A method for synthesizing an osimertinib intermediate

Abstract

This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing an intermediate of osimertinib. The invention uses 1-methyl-3-acetylindole as a starting material and reacts it with ethyl formate to obtain an intermediate. This intermediate, without purification, is directly cyclized with 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine to prepare N... 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine. This synthetic route has mild reaction conditions, simple post-processing, and high yield, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing an osimertinib intermediate. Background Technology

[0002] AstraZeneca's Tagrisso (osimertinib, AZD9291) is approved in the United States on November 13, 2015, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring the EGFR T790M mutation and unresponsive to EGFR tyrosine kinase inhibitor therapy. The structural formula of AZD9291 is shown below:

[0003]

[0004] The compound patent for osimertinib is WO2013014448 (applicant: AstraZeneca). This patent not only protects osimertinib but also discloses its synthetic method: the method uses 2-methoxy-4-fluoroaniline as a starting material, first nitrifying it to obtain 2-methoxy-4-fluoro-5-nitroaniline, then reacting it with 3-(2-chloropyrimidin-4-yl)-1-methylindole under the catalysis of p-toluenesulfonic acid to obtain N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indole-3-yl)pyrimidin-2-amine, followed by the nucleophilically substituted fluorine atom intermediate N of N,N,N'-trimethylethylenediamine. 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine, then the nitro group is reduced with iron powder, and the resulting amino group reacts with acryloyl chloride to give AZD9291 (Osimertinib). And this intermediate N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 The low yield of the preparation of -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine resulted in a low overall yield for this route. Similar routes and methods were also disclosed in J. Med. Chem., 57(20), 8249-8267, 2014; J. Chem. Res., 39(6), 318-320; 2015.

[0005] The reaction route is as follows:

[0006]

[0007] In addition, CN 114634484 A discloses a method for preparing osimertinib or its salts, an improvement on the above-mentioned route. Intermediate N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 The methanesulfonate of -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine is reduced to the nitro group under the action of hydrogen and palladium on carbon, and then directly coupled to the amide product by 3-chloropropionyl chloride without separation.

[0008] CN106366072A, CN106366022A, and Journal of Heterocyclic Chemistry, 54(5), 2898-2901; 2017 disclose a new synthetic method: (1) Cyclolysis: 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine and N,N,N'-trimethylethylenediamine are nucleophilically substituted to prepare 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine, which is then cyclized with 1-(1-methylindol-3-yl)-3-(dimethylamino)-2-propenone to prepare N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine. (2) Reduction: N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine was hydrogenated and reduced to prepare N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)phenyl-1,2,4-triamine. (3) Amideation: with N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4AZD9291 was prepared from 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)phenyl-1,2,4-triamine and acryloyl chloride. The cyclization of 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine with 1-(1-methylindol-3-yl)-3-(dimethylamino)-2-propenone requires a high-temperature and long-duration reaction. Furthermore, the synthesis of 1-(1-methylindol-3-yl)-3-(dimethylamino)-2-propenone from 1-methyl-3-acetylindole also requires a high-temperature reflux reaction in DMA-DMF solvent. This method employs a convergent synthesis strategy, which is beneficial for improving the overall yield and reducing the risks of chemical synthesis; however, the high temperature and long reaction time introduce operational difficulties and increased costs for industrial-scale preparation.

[0009] The specific reaction route is as follows:

[0010]

[0011] It can be seen that the intermediate N in the above route 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (structural formula below) is reduced to nitro and amidated to give osimertinib. The yield of this intermediate affects the yield of the entire route.

[0012] Summary of the Invention

[0013] To address the shortcomings of existing technologies, the osimertinib intermediate N in existing technologies is... 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 An improved method for synthesizing -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine is proposed, providing a synthetic method with readily available raw materials, simple process, convenient operation, and higher yield, thereby reducing costs.

