A synthetic method of osimertinib

Abstract

The present invention belongs to the technical field of pharmaceutical compound synthesis and specifically discloses a method for synthesizing osimertinib. The synthesis method of the present invention comprises mixing intermediate 1 and intermediate 2 with a solvent, then adding a base, and reacting at elevated temperature to obtain the product osimertinib. The synthesis method of osimertinib provided by the present invention produces few by-products, has a high yield of osimertinib, and undergoes mild reaction conditions, making it suitable for industrial scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compound synthesis, and particularly to a method for synthesizing osimertinib. Background Art

[0002] Osimertinib (structural formula shown in Formula I) is currently the world's best-selling third-generation EGFR inhibitor, mainly used to treat non-small cell lung cancer.

[0003]

[0004] Currently, there are many reports on the synthesis methods of osimertinib, but the reported synthesis methods basically use the following intermediate 1 to react with acryloyl chloride or 3-chloropropionyl chloride to prepare osimertinib.

[0005]

[0006] In the actual preparation of osimertinib, it was found that the method using the reaction of intermediate 1 with acryloyl chloride is prone to polymerization due to its poor stability, thus easily generating polymerized impurities. It also easily reacts with intermediate 1 to form other impurities, making product separation and purification difficult, resulting in low product purity and affecting yield. The method using the reaction of intermediate 1 with 3-chloropropionyl chloride is prone to producing two molecules of product (as shown in Formula II), which also suffers from the problems of difficult product separation and purification, low product purity, and low yield.

[0007]

[0008] In view of the above problems existing in the current preparation of osimertinib, it is necessary to develop a new synthesis method, which is of great significance to the industrial production of osimertinib. Summary of the Invention

[0009] The main technical problem solved by the present invention is to provide a method for synthesizing osimertinib, which can reduce the generation of by-products and improve the yield of the product.

[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0011] A method for synthesizing osimertinib, wherein the reaction equation of the synthesis method is:

[0012]

[0013] Wherein, the substituent R1 in intermediate 2 represents H, -CN or -NO2;

[0014] The synthesis method comprises the steps of: mixing intermediate 1, intermediate 2 and a solvent, then adding a base, and heating the mixture to react to obtain the product osimertinib.

[0015] As one embodiment of the present invention, the substituent R1 in the intermediate 2 represents -CN or -NO2.

[0016] Preferably, the substituent R1 in the intermediate 2 represents -NO2.

[0017] As an embodiment of the present invention, the solvent is selected from at least one of tetrahydrofuran, ethyl acetate, acetonitrile, and N,N-dimethylformamide.

[0018] Preferably, the solvent is selected from ethyl acetate and / or acetonitrile.

[0019] As an embodiment of the present invention, the base is selected from any one of triethylamine, sodium bicarbonate, sodium carbonate, and potassium carbonate.

[0020] Preferably, the base is sodium bicarbonate.

[0021] As one embodiment of the present invention, the base is added in batches.

[0022] As an embodiment of the present invention, the temperature-raising reaction comprises: heating to 20-50° C. and then keeping the temperature to react.

[0023] Preferably, the temperature-raising reaction comprises: heating to 38-42° C. and then keeping the temperature to react.

[0024] As an embodiment of the present invention, the molar ratio of the intermediate 1 to the intermediate 2 is 1:(1-1.5), preferably 1:(1.2-1.5), and more preferably 1:1.2.

[0025] As an embodiment of the present invention, the molar ratio of the intermediate 1 to the base is 1:(1-1.5), preferably 1:1.2.

[0026] As one embodiment of the present invention, the present invention provides a method for synthesizing osimertinib, comprising the steps of:

[0027] First, the intermediate 1 is added to a solvent to obtain a reaction solution 1;

[0028] Under stirring, adding a mixture of the intermediate 2 and the solvent to the reaction solution 1 to obtain a reaction solution 2;

[0029] The base was added to the reaction solution 2 in batches. The temperature of the reaction system was controlled to be ≤20° C. during the addition process. After the addition of the base was completed, the reaction system was heated and then kept warm for reaction to obtain the product osimertinib.

