A method for preparing an FGFR2 inhibitor, lirafugratinib (RLY-4008)

Abstract

The application belongs to the technical field of drug chemical synthesis, and particularly relates to a preparation method of an FGFR2 inhibitor Lirafugratinib (RLY-4008). The reaction steps of the synthetic method are as follows: 2-bromo-p-nitroacetophenone is reacted with 3-amidinopropionic acid ethyl ester hydrochloride, then is ring-closed with formamide (formamidine) to obtain a key intermediate 4-hydroxy-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, halogenation, aminolysis, methylation, suzuki coupling reaction, reduction, and finally reaction with methacryloyl chloride to obtain Lirafugratinib (RLY-4008).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis and relates to a novel preparation method of the FGFR2 inhibitor Lirafugratinib (RLY-4008). Background Technology

[0002] Cholangiocarcinoma (CCA) is a rare malignant tumor with a poor prognosis. Its malignancy is comparable to that of pancreatic cancer, widely considered the most dangerous cancer. Even with timely surgical treatment, the 3-year recurrence rate is as high as 85%, and the 5-year survival rate is only about 5%; for patients with unresectable cancer, the 5-year survival rate was once as low as 0. FGFR2 is a receptor tyrosine kinase, one of the four members of the FGFR family, a group of closely related proteins with highly similar protein sequences and properties. Mutations frequently occur in many cancers, including intrahepatic cholangiocarcinoma (10%-16%), endometrial cancer (7.5%-11%), and adenocarcinoma of the stomach or gastroesophageal junction (3.7%-7.9%). Oncogenic activation of FGFR2 can occur through gene amplification, activating mutations, or chromosomal rearrangements; the incidence of FGFR2 fusion / rearrangement in cholangiocarcinoma is 10-15%. Previous non-selective FGFR inhibitors have validated FGFR as a therapeutic target for CCA by achieving objective response rates (ORR) of 20-40% and duration of response (DOR) of 5-9 months. However, second-line treatment with pan-FGFR inhibitors (Infigratinib, Pemigatinib, Futibatinib) often results in adverse reactions such as hyperphosphatemia and diarrhea, and FGFR2 resistance mutations may also occur, requiring multiple dose adjustments and making it difficult to achieve the optimal drug dose. Selective inhibition of FGFR2 is expected to provide superior target coverage, thereby significantly improving drug efficacy.

[0003] Despite extensive research in structure-based drug design, selective targeting of FGFR2 still involves unknown kinase domains similar to FGFR1, FGFR3, and FGFR4. RLY-4008 is the first highly selective and potent FGFR2 inhibitor, selectively targeting driver alterations and FGFR resistance mutations based on unique conformational kinetics, exhibiting enhanced sensitivity and in vivo activity. Phase I / II clinical trial results for RLY-4008 showed an 88% efficacy rate in treating cholangiocarcinoma, without demonstrating limitations due to non-target toxicities such as hyperphosphatemia (FGFR1) and diarrhea (FGFR4). These preliminary data suggest that RLY-4008 has a manageable safety profile and can promote tumor regression in various FGFR2 mutations and tumor types. Summary of the Invention

[0004] In view of the above, the preparation of the FGFR2 inhibitor Lirafugratinib (RLY-4008) is very important. The inventors have solved the technical problems of this compound through experimental research, and the reaction route is as follows:

[0005]

[0006] Specific experimental methods

[0007] The present invention will be further described and illustrated below through embodiments, but these embodiments do not limit the scope of the invention.

[0008] Example 1:

[0009]

[0010] Step A

[0011] 3-Aminopropionic acid ethyl ester hydrochloride (8.3 g, 50.0 mmol) and NaOEt (5.1 g, 75.0 mmol) were dissolved in anhydrous ethanol and stirred under argon for 20 min. The mixture was heated to 60 °C, and 2-bromo-p-nitroacetophenone (6.1 g, 25.0 mmol) was added in portions over 5 min. After reacting for 1.5 h, the mixture was cooled to 20 °C, and the solvent was evaporated under reduced pressure. The residue was diluted with distilled water (20 mL) and extracted with ethyl acetate (3 × 80 mL). The organic layer was washed with water (3 × 20 mL) and brine (3 × 20 mL). The combined aqueous solution was extracted again with EtOAc (2 × 20 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-amino-5-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid (4.14 g, 60% yield). LC-MS (ESI): m / z = 275.3 [M+H] + .

