Synthetic method of osimertinib intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthetic method of an osimertinib intermediate. 1-methyl-3-acetyl indole is used as a raw material to react with ethyl formate; the obtained intermediate is not purified and is directly subjected to cyclization with 1-(4-((2-(dimethylamino) ethyl) (methyl) amino)-2-methoxy-5-nitrophenyl) guanidine to prepare N1-(2-(dimethylamino) ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indole-3-yl) pyrimidine-2-yl)-2-nitrobenzene-1, 4-diamine. The synthetic route is mild in reaction condition, simple in post-treatment, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular relates to a method for synthesizing an osimertinib intermediate. Background Art

[0002] AstraZeneca's Tagrisso (osimertinib, osimertinib, AZD9291) is used to treat patients with metastatic non-small cell lung cancer (NSCLC) carrying EGFR T790M mutation and who are refractory to EGFR tyrosine kinase inhibitors. It was approved in the United States on November 13, 2015 under accelerated approval. The structural formula of AZD9291 is as follows:

[0003]

[0004] The compound patent of osimertinib is WO2013014448 (applicant: AstraZeneca), which not only protects osimertinib but also discloses the synthesis method of osimertinib: the method uses 2-methoxy-4-fluoroaniline as the starting material, first nitrates to obtain 2-methoxy-4-fluoro-5-nitroaniline, then reacts 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-indol-3-yl)pyrimidin-2-amine, and then N,N,N'-trimethylethylenediamine nucleophilically replaces the fluorine atom of the intermediate 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, and then the nitro group is reduced with iron powder, and then the amino group formed by the reduction is reacted with acryloyl chloride to obtain AZD9291 (Osimertinib). And the intermediate N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 The yield of the preparation of -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine is not high, resulting in a low overall yield of the route. J. Med. Chem., 57(20), 8249-8267, 2014; J. Chem. Res., 39(6), 318-320; 2015, also disclosed a similar route method.

[0005] The reaction route is as follows:

[0006]

[0007] In addition, CN 114634484 A discloses a method for preparing osimertinib or its salts which is improved on the above-mentioned route. 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 was subjected to reduction of the nitro group under the action of hydrogen and palladium on carbon, and directly coupled with 3-chloropropionyl chloride to form an amide product without separation.

[0008] CN106366072A, CN106366022A and Journal of Heterocyclic Chemistry, 54(5), 2898-2901; 2017 disclose a new synthesis method: (1) Cyclization: 1-(2-methoxy-4-fluoro-5-nitrophenyl)guanidine and N,N,N'-trimethylethylenediamine are subjected to nucleophilic substitution 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 reduced by hydrogenation 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) Amidation: 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 and acryloyl chloride are used as raw materials to prepare AZD9291. Among them, the cyclization process of 1-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)guanidine and 1-(1-methylindol-3-yl)-3-(dimethylamino)-2-propenone requires high temperature and a long reaction process. In addition, 1-methyl-3-acetylindole also requires high temperature reflux reaction in DMA-DMF solvent during the synthesis of 1-(1-methylindol-3-yl)-3-(dimethylamino)-2-propenone. This method adopts a convergent synthesis strategy, which is beneficial to improve the overall yield and reduce the risk of chemical synthesis, but the high temperature and long reaction time bring operational difficulties and increased costs to industrial scale-up 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 as follows) is then subjected to reduction of the nitro group and amidation reaction to obtain osimertinib. The yield of this intermediate affects the yield of the entire route.

[0012] Summary of the invention

[0013] In view of the defects existing in the prior art, the osimertinib intermediate N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 The invention discloses an improved method for synthesizing 2-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine, and provides a method for synthesizing 2-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine, which has the advantages of easy raw material acquisition, simple process, convenient operation and higher yield, so as to reduce the cost.

[0014] The present invention is specifically implemented through the following technical solutions:

[0015] Add reaction solvent A and compound 2 to the reaction vessel, stir and cool to temperature T1, add NaH and ethyl formate, heat and reflux, and after detection, the reaction is complete, and concentrate to dryness under reduced pressure; then add solvent B and compound 3 to the concentrate, control the temperature to T2, stir and react, after detection, the reaction is complete, and the target product is obtained by post-treatment. The reaction route is as follows:

[0016]

[0017] Specific steps:

[0018] Add reaction solvent A and compound 2 to the reaction container, stir and cool to temperature T1, add NaH and ethyl formate, heat and reflux for 6 to 8 hours, and the reaction is complete after detection. Concentrate to dryness under reduced pressure to obtain unpurified compound 2-1; then add solvent B and compound 3 to the concentrate, control the temperature to T2, stir and react for 8 to 10 hours, and the reaction is complete after detection. Post-treatment is performed 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); preferably 1.00:1.20.

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

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

[0023] Preferably, the temperature T1 is 0-10°C.

[0024] Preferably, the temperature control temperature T2 is 95-105°C.

[0025] Preferred embodiment, the post-treatment: after the reaction is completed, cool to room temperature, add water to the reaction solution and then extract with dichloromethane, wash the organic phase with saturated brine, and then dry with anhydrous Na2SO4, concentrate to dryness to obtain a crude product, the crude product is slurried with an isopropyl acetate / n-heptane mixture at room temperature and then filtered, and the filter cake is dried to obtain a yellow to orange solid compound 1.

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

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

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

[0029] (2) When synthesizing the osimertinib intermediate, the present invention adopts a one-pot method to combine two-step reactions, which simplifies the experimental operation and reduces the discharge of experimental waste. The present invention has fewer reaction steps, mild reaction conditions, and convenient post-processing operations.

