A method for the synthesis of osimertinib

Abstract

The application provides a synthesis method of osimertinib, and belongs to the technical field of osimertinib synthesis, and comprises the following steps: S1, reacting compound 1 and N, N', N'-trimethyl-ethylenediamine in the presence of an alkali to generate compound 2; S2, reacting compound 2 with NIS to generate iodide 3; S3, reacting compound 3 with compound 4 under the catalysis of cuprous iodide to generate compound 5; S4, reducing the nitro group to an amino group under sulfide reduction to generate compound 6; S5, generating an amide by reacting compound A3 with 3-chloropropionyl chloride (SM03) under alkaline conditions, and then generating osimertinib by dechlorination; the synthesis method of osimertinib has the advantages of short synthesis route, high yield, short production cycle and simple operation, the production cost is greatly reduced compared with the reported method, and the method is especially suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of osimertinib synthesis technology, and more specifically to a method for synthesizing osimertinib. Background Technology

[0002] Lung cancer is the leading cause of death among the world's top ten cancers. In 2017, my country had 800,000 lung cancer cases and 700,000 deaths from lung cancer, accounting for a quarter of all cancer deaths. It is estimated that by 2025, lung cancer will be the cause of death for 1 million people in my country, with non-small cell lung cancer accounting for 80% of all lung cancer deaths.

[0003] Osimertinib is a selective inhibitor of the EGFR T790M mutant, with the molecular formula C. 28 H 33 N7O2, with a molecular weight of 499.61, is a drug developed by AstraZeneca in the UK. It is primarily used to treat patients with advanced non-small cell lung cancer carrying the EGFR T790M mutation and has a significant inhibitory effect on the T790M mutation that arises after resistance to EGFR-TKIs such as gefitinib and erlotinib.

[0004] Osimertinib, as a third-generation EGFR inhibitor, targets the subgroup of patients with the EGFR T790M mutation, meeting this unmet market demand. Osimertinib is highly selective, with IC50 values ​​of 11.4 nM for T790M / L858R mutations and 12.9 nM for exon 19 deletion EGFR (Chemicalbook), while its inhibitory activity (IC50) against wild-type EGFR is 494 nM. As an irreversible EGFR inhibitor, osimertinib can form a covalent bond with its molecular target, theoretically resulting in a longer-lasting response and a correspondingly reduced chance of developing resistance.

[0005] In 2015, AstraZeneca received FDA approval to market osimertinib mesylate tablets in the United States, under the brand name TAGRISSO. In 2016, it received EU approval and PMDA approval for marketing. In 2017, AstraZeneca obtained import permission in my country, with a dosage of 40mg (according to C). 28 H 33 80 mg (calculated as N7O2), based on C 28 H 33 (N7O2 calculation). Global sales in 2025: $7.254 billion, ranking first in AstraZeneca's oncology business, and is expected to grow to $16.74 billion by 2035.

[0006] The preparation methods of osimertinib reported in the literature mainly include the following: Method 1: According to AstraZeneca's patent CN103702990B, osimertinib is obtained through a 5-step reaction using 1-methylindole and 2,4-dichloropyrimidine as raw materials. The synthetic route is as follows:

[0007] The basic idea of ​​this route is to prepare the target compound by the stepwise accumulation of functional groups of the starting materials. It adopts the iron powder reduction method. The post-reaction processing requires pretreatment with ion exchange resin and then purification by column chromatography, which is not conducive to industrial production. Furthermore, the final amide reaction adopts ultra-low temperature reaction and column chromatography purification, which limits industrial application.

[0008] Method 2: Ji Min, Li Yuan, et al. reported in patent CN104817541B a synthetic route for preparing osimertinib by reacting 4-fluoro-2-methoxy-5-nitroaniline with N,N,N'-trimethylethylenediamine and acryloyl chloride through amino protection, followed by reaction with 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole. The synthetic route is as follows:

[0009] This method has a long synthetic route, and the use of Boc group protection increases costs. The condensation reaction is carried out in the last step, which means that the quality of the final product depends on the reaction and purification conditions in the last step, resulting in a high quality risk. At the same time, the use of persulfonic acid catalysts in the last step can easily generate genotoxic impurities such as sulfonates, leading to significant safety risks to the product and making it unsuitable for use in the production of active pharmaceutical ingredients.