[0012] Step B

[0013] Formic acid (11.3 mL), ethyl 2-amino-5-(4-nitrophenyl)-1H-pyrrolo-3-carboxylate (4.60 g, 16.57 mmol), and excess formamide (75 mL) were added to anhydrous DMF (28 mL), and the mixture was heated to 120 °C and reacted for 20 h. Then, 2-propanol (12 mL) was added, and the mixture was cooled to 20 °C. The mixture was filtered, washed with 2-propanol (10 mL) and n-hexane (2 × 15 mL), and dried under reduced pressure to give 4-hydroxy-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (2.52 g, 60% yield). LC-MS (ESI): m / z = 256.2 [M+H] +

[0014] Step C

[0015] 4-Hydroxy-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.9 g, 7.43 mmol) and POCl3 (13.3 mL) were mixed and reacted at 90 °C for 3 h. The mixture was cooled in an ice-salt bath, and then water (60 mL) was added. The pH was adjusted to 12 with NaOH (8 M, 80 mL). The mixture was filtered, washed with water and n-pentane, and dried to give the compound 4-chloro-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine (1.93 g, 92% yield). LC-MS (ESI): m / z = 274.7 [M+H] +

[0016] Step D

[0017] 4-Chloro-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine (179 mg, 0.653 mmol) and cesium carbonate (319 mg, 0.980 mmol) were dissolved in anhydrous DMF (2 mL). Iodomethane (0.65 mL, 1.31 mmol, 2 M in tert-butyl methyl ether) was added over 30 min, and the solution was stirred at room temperature for 90 min. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with saturated NaHCO3 (15 mL) and saturated NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the compound 4-chloro-7-methyl-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine (169 mg, 90% yield). LC-MS (ESI): m / z = 288.7 [M+H] + Step E

[0018] 531 g (1.84 mol) of compound 4-chloro-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine was suspended in ammonia water (30% H2O, 3.63 L) and reacted at 120 °C for 18 h with stirring in a pressure vessel. The mixture was then cooled to 20 °C, filtered, washed with H2O (1.80 L) and methanol (900 mL), and dried to give 371 g (75% yield) of compound 4-amino-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 269.3 [M+H] +

[0019] Step F

[0020] 18.9 g (70 mmol) of 4-amino-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine and N-iodosuccinimide were dissolved in 400 mL of LMF and reacted overnight in the dark at room temperature. The solvent was evaporated to dryness. The residue was suspended in a 10% hot solution of Na₂SO₃, filtered, washed twice with hot water, and then crystallized from ethanol to give 27.7 g (100% yield) of 4-amino-5-iodo-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 395.2 [M+H] +

[0021] Step G

[0022] In a sealable reaction flask, 4-amino-5-iodo-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (122 mg, 0.31 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenoxy)-5-methylpyrimidine (122 mg, 0.373 mmol) were added, along with Pd(DtBPF)Cl2 (20.1 mg, 0.031 mmol), CsF (240 mg, 0.930 mmol), DMF (4 mL), H2O (0.5 mL), and a stir bar. The mixture was purged with N2 three times and stirred at 90 °C for 2 h. The reaction mixture was then concentrated under vacuum. The crude substance was purified by TLC and concentrated under vacuum to give compound 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (8.8 mg, yield 6%). LC-MS (ESI): m / z = 471.5 [M+H] +

[0023] Step H

[0024] 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.2 g, 0.45 mmol) and triethylsilane (0.45 mmol) were dissolved in ethanol (5 mL) under argon atmosphere. A catalytic amount of palladium(II) chloride (10 mol%) was added, and the resulting mixture was stirred for 2 h. The solvent was evaporated, and the mixture was then decanted with water. The aqueous phase was extracted with diethyl ether, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.14 g, 70% yield). LC-MS (ESI): m / z = 441.5 [M+H] +

