.5 hours.

[0031] As a further improvement of the present invention, including but not limited to, the post-treatment method of step (1) is distillation and concentration after the reaction is completed; or further using an organic solvent for distillation, the organic solvent is not limited, for example, using DCM for distillation 1 to 6 times, 1 to 4 times, for example, 1 time, 2 times, 3 times or 4 times.

[0032] As a further improvement of the present invention, including but not limited to, the O-alkyl isourea salt in step (2) is selected from O-methyl isourea hydrochloride, O-methyl isourea sulfate, O-methyl isourea acetate, O-methyl isourea hydrobromide, O-ethyl isourea hydrochloride, O-ethyl isourea sulfate, O-ethyl isourea acetate, O-ethyl isourea hydrobromide, O-isopropyl isourea hydrochloride, O-isopropyl isourea sulfate, O-isopropyl isourea acetate, O-propyl isourea hydrochloride, O-propyl isourea hydrogensulfate, preferably O-methyl isourea hydrochloride.

[0033] As a further improvement of the present invention, including but not limited to, the S-alkyl isothiourea in step (2) is selected from one of S-methyl isothiourea hemisulfate, S-methyl isothiourea sulfate, S-methyl isothiourea hydrochloride, S-methyl isothiourea hydrogen bromide, S-methyl isothiourea hydrogen iodide, S-ethyl isothiourea sulfate, S-ethyl isothiourea hydrochloride, S-ethyl isothiourea hydrogen bromide, S-ethyl isothiourea hydrogen iodide, S-isopropyl isothiourea sulfate, S-isopropyl isothiourea hydrochloride, S-isopropyl isothiourea hydrogen bromide, S-isopropyl isothiourea hydrogen iodide, S-propyl isothiourea hydrochloride, S-propyl isothiourea hydrogen bromide, and S-propyl isothiourea hydrogen iodide.

[0034] As a further improvement of the present invention, including but not limited to, the molar ratio of compound A to O-alkyl isourea salt or S-alkyl isothiourea salt in step (2) is 1:(1.1-2.5), preferably 1:(1.1-1.5).

[0035] As a further improvement of the present invention, including but not limited to, the organic base in step (2) is selected from one or more of triethylamine, diisopropylethylamine, and pyridine, preferably diisopropylethylamine and triethylamine.

[0036] As a further improvement of the present invention, including but not limited to, the organic solvent in step (2) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and dimethyl sulfoxide, preferably acetonitrile.

[0037] As a further improvement of the present invention, including but not limited to, the volume amount of the organic solvent in step (2), mL, is 3 to 20 times, preferably 3 to 15 times, the mass amount of compound A, g.

[0038] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (2) is 10 to 30°C, preferably 15 to 25°C.

[0039] As a further improvement of the present invention, including but not limited to, the reaction time of step (2) is 5 to 24 hours, preferably 15 to 20 hours.

[0040] The second aspect of the present invention provides a method for preparing compound D, the reaction is as follows:

[0041]

[0042] The steps include:

[0043] Step (1): Compound A and an acylating agent are reacted in an organic solvent to obtain compound B;

[0044] Step (2): Compound B reacts with O-alkyl isourea salt or S-alkyl isothiourea salt under organic base conditions to obtain Compound C;

[0045] Step (3): Compound C is subjected to ring closure under alkaline conditions in an organic solvent to obtain Compound D;

[0046] Wherein R1, R2, R3, R4, and X substituents are as defined in the first aspect above;

[0047] The preparation methods of steps (1) to (2) are as described above in the first aspect of the present invention.

[0048] As a further improvement of the present invention, including but not limited to, the alkaline reagent in step (3) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably cesium carbonate and potassium phosphate.

[0049] As a further improvement of the present invention, including but not limited to, the molar ratio of compound C to the alkaline agent in step (3) is 1:(1.01-3), preferably 1:(2-3).

[0050] As a further improvement of the present invention, including but not limited to, the organic solvent in step (3) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, preferably N,N-dimethylformamide, N,N-dimethylacetamide.

[0051] As a further improvement of the present invention, the volume amount of the organic solvent in step (3) is 6 to 30 times, preferably 8 to 25 times, the mass amount of compound C.

[0052] As a further improvement of the present invention, the reaction temperature in step (3) is 20 to 55°C, preferably 30 to 50°C.

[0053] As a further improvement of the present invention, the reaction time of step (3) is 5 to 24 hours, preferably 15 to 20 hours.