[0014] This invention is specifically achieved through the following technical solutions:

[0015] Reaction solvent A and compound 2 were added to a reaction vessel, stirred, and cooled to temperature T1. NaH and ethyl formate were added, and the mixture was heated to reflux. After confirming the reaction was complete, the mixture was concentrated to dryness under reduced pressure. Solvent B and compound 3 were then added to the concentrate, and the mixture was stirred and heated to temperature T2. After confirming the reaction was complete, the final product was obtained through post-processing. The reaction route is as follows:

[0016]

[0017] Detailed operation steps:

[0018] Add reaction solvent A and compound 2 to the reaction vessel, stir and cool to temperature T1, add NaH and ethyl formate, heat under reflux for 6-8 hours, and check that the reaction is complete. Concentrate under reduced pressure to dryness to obtain unpurified compound 2-1. Then add solvent B and compound 3 to the concentrate, control the temperature T2 and stir for 8-10 hours. Check that the reaction is complete, and then process to obtain the target product.

[0019] In a preferred embodiment, the molar ratio of compound 2, NaH, and ethyl formate is 1.00:(1.10-1.30):(1.20-1.50); ​​preferably 1.00:1.20:1.30.

[0020] In a preferred embodiment, the molar ratio of compound 3 to compound 2 is 1.00:(1.10-1.30); more preferably 1.00:1.20.

[0021] In a preferred embodiment, solvent A is one of anhydrous tetrahydrofuran and anhydrous acetonitrile.

[0022] In a preferred embodiment, solvent B is one of n-butanol, 2-butanol, n-propanol, and 1,4-dioxane; preferably n-butanol.

[0023] In a preferred embodiment, the temperature T1 is 0–10°C.

[0024] In a preferred embodiment, the temperature control temperature T2 is 95–105°C.

[0025] In the preferred embodiment, the post-processing is as follows: after the reaction is completed and cooled to room temperature, water is added to the reaction solution and then extracted with dichloromethane. The organic phase is washed with saturated brine and dried with anhydrous Na2SO4. The solution is concentrated to dryness to obtain a crude product. The crude product is then slurried with a mixture of isopropyl acetate and n-heptane at room temperature and filtered. The filter cake is dried to obtain a yellow to orange-red solid compound 1.

[0026] In a preferred embodiment, the ratio of isopropyl acetate / n-heptane mixture is 1:1 (v / v).

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] (1) This invention provides a method for synthesizing osimertinib intermediates, using common N-methyl-3-acetylindole as the starting material, and using common chemicals such as sodium hydride and ethyl formate in the intermediate steps, which has the advantage of readily available raw materials.

[0029] (2) In the synthesis of osimertinib intermediate, the present invention adopts a one-pot method to combine two steps of reaction, which simplifies the experimental operation and reduces the discharge of experimental waste; the present invention has fewer reaction steps, milder reaction conditions, and convenient post-processing operation.

[0030] (3) This invention is a synthesis method with higher yield and better purity, which can effectively reduce costs and is conducive to the industrial production of the active pharmaceutical ingredient, and has good industrial application prospects. Attached Figure Description

[0031] Figure 1 This is the HPLC chromatogram of Example 1. Detailed Implementation

[0032] The beneficial effects of the present invention are further described below through embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0033] The materials used in the experiment can be purchased or prepared by referring to existing publicly available technologies;

[0034] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0035]

[0036] Compound 2-1: 1 H-NMR (400MHz, CDCl3)δ=8.36(m,1H),8.27(d,1H),7.73(s,1H),7.35-7.29(m,3H),6.19(d,1H),3.85(s,2H),3.80(s,3H).HRMS Cacld for C 12 H 12 NO2 + :([M+H] + 202.0863; Found: 202.0869.