[0010] Method 3: Using 2-fluoro-4-methoxyaniline 15 as a starting material, osimertinib was obtained through a total of 7 steps including amidation, substitution, nitration, reduction, guanidinolation of the amino group, and cyclization. The synthetic route is shown in the figure below:

[0011] The starting material 2-fluoro-4-methoxyaniline 15 is not readily available; the introduction of an acrylamide group in the first step of the reaction results in a large number of byproducts and a low overall yield; it requires the use of cyanamide, which is easily decomposed, difficult to transport and store; and the final pyrimidine cyclization reaction has many side reactions and a low yield. Therefore, method three is not suitable for industrial production.

[0012] Therefore, developing a method for the large-scale industrial production of osimertinib that is safe, environmentally friendly, low-cost, high-yield, and of controllable quality is a problem that needs to be solved. Summary of the Invention

[0013] The purpose of this invention is to provide a method for synthesizing osimertinib to solve the problems mentioned in the background art.

[0014] To achieve the above objectives, the present invention provides the following technical solution: A method for synthesizing osimertinib includes the following steps: S1. Dissolve compound 1 in a solvent, add N,N',N'-trimethyl-ethylenediamine and a base, and react at 80°C until the reaction is complete. Add purified water, cool down and crystallize to obtain compound 2. S2. Compound 2 was added to a solvent, and NIS (N-iodosuccinimide) was added in batches to react. After the reaction was completed, purified water was added, and then the organic phase was extracted, washed, dried, filtered, concentrated and recrystallized to obtain compound 3. S3. Compounds 3 and 4 were added to a solvent, along with CuI and potassium carbonate. The reaction was carried out at 100°C until completion under the catalysis of CuI. Purified water was added, and the organic phase was extracted. The organic phase was washed, dried, filtered, concentrated, and recrystallized to obtain compound 5. S4. Add hydrochloric acid to the solvent, add compound 5 and sulfur-containing reducing agent, and react at 50~90℃ until the reaction is complete. Then cool down to 20~30℃, add methanol, and add ammonia dropwise until pH>9. Stir to crystallize and obtain compound 6. S5. Add compound 6 to a solvent, add alkali, cool to -10℃, add 3-chloropropionyl chloride dropwise, keep warm to react and generate amide, wash and dechlorinate, add purified water, cool to crystallize, and obtain osimertinib; Among them, compound 1 is Compound 2 is ; Compound 3 is Compound 4 is ; Compound 5 is Compound 6 is .

[0015] The complete reaction process of this synthesis method is shown below:

[0016] Preferably, the molar ratio of compound 1, N,N',N'-trimethyl-ethylenediamine and base in S1 is 1:1.2:(1.5~1.8).

[0017] Preferably, the molar ratio of compound 2 and NIS in S2 is 1:1.5.

[0018] Preferably, in S3, the molar ratio of compound 3, compound 4, CuI and potassium carbonate is 1:1.1:0.1:2.

[0019] Preferably, in S4, the molar ratio of compound 5 to the sulfur-containing reducing agent is 1:4.

[0020] Preferably, in S5, the molar ratio of compound 6, the base, and 3-chloropropionyl chloride is 1:1.5:1.1.

[0021] Preferably, the base in S1 is selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, and 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene; the sulfur-containing reducing agent in S4 is selected from at least one of sodium sulfite, sodium bisulfite, sodium thiosulfate, thiourea dioxide, and sodium hydrosulfite; and the base in S5 is selected from at least one of sodium carbonate, potassium carbonate, N,N-diisopropylethylamine, triethylamine, and pyridine.

[0022] Preferably, acetone is used for recrystallization in S2; and a mixture of isoacetone and water in a volume ratio of 2:1 is used for recrystallization in S3.

[0023] Preferably, the solvent in S2 is selected from at least one of acetonitrile, THF, DCM, carbon tetrachloride, and acetone; the solvent in S3 is selected from at least one of DMF, DMAc, NMP, and acetonitrile; the solvent in S4 is selected from at least one of water, methanol, DMF, and ethanol; and the solvent in S5 is selected from at least one of tetrahydrofuran, ethyl acetate, acetone, acetonitrile, DMF, and dichloromethane.