[0025] Step I

[0026] 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.4 g, 10 mmol) and methacryloxychlorochloride (1.06 mL, 11 mmol) were dissolved in THF (100 mL) and stirred under argon atmosphere at 0 °C, and treated with potassium carbonate (1.38 g, 10 mmol). The reaction mixture was stirred for 2 h, then 2 M HCl was added and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (2 × 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography to give compound RLY-4008 (4.1 g, 80% yield); LC-MS (ESI): m / z = 509.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ1.95(s,3H),2.42(s,3H),3.59(s,3H),5.54(s,1H),5.80(s,1H),5.99(s,2H ),7.09(d,1H),7.18(d,2H),7.26-7.50(m,3H),7.75(d,2H),8.21(s,1H),8.47(d,1H),9.94(s,1H).

[0027] Example 2

[0028]

[0029] The compound 4-hydroxy-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine was obtained using a method similar to steps A and B of Example 1.

[0030] Step C

[0031] 17.9 g (70 mmol) of 4-hydroxy-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and N-iodosuccinimide were dissolved in 400 mL of DMF and reacted overnight in the dark at room temperature. The solvent was evaporated to dryness. The residue was suspended in a 10% hot solution of Na₂SO₃, filtered, washed twice with hot water, and then crystallized from ethanol to give 28 g (100% yield) of 4-hydroxy-5-iodo-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 400.6 [M+H] +

[0032] Step D

[0033] A mixture of compound 4-hydroxy-5-iodo-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (0.78 g, 2.03 mmol) and phosphorus oxychloride (10 mL) was refluxed for 3 h. The suspension was concentrated to remove phosphorus oxychloride. The residue was diluted with ethyl acetate, and the organic layer was washed with saturated NaHCO3 aqueous solution and dried over anhydrous sodium sulfate. The solution was then evaporated under reduced pressure to obtain compound 4-chloro-5-iodo-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (0.16 g, 20% yield). LC-MS (ESI): m / z = 400.6 [M+H] +

[0034] Step E

[0035] The compound 4-chloro-5-iodo-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (260 mg, 0.65 mmol) and cesium carbonate (319 mg, 0.980 mmol) were dissolved in anhydrous DMF (2 mL). Iodomethane (0.65 mL, 1.31 mmol, 2 M in tert-butyl methyl ether) was added over 30 min, and the solution was stirred at room temperature for 90 min. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with saturated NaHCO3 (15 mL) and saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the compound 4-chloro-5-iodo-7-methyl-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (215 mg, 80% yield). LC-MS (ESI): m / z = 414.6 [M+H] +

[0036] Step F

[0037] The compound 4-chloro-5-iodo-7-methyl-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (762 g, 1.84 mol) was suspended in ammonia water (30% H2O, 3.63 L) and reacted in a pressure vessel at 120 °C with stirring for 18 h. After cooling to 20 °C, the mixture was filtered, washed with H2O (1.80 L) and methanol (900 mL), and dried to give the compound 4-amino-5-iodo-7-methyl-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (545 g, 75% yield). LC-MS (ESI): m / z = 395.2 [M+H] +

[0038] The next three steps were performed using the same method as in Example 1 to prepare the target compound RLY-4008.

[0039] Example 3

[0040]

[0041] The compound 4-chloro-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine was obtained using a method similar to steps A and B in Example 1.

[0042] Step C

[0043] A mixture of compound 4-hydroxy-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (0.52 g, 2.03 mmol) and phosphorus oxychloride (10 mL) was refluxed for 3 hours. The suspension was concentrated to remove phosphorus oxychloride. The residue was diluted with ethyl acetate, and the organic layer was washed with saturated NaHCO3 aqueous solution and dried over anhydrous sodium sulfate. The solution was then evaporated under reduced pressure to obtain compound 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (0.11 g, 20% yield). LC-MS (ESI): m / z = 274.7 [M+H] +

[0044] Step D

[0045] 19.2 g (70 mmol) of 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and N-iodosuccinimide were dissolved in 400 mL of DMF and reacted overnight in the dark at room temperature. The solvent was evaporated to dryness. The residue was suspended in a hot 10% Na₂SO₃ solution, filtered, washed twice with hot water, and then crystallized from ethanol to give 27.5 g (98% yield) of 4-chloro-5-iodo-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 400.6 [M+H] +