[0037] Synthesis of Compound 1

[0038] Example 1

[0039] Compound 2 (20.78 g, 120 mmol) was added to anhydrous tetrahydrofuran (200 mL), cooled to 0–10 °C, stirred, and 60% NaH (5.76 g, 144 mmol) was added. Ethyl formate (11.56 g, 156 mmol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was heated under reflux for 6–8 hours. The reaction was confirmed to be complete, and the solvent was removed by concentration under reduced pressure to obtain unpurified compound 2-1. n-Butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, and the mixture was stirred at 100 °C for 11 hours. The reaction was confirmed to be complete, cooled to room temperature, and water (450 mL) was added. The mixture was then extracted with dichloromethane (450 mL × 2). The organic phase was washed with saturated brine and dried with anhydrous Na2SO4. The crude product was concentrated to dryness and added to a mixture of isopropyl acetate (200 mL) and n-heptane (200 mL). The mixture was stirred at room temperature for 1–2 hours. After filtration, the filter cake was dried under vacuum at 60–70 °C to give a yellow to orange-red solid compound 1 with a yield of 95.4% and an HPLC purity of 97.71%.

[0040] Example 2

[0041] Compound 2 (20.78 g, 120 mmol) was added to anhydrous tetrahydrofuran (200 mL), cooled to 0–10 °C, stirred, and 60% NaH (5.76 g, 144 mmol) was added. Ethyl formate (11.56 g, 156 mmol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was heated to reflux for 6–8 hours. The reaction was confirmed to be complete, and the solvent was removed by concentration under reduced pressure to obtain unpurified compound 2-1. Propanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, and the mixture was stirred at 95 °C for 12 hours. The reaction was confirmed to be complete, cooled to room temperature, and water (450 mL) was added. The mixture was then extracted with dichloromethane (450 mL × 2). The organic phase was washed with saturated brine and dried with anhydrous Na2SO4. The crude product was concentrated to dryness and added to a mixture of isopropyl acetate (200 mL) and n-heptane (200 mL). The mixture was stirred at room temperature for 1–2 hours. After filtration, the filter cake was dried under vacuum at 60–70 °C to obtain a yellow to orange-red solid compound 1 with a yield of 91.3% and an HPLC purity of 97.63%.

[0042] Example 3

[0043] Compound 2 (20.78 g, 120 mmol) was added to anhydrous tetrahydrofuran (200 mL), cooled to 0–10 °C, stirred, and 60% NaH (5.76 g, 144 mmol) was added. Ethyl formate (11.56 g, 156 mmol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was heated under reflux for 6–8 hours. The reaction was confirmed to be complete, and the solvent was removed by concentration under reduced pressure to obtain unpurified compound 2-1. 1,4-Dioxane (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, and the mixture was stirred at 105 °C for 10 hours. The reaction was confirmed to be complete, cooled to room temperature, and water (450 mL) was added. The mixture was then extracted with dichloromethane (450 mL × 2). The organic phase was washed with saturated brine and dried with anhydrous Na2SO4. The crude product was concentrated to dryness and added to a mixture of isopropyl acetate (200 mL) and n-heptane (200 mL). The mixture was stirred at room temperature for 1–2 hours. After filtration, the filter cake was dried under vacuum at 60–70 °C to give a yellow to orange-red solid compound 1 with a yield of 93.2% and an HPLC purity of 97.65%.

[0044] Example 4

[0045] Compound 2 (19.05 g, 110 mmol) was added to anhydrous tetrahydrofuran (200 mL), cooled to 0–10 °C, stirred, and 60% NaH (5.28 g, 132 mmol) was added. Ethyl formate (10.59 g, 143 mmol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was heated under reflux for 6–8 hours. The reaction was confirmed to be complete, and the solvent was removed by concentration under reduced pressure to obtain unpurified compound 2-1. To the concentrate, n-butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added, and the mixture was stirred at 100 °C for 11 hours. The reaction was confirmed to be complete, cooled to room temperature, and water (450 mL) was added. The mixture was then extracted with dichloromethane (450 mL × 2). The organic phase was washed with saturated brine and dried with anhydrous Na2SO4. The crude product was concentrated to dryness and added to a mixture of isopropyl acetate (200 mL) and n-heptane (200 mL). The mixture was stirred at room temperature for 1–2 hours. After filtration, the filter cake was dried under vacuum at 60–70 °C to give a yellow to orange-red solid compound 1 with a yield of 90.9% and an HPLC purity of 97.62%.