[0024] Preferably, in step S5, the washing is performed by washing the generated amide reaction solution once each with 5% sodium hydroxide, purified water, and 10% saline solution to obtain an organic phase; the dechlorination is performed by adding DMF solvent and pyridine to the washed organic phase and reacting at 65°C until the reaction is complete.

[0025] The beneficial effects of the above-described technical solution of the present invention are as follows: 1. Compared with previously reported methods, this invention uses cheaper starting materials, shortens the reaction steps, and effectively reduces the cost of producing osimertinib.

[0026] 2. This invention avoids the nitration reaction of previous methods, reduces production difficulty, reduces the emission of waste, and makes the production process greener and cheaper.

[0027] 3. Compared with previously reported methods, this invention focuses on optimizing the reduction of nitro groups, effectively avoiding the difficulties in handling metal reductions and the high risks and costs associated with hydrogenation.

[0028] 4. Compared with previously reported methods, the present invention avoids the use of acryloyl chloride and effectively reduces the formation of dimer impurities.

[0029] 5. The synthesis method described in this invention yields osimertinib with a purity of over 99%, and the product quality is significantly superior to that of reported methods.

[0030] 6. The method for synthesizing osimertinib described in this invention has the advantages of short synthetic route, high yield, short production cycle and simple operation. The production cost is significantly reduced compared with the reported methods, and it is especially suitable for large-scale industrial production. Attached Figure Description

[0031] The above and other objects, features, and advantages of exemplary embodiments of the present invention will become readily apparent upon reading the following detailed description with reference to the accompanying drawings. In the drawings, several embodiments of the invention are illustrated by way of example and not limitation, and like or corresponding reference numerals denote like or corresponding parts, wherein: Figure 1 MS spectrum of osimertinib mesylate prepared in Example 3; Figure 2 The HPLC chromatogram of osimertinib mesylate prepared in Example 3 is shown. Detailed Implementation

[0032] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0033] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products. Example 1

[0034] A method for synthesizing osimertinib, comprising the following steps: Preparation of Compound 2 (S1) Add 600 ml of DMF solvent to a three-necked flask, add compound 1 (3-fluoro-4-nitrobenzene ether) (60 g, 1 eq) while stirring, then add N,N',N'-trimethyl-ethylenediamine (42.7 g, 1.2 eq), followed by dropwise addition of triethylamine (63.4 g, 1.8 eq). Heat to 80 °C and react for 10 h. Add 600 ml of purified water, cool to 10 °C and stir to crystallize for 3 h. Filter, wash with purified water, and dry to obtain compound 2, a brown solid of 84.6 g, yield 93.16%.

[0035] Preparation of compound 3 (S2) Add 800 mL of acetonitrile to a three-necked flask, then add compound 2 (80 g, 1 eq) with stirring. Next, add NIS solid (83.1 g, 1.5 eq) in portions. Stir the reaction at room temperature for 16 h. Add 800 mL of purified water, then extract twice with ethyl acetate (800 mL * 2). Combine the organic phases. Wash the organic phase with 500 mL of saturated brine, dry to anhydrous sodium sulfate, filter, concentrate, and recrystallize the crude product from 800 mL of acetone to give compound 3, a deep yellow solid, 102.5 g, yield 86.20%.

[0036] Preparation of Compound 5 (S3) Compound 3 (100 g, 1 eq), compound 4 (63.8 g, 1.1 eq), and 800 ml of DMF solvent were added to a three-necked flask, followed by CuI (5 g, 0.1 eq) and potassium carbonate (71.7 g, 2 eq). The reaction mixture was heated to 100 °C and reacted for 16 h. After the reaction was complete, the reaction mixture was poured into 2 L of water and extracted three times with ethyl acetate (800 ml * 3). The organic phases were combined. The organic phase was washed with 500 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was recrystallized from isopropanol / water = 2 / 1 (1 L) to give compound 5, a deep yellow solid of 109.5 g, with a yield of 88.62%.