[0046] Step E

[0047] The compound 4-chloro-5-iodo-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (260 mg, 0.65 mmol) and cesium carbonate (319 mg, 0.980 mmol) were dissolved in anhydrous DMF (2 mL). Iodomethane (0.65 mL, 1.31 mmol, 2 M in tert-butyl methyl ether) was added over 30 minutes, and the solution was stirred at room temperature for 90 minutes. The reaction was quenched with H₂O (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with saturated NaHCO₃ (15 mL) and saturated NaCl (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the compound 4-chloro-5-iodo-7-methyl-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (238 mg, 88% yield). LC-MS (ESI): m / z = 414.6 [M+H] +

[0048] Step F

[0049] 762 g (1.84 mol) of compound 4-chloro-5-iodo-7-methyl-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine was suspended in ammonia water (30%, in H2O, 3.63 L) and reacted at 120 °C for 18 h with stirring in a pressure vessel. The mixture was then cooled to 20 °C, filtered, washed with H2O (1.80 L) and methanol (900 mL), and dried to give 545 g (75% yield) of compound 4-amino-5-iodo-7-methyl-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 395.2 [M+H] +

[0050] The next three steps were performed using the same method as in Example 1 to prepare the target compound RLY-4008.

[0051] Example 4

[0052]

[0053] The compound 4-chloro-7-methyl-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine was obtained using a method similar to steps A, B, C, and D of Example 1.

[0054] Step E

[0055] 20.21 g (70 mmol) of 4-chloro-7-methyl-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine and N-iodosuccinimide were dissolved in 400 mL of LMF and reacted overnight in the dark at room temperature. The solvent was evaporated to dryness. The residue was suspended in a 10% hot solution of Na₂SO₃, filtered, washed twice with hot water, and then crystallized from ethanol to give 27.65 g (75% yield) of 4-chloro-5-iodo-7-methyl-6-(4-nitrophenyl)-7h-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 414.6 [M+H] +

[0056] Step F

[0057] 763 g (1.84 mol) of compound 4-chloro-5-iodo-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine was suspended in ammonia water (30%, H2O, 3.63 L) and reacted at 120 °C for 18 h with stirring in a pressure vessel. The mixture was then cooled to 20 °C, filtered, washed with H2O (1.80 L) and methanol (900 mL), and dried to give 545 g (75% yield) of compound 4-amino-5-iodo-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LC-MS (ESI): m / z = 395.2 [M+H] + .

[0058] The next three steps were performed using the same method as in Example 1 to prepare the target compound RLY-4008.

[0059] The above examples are merely illustrative of embodiments of the present invention, but the present invention is not limited to the examples described above. Various changes and modifications can be made to the present invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as defined by the claims and their equivalents.

Claims

1. A method for preparing the FGFR2 inhibitor RLY-4008, characterized in that, The specific steps are as follows: 1) 2-Amino-5-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid ethyl ester was obtained by reacting the raw material 2-bromo-p-nitroacetophenone with ethyl 3-amidinepropionate hydrochloride; 2) After reaction with excess formamide, 4-hydroxy-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained; 3) The compound 4-amino-5-iodo-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine was prepared by sequential chlorination, methylation, ammoniation and iodination; 4) The compound obtained in step 3) undergoes a Suzuki coupling reaction with 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenoxy)-5-methylpyrimidine to give 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5) The nitro group of 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was reduced to an amino group to obtain the compound 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 6) Finally, the amino group in compound 5-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-6-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine reacts with methacryloyl chloride to give target compound 11, namely RLY-4008; Furthermore, in step 4), the reaction temperature of the Suzuki coupling reaction is selected from 10-200 °C, the reaction time is selected from 0-72 h, and the solvent is selected from one or more of diethyl ether, acetonitrile, THF, DMF, DME, 1,4-dioxane, H2O, NMP, DMA, DMSO, benzene, and toluene; the catalyst used in the reaction is selected from bis(triphenylphosphine)-palladium dichloride, bis(triphenylphosphine)ferrocene palladium dichloride, bis(triphenylphosphine)ferrocene palladium dichloride dichloromethane complex, and Pd2(dba)3. One or more of pd(dppe)Cl2, tetra-triphenylphosphine palladium, and bis(triphenylphosphine)ferrocene nickel dichloride are used in the reaction. The base used in the reaction is selected from one of triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, CsCO3, KOAc, NaOAc, K2CO3, Na2CO3, Li2CO3, tBuOK, tBuONa, K3PO4, NaOH, KOH, and Ba(OH)2. Purification is performed by column chromatography, pulping, or recrystallization.