[0054] The third aspect of the present invention provides a method for preparing compound E, the reaction is as follows:

[0055]

[0056] Wherein R1, R2, R3, R4, and X substituents are as defined in the first aspect above;

[0057] The steps include:

[0058] Step (4): In a solvent, the compound D prepared in the second aspect is subjected to a hydrolysis reaction under acidic conditions to obtain a compound E.

[0059] As a further improvement of the present invention, including but not limited to, the acid for the hydrolysis reaction in step (4) is selected from one or more of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid.

[0060] As a further improvement of the present invention, including but not limited to, the volume amount mL of the acid in the hydrolysis reaction of step (4) is 1 to 8 times the mass amount g of compound D, preferably 3 to 5 times.

[0061] As a further improvement of the present invention, including but not limited to, the solvent in step (4) is selected from one or more of the organic solvents selected from ethyl acetate, ether, dichloromethane, tetrahydrofuran, toluene, water, and dioxane, preferably water.

[0062] As a further improvement of the present invention, the volume amount of the solvent in the hydrolysis reaction of step (4) is 0.5 to 5 times the mass amount of compound D in g, preferably 0.8 to 1.5 times.

[0063] As a further improvement of the present invention, the reaction temperature in step (4) is 10 to 45°C, preferably 15 to 30°C.

[0064] As a further improvement of the present invention, the reaction time of step (4) is 5 to 24 hours, preferably 10 to 20 hours.

[0065] The fourth aspect of the present invention provides a new key intermediate compound C1 and compound D1, the structures of which are as follows:

[0066]

[0067] Wherein R1, R2, R3, R4 substituents are defined as described in the first aspect above;

[0068] As a further improvement of the present invention, the compound structure is as follows:

[0069]

[0070] The fifth aspect of the present invention further provides a method for preparing a KRAS G12D inhibitor, comprising preparing compound D using the method for preparing compound D according to the second aspect of the present invention, further preparing compound E from compound D, and further preparing a KRAS G12D inhibitor from compound E.

[0071] Beneficial technical effects of the present invention:

[0072] 1) The present invention uses 4-bromo-2,6-dichloro-5-fluoronicotinic acid as a starting material, and prepares compound E through amidation, ring closure, and hydrolysis, avoiding the use of toxic reagents and metal catalysts, with a total yield of 59.2% and a purity of up to 99.5%. Compared with the synthetic method for preparing compound E in the prior art, the yield is increased by 40% to 52.8%, greatly reducing the production cost;

[0073] 2) The second step of the present invention uses an organic base reaction, which increases the yield by about 50% compared with the condition using NaHCO3 reported in the prior art, greatly reducing the production cost;

[0074] 3) The process route of the present invention obtains multiple new intermediates during the synthesis process, and the intermediates have stable properties and good reproducibility. The preparation method is simple to operate, has a high yield, good product quality, and is easy to realize industrial production;

[0075] 4) The process route of the present invention is short, the conditions are mild, the operation is simple, the yield is high, the post-treatment is simple, and the product can be obtained only by a pulping purification method, which reduces "three wastes" and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 The product obtained in Example 1 of the present invention 1 H-NMR spectrum.

[0077] Figure 2 The product obtained in Example 1 of the present invention 19 F-NMR spectrum.

[0078] Figure 3 The product obtained by Example 2 of the present invention 1 H-NMR spectrum.

[0079] Figure 4 The product obtained by Example 2 of the present invention 19 F-NMR spectrum.

[0080] Figure 5 The product obtained by Example 3 of the present invention 1 H-NMR spectrum.

[0081] Figure 6 The product obtained by Example 3 of the present invention 19 F-NMR spectrum.

[0082] Figure 7 The HPLC spectrum of the product obtained in Example 3 of the present invention.

[0083] Figure 8 The LCMS spectrum of the product obtained in Example 3 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0084] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0085] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0086] Example 1: Preparation of Compound C-1

[0087]

[0088] Compound A-1 (3kg, 10.38mol) was dissolved in DCM (9L), followed by the addition of DMF (37.95g, 519.24mmol) and oxalyl chloride (1.34L, 15.58mol), and then the temperature was raised to 35-45°C for reaction for 1h. Direct concentration was performed, followed by distillation with DCM twice, and after concentration to dryness, the mixture was dissolved in MeCN. O-methylisourea hydrochloride (1.38kg, 12.46mol) was dissolved in MeCN (12L) and the temperature was controlled below 25°C, followed by the addition of DIPEA (4.52L, 25.96mol), and the above-mentioned acyl chloride solution was slowly added dropwise for reaction for 18h. The solution was concentrated to a volume of about 6L, H2O was added for slurrying, filtration was performed, and drying was performed to obtain solid compound C (3kg, yield 83.8%). 1 H-NMR spectrum Figure 1 As shown, 19 F-NMR spectrum Figure 2 shown.