[0037] Preparation of compound 6 (S4) Add 450 ml of purified water and 10 ml of hydrochloric acid to a three-necked flask. Add compound 5 (45.2 g, 1 eq) while stirring, and stir until dissolved. Add sodium sulfite (47.6 g, 4 eq), and heat to 90 °C for 10 h. After the reaction is complete, cool to 30 °C, add 450 ml of methanol, and then add ammonia dropwise until the pH is above 9. A solid precipitates, and the mixture is stirred to crystallize for 3 h. Filter, wash with purified water, and dry to obtain compound 6, a gray solid of 34.4 g, yield 81.56%.

[0038] S5. Preparation of osimertinib Add 500 mL of dichloromethane to a three-necked flask, and add compound 6 (25.3 g, 1 eq) and triethylamine (17.2 g, 1.5 eq) while stirring. Cool to -10 °C, and add 3-chloropropionyl chloride (9.3 g, 1.1 eq) dropwise. Maintain the reaction temperature for 3 h. Wash the reaction solution once each with 250 mL of 5% sodium hydroxide aqueous solution, 250 mL of purified water, and 250 mL of 10% saline solution. Concentrate the organic phase to obtain a brown oily substance. Add 200 mL of DMF solvent and 16.2 g of pyridine to the oily substance, heat to 65 °C and react for 6 h. Then add 400 mL of purified water, cool to 10 °C and stir to crystallize for 16 h. Filter, wash with purified water, and dry to obtain osimertinib, a white solid of 23.4 g, yield 83.65%. Example 2

[0039] This embodiment provides a method for synthesizing osimertinib, including the following steps: Preparation of Compound 2 (S1) Add 400 ml of DMF solvent to a three-necked flask, add compound 1 (3-fluoro-4-nitrobenzene) (40 g, 1 eq) while stirring, then add N,N',N'-trimethyl-ethylenediamine (28.5 g, 1.2 eq), and dropwise add 1,8-diazobisspirocyclic [5.4.0]undec-7-ene (63.6 g, 1.8 eq). Heat to 80 °C and react for 10 h. Add 600 ml of purified water, cool to 10 °C and stir to crystallize for 3 h. Filter, wash with purified water, and dry to obtain compound 2, 82.0 g of brown solid, yield 90.28%.

[0040] Preparation of compound 3 (S2) Add 800 mL of acetonitrile to a three-necked flask, then add compound 2 (80 g, 1 eq) with stirring. Next, add NIS solid (83.1 g, 1.5 eq) in portions. Stir the reaction at room temperature for 16 h. Add 800 mL of purified water and extract twice with ethyl acetate (800 mL * 2). Combine the organic phases. Wash the organic phase with 500 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and recrystallize the crude product from 400 mL of acetone to give compound 3, a deep yellow solid, 105.3 g, yield 88.56%.

[0041] Preparation of Compound 5 (S3) Compound 3 (50 g, 1 eq), compound 4 (31.6 g, 1.1 eq), and 400 mL of DMF solvent were added to a three-necked flask, followed by CuI (2.5 g, 0.1 eq) and potassium carbonate (35.8 g, 2 eq). The reaction mixture was heated to 100 °C and reacted for 16 h. After the reaction was complete, the reaction mixture was poured into 1 L of water and extracted three times with ethyl acetate (400 mL * 3). The organic phases were combined. The organic phase was washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from the crude product with isopropanol / water = 2 / 1 (500 mL) to give compound 5, a deep yellow solid, 53.8 g, yield 87.15%.

[0042] Preparation of compound 6 (S4) Add 450 ml of purified water and 10 ml of hydrochloric acid to a three-necked flask. Add compound 5 (50 g, 1 eq) while stirring, and stir until dissolved. Add sodium thiosulfate (66.5 g, 4 eq), and heat to 50 °C for 6 h. After the reaction is complete, cool to room temperature, add 450 ml of methanol, and then add ammonia dropwise until the pH is above 9. A solid precipitates, and the mixture is stirred to crystallize for 3 h. Filter, wash with purified water, and dry to obtain compound 6, a gray solid of 43.1 g, yield 92.1%.