2. The preparation method of the FGFR2 inhibitor RLY-4008 as described in claim 1, characterized in that, In step 1), the reaction time is selected from 0-36 h, the temperature is selected from 10-120 ℃, the solvent is selected from one or more of ethanol, diethyl ether, dimethyl sulfoxide, water, methanol, and dimethylformamide, and the purification is selected from column chromatography, pulping, or recrystallization.

3. The preparation method of the FGFR2 inhibitor RLY-4008 as described in claim 1, characterized in that, In step 2), the reaction solvent is selected from one or more of the following: diethyl ether, acetonitrile, THF, DMF, DME, 1,4-dioxane, H2O, NMP, DMA, DMSO, benzene, toluene, chlorobenzene, diphenyl methyl ether, xylene, DCM, and 1,2-dichloroethane; the temperature is selected from 10-200 ℃; the time is selected from 0-24 h; the acid used in the reaction is selected from one or more of the following: trifluoroacetic acid, acetic acid, and formic acid; and the purification process includes washing the filter cake, column chromatography, slurrying, or recrystallization during filtration.

4. The preparation method of the FGFR2 inhibitor RLY-4008 as described in claim 1, characterized in that, In step 3) the methylation reaction, the reaction temperature is selected from 0-200 ℃, the reaction time is 1-20 h, the solvent is selected from one or more of diethyl ether, dimethyl sulfoxide, water, methanol, and dimethylformamide, the methylating reagent is selected from one or more of methyl trifluoromethanesulfonate, dimethyl sulfoxide, methyl cobalt trioxide, iodomethane, a mixed solution of formaldehyde and formic acid, Grignard reagent, methyl zinc reagent, or methyl ketone reagent, the catalyst is selected from one or more of potassium hydroxide, sodium hydroxide, sodium iodide, copper iodide, and cesium carbonate, and the purification is selected from column chromatography, pulping, or recrystallization.

5. The preparation method of the FGFR2 inhibitor RLY-4008 as described in claim 1, characterized in that, In step 3), the reaction solvent is selected from one or more of DMF, water, and ethanol; the reaction temperature is selected from 50-120 ℃; the time is selected from 0-24 h; the amination agent is ammonia water; and the purification is selected from column chromatography, pulping, or recrystallization.

6. The method for preparing the FGFR2 inhibitor RLY-4008 as described in claim 1, characterized in that, In step 5), the reaction of reducing nitro to amine is carried out at a temperature of 50-120 °C, the solvent is selected from one or more of water, ethanol, and diethyl ether, the catalyst is selected from one of Ag, Ti, Zn, Al, Cu, Yb, Si, Na, K, Mg, and Pd catalysts, and the purification is carried out by column chromatography, pulping, or recrystallization.

7. The method for preparing the FGFR2 inhibitor RLY-4008 as described in claim 1, characterized in that, In step 6), the reaction temperature is selected from -50 to 100 ℃, the reaction time is selected from 0 to 24 h, the solvent is selected from one or more of DCM, 1,2-dichloroethane, chlorobenzene, acetonitrile, THF, 2-MeTHF, DMF, DME, 1,4-dioxane, H2O, NMP, DMAC, and DMSO, the base used is selected from one or more of triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, DMAP, CsCO3, KOAc, NaOAc, K2CO3, and Na2CO3, and the product purification is selected from column chromatography, pulping, Prep-TLC, Prep-HPLC, or recrystallization.

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