[0030] As an embodiment of the present invention, the insulation reaction time is 10 to 18 hours, preferably 10 to 15 hours.

[0031] The synthesis method of osimertinib provided by the present invention has few by-products produced by the reaction, a high yield of osimertinib product, low toxicity of raw materials, mild reaction conditions, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is described in detail below through examples.

[0033] The raw materials used in the following examples were purchased unless otherwise specified.

[0034] Example 1

[0035] This embodiment provides a method for synthesizing osimertinib, and the reaction equation is:

[0036]

[0037] Specifically, in this embodiment, the substituent R1 on the intermediate 2 represents H, that is, the intermediate 2 is phenyl acrylate, and the structural formula is:

[0038]

[0039] The synthesis method comprises the following steps:

[0040] 445 g of intermediate 1 was added to 2 L of tetrahydrofuran solvent to obtain reaction solution 1;

[0041] 177.6 g of intermediate 2 (1.2 eq) was diluted with 1 L of tetrahydrofuran solvent to obtain a mixed solution of intermediate 2 and tetrahydrofuran solvent;

[0042] Then, a mixture of the prepared intermediate 2 and tetrahydrofuran solvent was added to the reaction solution 1 under stirring to obtain a reaction solution 2;

[0043] Then, 121.2 g (1.2 eq) of triethylamine was added to the reaction solution 2 in batches, and the temperature of the reaction system was controlled not to exceed 20° C. during the addition process. After the addition of triethylamine was completed, the reaction system was heated to 40° C. and then kept warm for 12 hours. The reaction was terminated by monitoring the disappearance of the raw material intermediate 1.

[0044] The reaction was post-processed by first removing the solvent by rotary evaporation. The residue was then cooled to below 5°C, followed by the slow addition of 1.5 L of a 1 mol / L dilute hydrochloric acid solution. The mixture was stirred for 30 minutes and then extracted twice with ethyl acetate. The remaining aqueous phase was cooled to approximately 0°C, followed by the slow addition of 1.5 L of a 1 mol / L aqueous sodium hydroxide solution. The mixture was then stirred at 0°C for 5 hours to allow crystallization. 224.5 g of osimertinib solid was obtained, with a yield of 45.0%. The product had an HPLC purity of 99.1%.

[0045] Example 2-3

[0046] Example 2 and Example 3 respectively provide a method for synthesizing osimertinib, which mainly investigates the effects of using different intermediates 2 on the reaction.

[0047] The difference between Example 2 and Example 3 and Example 1 is only that different intermediates 2 are used, and other conditions are the same.

[0048] The structural formula and experimental results of the intermediate 2 used in Examples 2 and 3 are shown in Table 1.

[0049] Table 1

[0050]

[0051] As can be seen from the table above, when the substituent R1 in intermediate 2 is -NO2, the product yield is significantly improved. Therefore, it is preferred that the substituent R1 in intermediate 2 represents -NO2, followed by the substituent R1 in intermediate 2 representing -CN.

[0052] Examples 4-6

[0053] Examples 4-6 respectively provide a method for synthesizing osimertinib, mainly examining the effects of different bases on the reaction.

[0054] The difference between Example 4-6 and Example 2 is only that different bases are used, and other conditions are the same.

[0055] The bases used in Examples 4-6 and the experimental results are shown in Table 2.

[0056] Table 2

[0057]

[0058]

[0059] As can be seen from the table above, when sodium bicarbonate is used as the base, under the same conditions, the yield of the product is the highest, reaching more than 90%. Therefore, sodium bicarbonate is preferably used as the base.

[0060] Examples 7-9

[0061] Examples 7-9 respectively provide a method for synthesizing osimertinib, mainly examining the effects of different solvents on the reaction.

[0062] The difference between Examples 7-9 and Example 4 is only that different solvents are used, and other conditions are the same.

[0063] The solvents used in Examples 7-9 and the experimental results are shown in Table 3.