[0043] S5. Preparation of osimertinib Add 500 mL of dichloromethane to a three-necked flask, and while stirring, add compound 6 (40 g, 1 eq) and triethylamine (27.2 g, 1.5 eq). Cool to -10 °C, and add 3-chloropropionyl chloride (14.7 g, 1.1 eq) dropwise. Maintain the reaction temperature for 3 h. Wash the reaction solution once each with 300 mL of 5% sodium hydroxide aqueous solution, 300 mL of purified water, and 300 mL of 10% saline solution. Concentrate the organic phase to obtain a brown oily substance. Add 250 mL of DMF solvent and 25.6 g of pyridine to the oily substance, heat to 65 °C, and react for 6 h. Then add 600 mL of purified water, cool to 10 °C, and stir to induce crystallization for 16 h. Filter, wash with purified water, and dry to obtain osimertinib, a white solid of 39.2 g, with a yield of 88.63%. Example 3

[0044] This embodiment provides a method for synthesizing osimertinib, including the following steps: Preparation of Compound 2 (S1) 600 L of DMF solvent was added to the reaction vessel, and compound 1 (3-fluoro-4-nitrobenzene ether) (60 kg, 1 eq) was added with stirring. Then N,N',N'-trimethyl-ethylenediamine (42.7 kg, 1.2 eq) was added, followed by the dropwise addition of triethylamine (52.8 kg, 1.5 eq). The mixture was heated to 80 °C and reacted for 18 h. 600 L of purified water was added, and the mixture was cooled to 10 °C and stirred to induce crystallization for 3 h. The mixture was filtered, washed with purified water, and dried to obtain compound 2, a brown solid weighing 86.75 kg, with a yield of 95.5%.

[0045] Preparation of compound 3 (S2) 800 L of acetonitrile was added to a three-necked flask, and compound 2 (86 kg, 1 eq) was added with stirring. Then, NIS solid (89.3 kg, 1.5 eq) was added in portions. The mixture was stirred at room temperature for 24 h. 800 L of purified water was added, and the mixture was extracted twice with ethyl acetate (800 L * 2). The organic phases were combined. The organic phase was washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from the crude product with 400 L of acetone to give compound 3, a deep yellow solid of 113.8 kg, yield 89.0%.

[0046] Preparation of Compound 5 (S3) Compound 3 (113 kg, 1 eq), compound 4 (72.1 kg, 1.1 eq), and 800 L of DMF solvent were added to a three-necked flask, followed by CuI (5.6 kg, 0.1 eq) and potassium carbonate (81.0 g, 2 eq). The reaction mixture was heated to 100 °C and reacted for 24 h. After the reaction was complete, the reaction mixture was poured into 2000 L of water and extracted three times with ethyl acetate (800 L * 3). The organic phases were combined. The organic phase was washed with 500 L of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from the crude product using isopropanol / water = 2 / 1 (1100 L) to give compound 5, a deep yellow solid, in a yield of 124.5 kg (89.15%).

[0047] Preparation of compound 6 (S4) 1240 L of purified water and 27.4 L of hydrochloric acid were added to a three-necked flask. Compound 5 (124 kg, 1 eq) was added with stirring and stirred until dissolved. Thiourea dioxide (112.8 kg, 4 eq) was added, and the mixture was heated to 60 °C and reacted for 24 h. After the reaction was complete, the temperature was lowered to 20-30 °C, 1000 L of methanol was added, and ammonia was added dropwise until the pH reached above 9. A solid precipitated out, and the mixture was stirred to crystallize for 3 h. The crystals were filtered, washed with purified water, and dried to obtain compound 6, a gray solid of 111.1 kg, with a yield of 95.6%.

