CN116655601A - A kind of synthetic method of osimertinib - Google Patents

Abstract

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

Description

A kind of synthetic method of osimertinib

technical field

The invention relates to the technical field of synthesis of pharmaceutical compounds, in particular to a synthesis method of osimertinib.

Background technique

Osimertinib (structural formula shown in formula I) is currently the best-selling third-generation EGFR inhibitor in the world, and is mainly used for the treatment of non-small cell lung cancer.

At present, there are many reports on the synthesis method 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.

In the actual preparation of osimertinib, it was found that the method of reacting intermediate 1 with acryloyl chloride, due to the poor stability of acryloyl chloride, is easy to polymerize, thereby easily producing polymerized impurities, and it is also easy to generate other impurities with intermediate 1, resulting in Product separation and purification are difficult, and the product purity is low, which also affects the yield. Adopt the method that intermediate 1 reacts with 3-chloropropionyl chloride, then easily produce two molecular products (as shown in formula II), also exist product separation and purification difficulty, product purity is low, the problem such as yield is not high.

In view of the above problems existing in the preparation of osimertinib at present, it is necessary to develop a new synthesis method, which is of great significance to realize the industrial production of osimertinib.

Contents of the invention

The technical problem mainly solved by the present invention is to provide a synthetic method of osimertinib, which can reduce the generation of by-products and improve the yield of the product.

In order to solve the problems of the technologies described above, the present invention adopts the following technical solutions:

A kind of synthetic method of osimertinib, the reaction equation of described synthetic method is:

Wherein, the substituent R ₁ in the intermediate 2 represents H, -CN or -NO ₂ ;

The synthesis method comprises the steps of: mixing the intermediate 1, the intermediate 2 and a solvent, then adding a base, and reacting at elevated temperature to obtain the product osimertinib.

As an embodiment of the present invention, the substituent R ₁ in the intermediate 2 represents -CN or -NO ₂ .

Preferably, the substituent R ₁ in the intermediate 2 represents -NO ₂ .

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

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

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

Preferably, the base is sodium bicarbonate.

As one embodiment of the present invention, the alkali is added in batches.

As an embodiment of the present invention, the heating reaction includes: heating to 20-50° C., and then keeping warm for reaction.

Preferably, the temperature raising reaction includes: heating to 38-42° C., and then maintaining the temperature for the reaction.

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

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

As an embodiment of the present invention, the synthetic method of osimertinib provided by the present invention comprises steps:

Firstly, the intermediate 1 is added into the solvent to obtain the reaction solution 1;

Under stirring, add the mixed solution of the intermediate 2 and the solvent to the reaction solution 1 to obtain the reaction solution 2;

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

As an embodiment of the present invention, the time for the heat preservation reaction is 10-18 hours, preferably the reaction time is 10-15 hours.

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

Detailed ways

The technical solutions of the present invention will be described in detail below through examples.

The raw materials used in the following examples, unless otherwise specified, were purchased.

Example 1

This embodiment provides a kind of synthetic method of osimertinib, and the reaction equation is:

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

This synthetic method comprises the following steps:

Add 445g of intermediate 1 into 2L of tetrahydrofuran solvent to obtain reaction solution 1;

Dilute 177.6g of intermediate 2 (1.2eq) with 1L of tetrahydrofuran solvent to obtain a mixture of intermediate 2 and tetrahydrofuran solvent;

Then, under stirring, add the prepared mixed solution of intermediate 2 and tetrahydrofuran solvent to the reaction solution 1 to obtain the reaction solution 2;

Then add 121.2g (1.2eq) triethylamine in batches to the reaction solution 2, and control the temperature of the reaction system not to exceed 20°C during the addition process; after the triethylamine is added, heat the reaction system, heat it to 40°C and keep it warm After 12 hours, the monitoring raw material intermediate 1 disappeared, and the reaction ended.

Post-treatment the reaction, first remove the solvent by rotary evaporation, then cool the residue of rotary evaporation to below 5°C, then slowly add 1.5L of 1mol/L dilute hydrochloric acid solution, stir for 30 minutes after the addition, and then extract with ethyl acetate for 2 Once, the temperature of the remaining water phase was lowered to about 0°C. At this time, 1.5 L of 1 mol/L sodium hydroxide aqueous solution was slowly added, and then stirred and crystallized at 0°C for 5 hours to obtain 224.5 g of osimertinib solids, with a yield of 45.0 %. The HPLC purity of the product is 99.1%.

Example 2-3

Example 2 and Example 3 respectively provide a synthesis method of osimertinib, mainly investigating the influence of using different intermediates 2 on the reaction.

The difference between embodiment 2 and embodiment 3 and embodiment 1 is that the intermediate 2 adopted is different, and other conditions are all the same.

The structural formula and experimental results of the intermediate 2 used in Example 2 and Example 3 are specifically shown in Table 1.