[0089] 1 H NMR (400MHz, DMSO) δ8.97(s,1H),8.77(s,1H),3.75(s,3H); 19 F NMR(377MHz, DMSO)δ-114.56(s).MS:[M+1]=343.8.

[0090] Example 2: Preparation of Compound D

[0091]

[0092] Compound C-1 (2.8 kg, 8.117 mol) was dissolved in DMAc (56 L), Cs2CO3 (6.61 kg, 20.29 mol) was added, and the temperature was raised to 35-45°C for reaction for 18 hours. The mixture was cooled and filtered, H2O was added to the filtered solid and stirred, and HCl was added to adjust the pH to 6-8, filtered, dried, slurried with DCM, filtered, and dried to obtain compound D-1 (1.7 kg, yield 79.3%). 1 H-NMR spectrum Figure 3 As shown, 19 F-NMR spectrum Figure 4 shown.

[0093] 1 H NMR (400MHz, DMSO) δ4.03 (s, 3H); 19 F NMR(377MHz,DMSO)δ-135.89(s).MS:[M+1]=263.9.

[0094] Example 3: Preparation of Compound E-1

[0095]

[0096] Compound D-1 (1.6 kg, 6.06 mol) was added to H2O (1.6 L) and stirred. Then 12N HCl (4.8 L) was added and reacted at 15-30°C for 18 hours. The filter cake was slurried with ethyl acetate, filtered and dried to obtain compound E-1 (1.35 kg, yield 89.1%, HPLC purity 99.53%, retention time RT = 9.659). 1 H-NMR spectrum Figure 5 As shown, 19 F-NMR spectrum Figure 6 As shown, the HPLC spectrum is as Figure 7 As shown, the LCMS spectrum is as Figure 8 shown.

[0097] 1 H NMR (400MHz, DMSO) δ12.18(s,1H),11.76(s,1H); 19 F NMR (377MHz, DMSO) δ-137.23 (s). [M+1] = 249.9.

Claims

1. A method for preparing compound C, the reaction formula is as follows: Wherein R1, R2, R3 are each independently selected from F or Cl, R4 is selected from methyl, ethyl, propyl, isopropyl, and X is O or S; The steps include: Step (1): In an organic solvent, compound A is subjected to an acylation reaction with an acylating agent to obtain compound B; Step (2): Compound B reacts with O-alkyl isourea salt or S-alkyl isothiourea salt under organic base conditions to obtain compound C.

2. A method for preparing compound D, the reaction formula is as follows: Wherein R1, R2, R3, R4, and X are the same as those defined in claim 1; The steps include: Step (1): Compound A and an acylating agent are reacted in an organic solvent to obtain compound B; Step (2): Compound B reacts with O-alkyl isourea salt or S-alkyl isothiourea salt under organic base conditions to obtain Compound C; Step (3): Compound C is subjected to ring closure under alkaline conditions in an organic solvent to obtain compound D.

3. The preparation method according to claim 1 or claim 2, characterized in that: The acylation reaction in step (1) comprises: in an organic solvent, compound A and an acylating agent are subjected to an acylation reaction in the presence of a catalyst to obtain compound B; The step (1) further satisfies one or more of the following conditions: And / or, the acylation reaction catalyst in step (1) is selected from DMF; And / or, the acylating agent in step (1) is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride, preferably oxalyl chloride; And / or, in step (1), the molar ratio of compound A to catalyst is 1:(0.01-0.1), preferably 1:(0.03-0.06); And / or, the molar ratio of compound A to acylating agent in step (1) is 1:(1.1-2.5), preferably 1:(1.3-1.6); and / or, the organic solvent in step (1) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and dimethyl sulfoxide, preferably dichloromethane; And / or, the volume of the organic solvent in step (1) is 3 to 20 times, preferably 3 to 15 times, the mass of compound A in g; And / or, the reaction temperature of the acylation reaction in step (1) is 20 to 55° C., preferably 25 to 50° C.; And / or, the reaction time of the acylation reaction in step (1) is 0.2 to 3 hours, preferably 0.5 to 1.5 hours; And / or, the post-treatment method of step (1) is to distill and concentrate after the reaction is completed; or further use an organic solvent for distillation, the organic solvent is not limited, for example, use DCM for distillation 1 to 6 times, 1 to 4 times, for example, 1 time, 2 times, 3 times or 4 times.