[0048] S5. Preparation of osimertinib 550 L of dichloromethane was added to a three-necked flask, and compound 6 (110 kg, 1 eq) and triethylamine (74.8 kg, 1.5 eq) were added with stirring. The mixture was cooled to -10 °C, and 3-chloropropionyl chloride (40.4 kg, 1.1 eq) was added dropwise. The reaction mixture was kept at this temperature for 8 h. The reaction solution was washed once each with 500 L of 5% sodium hydroxide aqueous solution, 500 L of purified water, and 500 L of 10% saline solution. The organic phase was concentrated to obtain a brown oily substance. 500 L of DMF solvent and 35.6 kg of pyridine were added to the oily substance, and the mixture was heated to 65 °C and reacted for 10 h. Then, 1000 L of purified water was added, and the mixture was cooled to 10 °C and stirred to induce crystallization for 16 h. The crystals were filtered, washed with purified water, and dried to obtain osimertinib, a white solid, weighing 114.1 kg, with a yield of 95.5%. The MS spectrum of the prepared osimertinib is shown below. Figure 1 As shown, the HPLC detection chromatogram is as follows: Figure 2 As shown, the purity obtained was 99.94%.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Any other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention, as long as they do not depart from the spirit and scope of the technical solutions of the present invention, should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing osimertinib, characterized in that, Includes the following steps: S1. Dissolve compound 1 in a solvent, add N,N',N'-trimethyl-ethylenediamine and a base, and react at 80°C until the reaction is complete. Add purified water, cool down and crystallize to obtain compound 2. S2. Compound 2 was added to a solvent and NIS was added in batches for reaction. After the reaction was completed, purified water was added, and then the organic phase was extracted, washed, dried, filtered, concentrated and recrystallized to obtain compound 3. S3. Compounds 3 and 4 were added to a solvent, along with CuI and potassium carbonate. The reaction was carried out at 100°C until completion under the catalysis of CuI. Purified water was added, and the organic phase was extracted. The organic phase was washed, dried, filtered, concentrated, and recrystallized to obtain compound 5. S4. Add hydrochloric acid to the solvent, add compound 5 and sulfur-containing reducing agent, and react at 50~90℃ until the reaction is complete. Then cool down to 20~30℃, add methanol, and add ammonia dropwise until pH>9. Stir to crystallize and obtain compound 6. S5. Add compound 6 to a solvent, add alkali, cool to -10℃, add 3-chloropropionyl chloride dropwise, keep warm to react and generate amide, wash and dechlorinate, add purified water, cool to crystallize, and obtain osimertinib; Among them, compound 1 is Compound 2 is ; Compound 3 is Compound 4 is ; Compound 5 is Compound 6 is .

2. The method for synthesizing osimertinib according to claim 1, characterized in that, The molar ratio of compound 1, N,N',N'-trimethyl-ethylenediamine and base in S1 is 1:1.2:(1.5~1.8).

3. The method for synthesizing osimertinib according to claim 1, characterized in that, The molar ratio of compound 2 and NIS in S2 is 1:1.

5.

4. The method for synthesizing osimertinib according to claim 1, characterized in that, In S3, the molar ratio of compound 3, compound 4, CuI and potassium carbonate is 1:1.1:0.1:

2.

5. The method for synthesizing osimertinib according to claim 1, characterized in that, In S4, the molar ratio of compound 5 to the sulfur-containing reducing agent is 1:

4.

6. The method for synthesizing osimertinib according to claim 1, characterized in that, In S5, the molar ratio of compound 6, the base, and 3-chloropropionyl chloride is 1:1.5:1.

1.

7. The synthesis method according to claim 1, characterized in that, The base in S1 is selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, and 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene; the sulfur-containing reducing agent in S4 is selected from at least one of sodium sulfite, sodium bisulfite, sodium thiosulfate, thiourea dioxide, and sodium hydrosulfite; the base in S5 is selected from at least one of sodium carbonate, potassium carbonate, N,N-diisopropylethylamine, triethylamine, and pyridine.

8. The synthesis method according to claim 1, characterized in that, In S2, acetone was used for recrystallization; in S3, a mixture of isoacetone and water in a volume ratio of 2:1 was used for recrystallization.

9. The synthesis method according to claim 1, characterized in that, The solvent in S2 is selected from at least one of acetonitrile, THF, DCM, carbon tetrachloride, and acetone; the solvent in S3 is selected from at least one of DMF, DMAc, NMP, and acetonitrile; the solvent in S4 is selected from at least one of water, methanol, DMF, and ethanol; and the solvent in S5 is selected from at least one of tetrahydrofuran, ethyl acetate, acetone, acetonitrile, DMF, and dichloromethane.

10. The method for synthesizing osimertinib according to claim 1, characterized in that, In S5, the washing process involves washing the generated amide reaction solution once each with 5% sodium hydroxide, purified water, and 10% saline solution to obtain an organic phase. The dechlorination process involves adding DMF solvent and pyridine to the washed organic phase and reacting at 65°C until the reaction is complete.

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