[0046] Example 5

[0047] Compound 2 (22.52 g, 130 mmol) was added to anhydrous tetrahydrofuran (200 mL), cooled to 0–10 °C, stirred, and 60% NaH (6.24 g, 156 mmol) was added. Ethyl formate (12.52 g, 169 mmol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was heated under reflux for 6–8 hours. The reaction was confirmed to be complete, and the solvent was removed by concentration under reduced pressure to obtain unpurified compound 2-1. n-Butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, and the mixture was stirred at 100 °C for 11 hours. The reaction was confirmed to be complete, cooled to room temperature, and water (450 mL) was added. The mixture was then extracted with dichloromethane (450 mL × 2). The organic phase was washed with saturated brine and dried with anhydrous Na2SO4. The crude product was concentrated to dryness and added to a mixture of isopropyl acetate (200 mL) and n-heptane (200 mL). The mixture was stirred at room temperature for 1–2 hours. After filtration, the filter cake was dried under vacuum at 60–70 °C to give a yellow to orange-red solid compound 1 with a yield of 94.5% and an HPLC purity of 97.60%.

[0048] Example 6

[0049] Compound 2 (20.78 g, 120 mmol) was added to anhydrous acetonitrile (200 mL), cooled to 0–10 °C, stirred, and 60% NaH (6.24 g, 156 mmol) was added. Ethyl formate (13.33 g, 180 mmol) was added dropwise at 0–10 °C. After the addition was complete, the mixture was heated to reflux for 6 hours. The reaction was confirmed to be complete, and the solvent was removed by concentration under reduced pressure to obtain unpurified compound 2-1. n-Butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, and the mixture was stirred at 100 °C for 11 hours. The reaction was confirmed to be complete, cooled to room temperature, and water (450 mL) was added. The mixture was then extracted with dichloromethane (450 mL × 2). The organic phase was washed with saturated brine and dried with anhydrous Na2SO4. The crude product was concentrated to dryness and added to a mixture of isopropyl acetate (200 mL) and n-heptane (200 mL). The mixture was stirred at room temperature for 1–2 hours. After filtration, the filter cake was dried under vacuum at 60–70 °C to give a yellow to orange-red solid compound 1 with a yield of 94.9% and an HPLC purity of 97.62%.

Claims

1. A method for synthesizing an osimertinib intermediate, characterized in that, Reaction solvent A and compound 2 were added to a reaction vessel, stirred, and cooled to temperature T1. NaH and ethyl formate were added, and the mixture was heated to reflux. After confirming the reaction was complete, the mixture was concentrated to dryness under reduced pressure. Then, solvent B and compound 3 were added to the concentrate, and the mixture was stirred and heated to temperature T2. After confirming the reaction was complete, the product was obtained through post-processing. The reaction route is as follows: ； Solvent A is one of anhydrous tetrahydrofuran and anhydrous acetonitrile; Solvent B is one of n-butanol, 2-butanol, n-propanol, and 1,4-dioxane; The temperature T1 is 0–10℃; The temperature control temperature T2 is 95-105℃.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 2, NaH, and ethyl formate is 1.00:(1.10-1.30):(1.20-1.50).

3. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 2, NaH, and ethyl formate is 1.00:1.20:1.

30.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 3 to compound 2 is 1.00:(1.10~1.30).

5. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 3 to compound 2 is 1.00:1.

20.

6. The synthesis method according to claim 1, characterized in that, The solvent B is n-butanol.

7. The synthesis method according to claim 1, characterized in that, The post-processing is as follows: After the reaction is completed and cooled to room temperature, water is added to the reaction solution and then extracted with dichloromethane. The organic phase is washed with saturated brine and dried with anhydrous Na2SO4. The solution is concentrated to dryness to obtain a crude product. The crude product is slurried with a mixture of isopropyl acetate and n-heptane at room temperature and then filtered. The filter cake is dried to obtain a yellow to orange-red solid compound 1.

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