4. The preparation method according to claim 1 or claim 2, characterized in that: The organic base in step (2) is selected from one or more of triethylamine, diisopropylethylamine and pyridine, preferably diisopropylethylamine and triethylamine.

5. The preparation method according to claim 1 or claim 2, characterized in that: The O-alkyl isourea salt in step (2) is selected from O-methyl isourea hydrochloride, O-methyl isourea sulfate, O-methyl isourea acetate, O-methyl isourea hydrobromide, O-ethyl isourea hydrochloride, O-ethyl isourea sulfate, O-ethyl isourea acetate, O-ethyl isourea hydrobromide, O-isopropyl isourea hydrochloride, O-isopropyl isourea sulfate, O-isopropyl isourea acetate, O-propyl isourea hydrochloride, One of O-propylisourea hydrogen sulfate, preferably O-methylisourea hydrochloride; The step (2) also satisfies one or more of the following conditions: And / or, the S-alkylisothiourea of ​​step (2) is selected from S-methylisothiourea hemisulfate, S-methylisothiourea sulfate, S-methylisothiourea hydrochloride, S-methylisothiourea hydrogen bromide, S-methylisothiourea hydrogen iodide, S-ethylisothiourea sulfate, S-ethylisothiourea hydrochloride, S-ethylisothiourea hydrogen bromide, S-ethylisothiourea hydrogen iodide, S-isopropylisothiourea sulfate, S-isopropylisothiourea hydrochloride, S-isopropylisothiourea hydrogen bromide, S-isopropylisothiourea hydrogen iodide, S-propylisothiourea hydrochloride, S-propylisothiourea hydrogen bromide, S-propylisothiourea hydrogen iodide; and / or, preferably, the molar ratio of compound A to O-alkylisothiourea salt or S-alkylisothiourea in step (2) is 1: (1.1~2.5), preferably 1:(1.1~1.5); and / or, the organic solvent in step (2) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and dimethyl sulfoxide, preferably acetonitrile; And / or, the volume amount of the organic solvent in step (2) mL is 3 to 20 times the mass amount of compound A g, preferably 3 to 15 times; And / or, the reaction temperature of step (2) is 10 to 30°C, preferably 15 to 25°C; And / or, the reaction time of step (2) is 5 to 24 hours, preferably 15 to 20 hours.

6. The preparation method according to claim 2, characterized in that: The alkaline reagent in step (3) is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably cesium carbonate and potassium phosphate; The step (3) also satisfies one or more of the following conditions: And / or, the molar ratio of compound C to alkaline agent in step (3) is 1:(1.01-3), preferably 1:(2-3); And / or, the organic solvent in step (3) is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, preferably N,N-dimethylformamide and N,N-dimethylacetamide; And / or, the volume of the organic solvent in step (3) is 6 to 30 times, preferably 8 to 25 times, the mass of compound C in mL; And / or, the reaction temperature of step (3) is 20 to 55°C, preferably 30 to 50°C; And / or, the reaction time of step (3) is 5 to 24 hours, preferably 15 to 20 hours.

7. A method for preparing compound E, the reaction formula is as follows: Wherein R1, R2, R3, R4, and X are the same as those defined in claim 1; The steps include: Step (4): In a solvent, subjecting the compound D prepared according to claim 2 to a hydrolysis reaction under acidic conditions to obtain compound E.

8. The preparation method according to claim 7, characterized in that: The acid for the hydrolysis reaction in step (4) is selected from one or more of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid; The step (4) also satisfies one or more of the following conditions: And / or, the volume amount of the acid in the hydrolysis reaction of step (4) mL is 1 to 8 times the mass amount of compound D g, preferably 3 to 5 times; And / or, the organic solvent in step (4) is selected from one or more of ethyl acetate, ether, dichloromethane, tetrahydrofuran, toluene, water, and dioxane, preferably water; And / or, the volume of the organic solvent in the hydrolysis reaction of step (4) is 0.5 to 5 times, preferably 0.8 to 1.5 times, the mass of the compound D in g; And / or, the reaction temperature of step (4) is 10 to 45°C, preferably 15 to 30°C; And / or, the reaction time of step (4) is 5 to 24 hours, preferably 10 to 20 hours.

9. A compound C1 and a compound D1, the structures of which are as follows: Wherein R1, R2, R3, R4 substituents are as defined in claim 1; Compound C1 and compound D1 are further preferably the following compounds:

10. A method for preparing a KRAS G12D inhibitor, comprising further preparing a KRAS G12D inhibitor from compound E prepared by the preparation method of claim 7.

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