[0030] (3) The present invention is a synthesis method with higher yield and better purity, which can effectively reduce costs, is conducive to the industrial production of the raw material drug, and has good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the HPLC spectrum of Example 1. DETAILED DESCRIPTION

[0032] The beneficial effects of the present invention are further described below by way of examples. It should be correctly understood that the examples of the present invention are provided only for the purpose of illustrating the present invention, rather than limiting the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention all fall within the scope of protection claimed in the present invention.

[0033] The materials used in the experiment can be purchased or prepared according to existing public technologies;

[0034] In the following embodiments, 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, heated under reflux for 6-8 hours after the addition, and the reaction was complete after detection, and the solvent was removed by decompression and concentration to obtain unpurified compound 2-1. n-Butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, stirred at 100°C for 11 hours, and the reaction was complete after detection, cooled to room temperature, added with water (450 mL) and extracted with dichloromethane (450 mL×2). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to obtain a crude product. The crude product was added to a mixture of isopropyl acetate (200 mL) / n-heptane (200 mL), stirred at room temperature for 1 to 2 hours, and filtered. The filter cake was dried at 60 to 70°C under vacuum to obtain 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, heated under reflux for 6-8 hours after the addition, and the reaction was complete after detection, and the solvent was removed by decompression and concentration to obtain unpurified compound 2-1. n-Propanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, stirred at 95°C for 12 hours, and the reaction was complete after detection, cooled to room temperature, added with water (450 mL) and extracted with dichloromethane (450 mL×2). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to obtain a crude product. The crude product was added to a mixture of isopropyl acetate (200 mL) / n-heptane (200 mL), stirred at room temperature for 1 to 2 hours, and filtered. The filter cake was dried at 60 to 70°C under vacuum to obtain a yellow to orange 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, heated under reflux for 6-8 hours after the addition, and the reaction was complete after detection, and the solvent was removed by decompression and concentration to obtain unpurified compound 2-1. 1,4-dioxane (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, stirred at 105°C for 10 hours, and the reaction was complete after detection, cooled to room temperature, added with water (450 mL) and extracted with dichloromethane (450 mL×2). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to obtain a crude product. The crude product was added to a mixture of isopropyl acetate (200 mL) / n-heptane (200 mL), stirred at room temperature for 1 to 2 hours, and filtered. The filter cake was dried at 60 to 70°C under vacuum to obtain a yellow to orange 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, heated under reflux for 6-8 hours after the addition, and the reaction was complete after detection, and the solvent was removed by decompression and concentration to obtain unpurified compound 2-1. n-Butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, stirred at 100°C for 11 hours, and the reaction was complete after detection, cooled to room temperature, added with water (450 mL) and extracted with dichloromethane (450 mL×2). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to obtain a crude product. The crude product was added to a mixture of isopropyl acetate (200 mL) / n-heptane (200 mL), stirred at room temperature for 1 to 2 hours, and filtered. The filter cake was dried at 60 to 70°C under vacuum to obtain a yellow to orange 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, heated under reflux for 6-8 hours after the addition, and the reaction was complete after detection, 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, stirred at 100°C for 11 hours, and the reaction was complete after detection, cooled to room temperature, added with water (450 mL) and extracted with dichloromethane (450 mL×2). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to obtain a crude product. The crude product was added to a mixture of isopropyl acetate (200 mL) / n-heptane (200 mL), stirred at room temperature for 1 to 2 hours, and filtered. The filter cake was dried at 60 to 70°C under vacuum to obtain a yellow to orange 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, heated under reflux for 6 hours after the addition, and the reaction was complete after detection, and the solvent was removed by decompression and concentration to obtain unpurified compound 2-1. n-Butanol (150 mL) and compound 3 (31.04 g, 100 mmol) were added to the concentrate, stirred at 100°C for 11 hours, and the reaction was complete after detection, cooled to room temperature, added with water (450 mL) and extracted with dichloromethane (450 mL×2). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to dryness to obtain a crude product. The crude product was added to a mixture of isopropyl acetate (200 mL) / n-heptane (200 mL), stirred at room temperature for 1 to 2 hours, and filtered. The filter cake was dried at 60 to 70°C under vacuum to obtain a yellow to orange 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: Add reaction solvent A and compound 2 to the reaction container, stir and cool to temperature T1, add NaH and ethyl formate, heat and reflux, and after detection, the reaction is complete, and concentrate to dryness under reduced pressure; then add solvent B and compound 3 to the concentrate, control the temperature to T2, stir and react, after detection, the reaction is complete, and post-process to obtain the target product; the reaction route is as follows:

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); ​​preferably 1.00:1.20:1.

30.

3. 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); preferably 1.00:1.

20.

4. The synthesis method according to claim 1, characterized in that The solvent A is one of anhydrous tetrahydrofuran and anhydrous acetonitrile.

5. The synthesis method according to claim 1, characterized in that The solvent B is one of n-butanol, 2-butanol, n-propanol and 1,4-dioxane; n-butanol is preferred.

6. The synthesis method according to claim 1, characterized in that The temperature T1 is 0-10°C.

7. The synthesis method according to claim 1, characterized in that The temperature control temperature T2 is 95-105°C.

8. The synthesis method according to claim 1, characterized in that The post-treatment: After the reaction is completed, cool to room temperature, add water to the reaction solution and then extract with dichloromethane, wash the organic phase with saturated brine, and then dry with anhydrous Na2SO4, concentrate to dryness to obtain a crude product, and the crude product is slurried with an isopropyl acetate / n-heptane mixture at room temperature and then filtered, and the filter cake is dried to obtain a yellow to orange solid compound 1.

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