[0064] Table 3

[0065]

[0066] As can be seen from the table above, when acetonitrile or ethyl acetate is used as the solvent, under the same conditions, the yield of the product is improved compared to that of tetrahydrofuran, up to 93.6%. Therefore, acetonitrile or ethyl acetate is preferably used as the reaction solvent.

[0067] Examples 10-11

[0068] Examples 10-11 respectively provide a method for synthesizing osimertinib, which mainly examines the effects of different reaction temperatures on the reaction.

[0069] The difference between Example 10-11 and Example 7 is only the reaction temperature, and other conditions are the same.

[0070] The reaction temperatures and experimental results used in Examples 10-11 are shown in Table 4.

[0071] Table 4

[0072]

[0073] As can be seen from the above table, the reaction temperature has a certain influence on the yield of the reaction product. The reaction temperature is preferably in the range of 25 to 40°C, and more preferably around 40°C.

[0074] Examples 12-13

[0075] Examples 12-13 respectively provide a method for synthesizing osimertinib, which mainly investigates the effects of different feed equivalents of intermediate 2 on the reaction.

[0076] The difference between Example 12-13 and Example 7 is only that the charging equivalent of intermediate 2 is different, and other conditions are the same.

[0077] The feed equivalents and experimental results used in Examples 12-13 are shown in Table 5.

[0078] Table 5

[0079]

[0080]

[0081] As can be seen from the above table, the feeding amount of intermediate 2 is preferably: the feeding molar ratio of intermediate 1 to intermediate 2 is 1:(1.2-1.5), more preferably 1:1.2.

[0082] The above examples demonstrate that the synthetic methods of the present invention can successfully produce the target product, osimertinib. In particular, under specific conditions, such as by optimizing the reactants, reaction solvent, reaction temperature, and feed amount, the target product can be obtained in high yield.

[0083] After testing, the HPLC purity of the osimertinib products obtained in the above Examples 1-13 was between 99.0% and 99.5%, and the product purity was high.

[0084] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent transformations made using the contents of the present invention specification, or any direct or indirect application in other related technical fields, are included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing osimertinib, characterized in that: The reaction equation of the synthesis method is: ； Wherein, R1 represents -NO2; The synthesis method comprises the steps of: mixing intermediate 1, intermediate 2 and a solvent, then adding a base, and reacting at a high temperature to obtain the product osimertinib; the solvent is selected from ethyl acetate and / or acetonitrile; and the base is sodium bicarbonate.

2. The synthesis method according to claim 1, wherein The base was added in portions.

3. The synthesis method according to claim 1 or 2, characterized in that The temperature-raising reaction comprises heating to 20-50° C. and then keeping the temperature to react.

4. The synthesis method according to claim 3, characterized in that The temperature-raising reaction comprises: heating to 38-42° C. and then keeping the temperature to react.

5. The synthesis method according to claim 1, characterized in that The molar ratio of the intermediate 1 to the intermediate 2 is 1:(1.2-1.5).

6. The synthesis method according to claim 5, characterized in that The molar ratio of the intermediate 1 to the intermediate 2 is 1:1.

2.

7. The synthesis method according to claim 1, characterized in that The molar ratio of the intermediate 1 to the base is 1:1.

2.

8. The synthesis method according to claim 1, characterized in that The synthesis method comprises the steps of: First, the intermediate 1 is added to a solvent to obtain a reaction solution 1; Under stirring, adding a mixture of the intermediate 2 and the solvent to the reaction solution 1 to obtain a reaction solution 2; The base was added to the reaction solution 2 in batches. The temperature of the reaction system was controlled to be ≤20° C. during the addition process. After the addition of the base was completed, the reaction system was heated and then kept warm for reaction to obtain the product osimertinib.

9. The synthesis method according to claim 8, characterized in that The heat preservation reaction time is 10 to 18 hours.

10. The synthesis method according to claim 9, characterized in that The heat preservation reaction time is 10 to 15 hours.

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