Table 1

It can be seen from the above table that when the substituent R in the intermediate ₂ is -NO ₂ , the product yield is significantly improved. It is therefore preferred that the substituent R ₁ in intermediate 2 represents —NO ₂ , followed by the substituent R ₁ in intermediate 2 representing —CN.

Example 4-6

Examples 4-6 respectively provide a synthesis method of osimertinib, mainly investigating the influence of using different bases on the reaction.

The difference between embodiment 4-6 and embodiment 2 is that the alkali that adopts is different, and other conditions are all the same.

The alkalis and experimental results used in Examples 4-6 are specifically shown in Table 2.

Table 2

As can be seen from the above table, when the alkali used is sodium bicarbonate, under the same conditions, the yield of the product is the highest, which can reach more than 90%. So the base is preferably sodium bicarbonate.

Example 7-9

Examples 7-9 respectively provide a synthesis method of osimertinib, mainly investigating the influence of using different solvents on the reaction.

The difference between embodiment 7-9 and embodiment 4 is only that the solvent adopted is different, and other conditions are all the same.

The solvents and experimental results used in Examples 7-9 are specifically shown in Table 3.

table 3

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

Examples 10-11

Examples 10-11 respectively provide a synthesis method of osimertinib, mainly investigating the influence of different reaction temperatures on the reaction.

The difference between embodiment 10-11 and embodiment 7 is only that the reaction temperature is different, and other conditions are all the same.

The reaction temperature and experimental results used in Examples 10-11 are specifically shown in Table 4.

Table 4

It can be seen from the above table that the reaction temperature has a certain influence on the yield of the reaction product, and the reaction temperature is preferably in the range of 25-40°C, more preferably at about 40°C.

Example 12-13

Examples 12-13 respectively provide a synthesis method of osimertinib, mainly investigating the influence of using different feeding equivalents of intermediate 2 on the reaction.

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

The feeding equivalents and experimental results used in Examples 12-13 are specifically shown in Table 5.

table 5

It can be seen from the above table that the feeding amount of intermediate 2 is preferably: the feeding molar ratio of intermediate 1 and intermediate 2 is 1: (1.2-1.5), more preferably 1:1.2.

It can be seen from the above examples that the synthesis method of the present invention can successfully prepare the target product osimertinib. Especially under specific conditions, for example, through specific optimization of reactants, reaction solvent, reaction temperature and feed amount, etc., the target product can be obtained in high yield.

After testing, the HPLC purity of the osimertinib product obtained in the above Examples 1-13 is between 99.0% and 99.5%, and the product purity is high.

The above descriptions are only examples of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent transformations made using the content of the description of the present invention, or directly or indirectly used in other related technical fields, are included in the scope of the present invention. within the scope of patent protection.

Claims (10)

1. a synthetic method of osimertinib, is characterized in that, the reaction equation of described synthetic method is: Wherein, R ₁ represents H, -CN or -NO ₂ ; The synthesis method comprises the steps of: mixing the intermediate 1, the intermediate 2 and a solvent, then adding a base, and reacting at elevated temperature to obtain the product osimertinib. 2. The synthesis method according to claim 1, wherein the substituent R ₁ in the intermediate 2 represents -CN or -NO ₂ , preferably, the substituent R ₁ in the intermediate 2 represents -NO ₂ . 3. the synthetic method according to claim 1 or 2, is characterized in that, described solvent is selected from at least one in THF, ethyl acetate, acetonitrile, N,N-dimethylformamide; Preferably, the Said solvent is selected from ethyl acetate and/or acetonitrile. 4. synthetic method according to claim 3, is characterized in that, described alkali is selected from any one in triethylamine, sodium bicarbonate, sodium carbonate, salt of wormwood, preferably, described alkali is sodium bicarbonate . 5. synthetic method according to claim 4, is characterized in that, described alkali is added in batches. 6. The synthesis method according to any one of claims 1-5, characterized in that, the heating reaction comprises: heating to 20-50°C, and then keeping warm for reaction; preferably, heating to 38-42°C , and then keep warm for the reaction. 7. The synthesis method according to claim 6, characterized in that, the molar ratio of intermediate 1 and intermediate 2 is 1:(1-1.5), preferably 1:(1.2-1.5), more preferably It is 1:1.2. 8. The synthesis method according to claim 7, characterized in that the molar ratio of the intermediate 1 and the base is 1:(1-1.5), preferably 1:1.2. 9. according to the synthetic method described in any one of claim 1-8, it is characterized in that, described synthetic method comprises the steps: Firstly, the intermediate 1 is added into the solvent to obtain the reaction solution 1; Under stirring, add the mixed solution of the intermediate 2 and the solvent to the reaction solution 1 to obtain the reaction solution 2; The alkali is added in batches to the reaction solution 2, and the temperature of the reaction system is controlled to be ≤20°C during the addition. After the addition of the alkali is completed, the reaction system is heated, and then kept warm for reaction to obtain the product osimertinib. 10. The synthesis method according to claim 9, characterized in that the time for the heat preservation reaction is 10-18 hours, preferably 10-15 hours.