Preparation method of osimertinib

Abstract

The invention provides a preparation method of osimertinib, which belongs to the field of chemical synthesis and comprises the following steps: performing palladium-carbon catalytic hydrogenation reduction on a compound I serving as a raw material; after reduction is finished, hydrogen protection is replaced by nitrogen protection, then 3-chloropropionyl chloride and organic alkali are added, after acylation reaction is finished, direct heating is performed to generate elimination reaction, and a compound II osimertinib is obtained through refining. According to the process, reduction acylation elimination is carried out in the same reaction system, meanwhile, 3-chloropropionyl chloride which is cheaper and easier to obtain is used, acryloyl is eliminated and introduced after acylation, and the whole synthesis process is efficient, economical and environmentally friendly. According to the method, a one-pot strategy is utilized for the first time to combine multiple steps of reactions into one step, the reductive acylation elimination reaction of the compound I is simply and efficiently achieved, and synthesis of osimertinib is completed.

Description

Technical Field

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

[0002] Osimertinib, also known as AZD9291, with the chemical name N-[2-[[2-(dimethylamino)-ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-acrylamide, is an oral, irreversible third-generation EGFR inhibitor developed by AstraZeneca. It was approved by the FDA in November 2015 for the treatment of non-small cell lung cancer (NSCLC). The structure of osimertinib is as follows:

[0003]

[0004] Patent CN107556293A discloses a synthetic process for osimertinib, using N-(2-dimethylamino-ethyl)-2-methoxy-N-methyl-N-[4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-yl]-5-nitro-phenyl-1,4-diamine as a starting material. The nitro group is reduced to an amino group under palladium-on-carbon catalysis, followed by acylation with acryloyl chloride to obtain osimertinib. The reaction route is as follows:

[0005]

[0006] The above-mentioned technical route provides a synthetic process for osimertinib, realizing the two-step reductive acylation reaction in the same reaction system. However, this route uses acryloyl chloride, which is highly toxic, as a raw material. Acryloyl chloride has a low flash point, easily releases highly toxic gases, and is expensive, thus failing to meet the standards of green chemistry. Furthermore, the above-mentioned technical route requires column chromatography purification, making it unsuitable for industrial production. Summary of the Invention

[0007] This invention addresses the shortcomings of existing technologies by providing a method for preparing osimertinib. This process achieves reductive acylation and elimination within the same reaction system, while using the cheaper and more readily available 3-chloropropionyl chloride. Acylation followed by elimination introduces an acryloyl group, making the entire synthesis process highly efficient, economical, and environmentally friendly.

[0008] This invention achieves this objective through the following technical solution:

[0009] A method for preparing osimertinib, the synthetic route is as follows:

[0010]

[0011] Includes the following steps:

[0012] Step 1: In the reaction vessel, the solution of compound I undergoes a hydrogenation reduction reaction under hydrogen protection and is catalyzed by palladium on carbon to generate intermediate I;

[0013] Step 2: Replace hydrogen protection with nitrogen protection, add 3-chloropropionyl chloride and an organic base to the reaction system, and obtain intermediate II after acylation.

[0014] Step 3: Intermediate II undergoes an elimination reaction upon direct heating to generate compound II, osimertinib.

[0015] Furthermore, the reaction temperature for the palladium-carbon catalytic hydrogenation reduction in step one is 15-30℃.

[0016] Furthermore, the diacylation reaction temperature in the step is 0-10℃.

[0017] Furthermore, the reaction temperature for the elimination reaction in step three is 75-85℃.

[0018] Furthermore, the catalyst used in the palladium-carbon hydrogenation reduction in step one is 5% palladium-carbon, and the amount used is 5%-10% of the weight of compound I.

[0019] Furthermore, the reaction solvent in step one is tetrahydrofuran or 1,4-dioxane.

[0020] Furthermore, in step two, the amount of 3-chloropropionyl chloride used is 1-1.2 molar equivalents of compound I.

[0021] Furthermore, the organic base in step two is N,N-diisopropylethylamine or triethylamine.

[0022] Furthermore, the amount of organic base used in step two is 6-10 molar equivalents of compound I.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] In the synthetic route designed in this invention, compound I undergoes a reduction reaction under palladium-carbon catalysis, followed by a direct condensation reaction with 3-chloropropionyl chloride without post-treatment or purification. After condensation, a direct heating reaction is performed to induce an elimination reaction, yielding osimertinib. This innovative "one-pot" strategy combines multiple reactions into a single step, achieving the reductive acylation elimination reaction of compound I. The process is simple, stable, efficient, economical, and environmentally friendly. Acylation is achieved using inexpensive, low-toxicity, stable, and readily available 3-chloropropionyl chloride. The reaction conditions are mild, the operation is simple, column chromatography purification is unnecessary, and the product can be obtained in high yield, making it suitable for industrial production. Attached Figure Description

[0025] Figure 1 Compound II prepared in Example 11 HMNR spectrum;

[0026] Figure 2 The HPLC spectrum of compound II prepared in Example 1 is shown. Detailed Implementation

[0027] Exemplary embodiments of the present invention will now be described in more detail with reference to the accompanying drawings. While exemplary embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the invention to those skilled in the art. It should be noted that, unless otherwise specified, the embodiments and features described herein can be combined with each other. The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0028] This invention discloses a method for preparing osimertinib. The specific reaction process is as follows: Compound I is added to a reaction solvent and heated to dissolve it. Then, 5% palladium on carbon is added at room temperature. Nitrogen is purged three times, followed by hydrogen. The reaction is carried out at 15-30°C for 12 hours (based on TLC monitoring). After hydrogenation, hydrogen is replaced with nitrogen, and the temperature is lowered to 0-10°C. Triethylamine and 3-chloropropionyl chloride are added dropwise, and the temperature is maintained at 0-10°C for approximately 4 hours (based on TLC monitoring). After acylation, the temperature is raised to 75-85°C, and the reaction is carried out for 8-12 hours (based on TLC monitoring). After the reaction is completed, the mixture is filtered. The filtrate is heated to 75-85°C, and water is added dropwise. After the addition is completed, the temperature is lowered to room temperature, and the mixture is stirred for 2-3 hours. The mixture is then filtered, and the filter cake is washed with a 1:1 mixture of reaction solvent and water. After vacuum drying, crude compound II is obtained. The crude product is purified by recrystallization from acetonitrile / water to obtain compound II, osimertinib.

[0029] The present invention will be further described below with reference to specific embodiments.

[0030] Example 1

[0031] 9.6 kg of compound I was added to 85.4 kg of tetrahydrofuran, heated to 45 °C to dissolve, then cooled to room temperature. 480 g of 5% palladium on carbon was added, and the mixture was purged with nitrogen three times, followed by hydrogen (0.1 MPa). The reaction was carried out at 15 °C for 12 hours (tracked by TLC). After hydrogenation, the mixture was purged with nitrogen, cooled to 0 °C, and 12.2 kg of triethylamine and 2.8 kg of 3-chloropropionyl chloride were slowly added dropwise at 0-10 °C, maintaining the temperature at 0 °C for 4 hours (tracked by TLC). After acylation, the temperature was raised to 75 °C and the reaction was carried out for 12 hours (tracked by TLC). After the reaction was complete, the mixture was filtered, and the filtrate was heated to 75 °C with 86 kg of water added dropwise. After the addition was complete, the mixture was cooled to room temperature and stirred for 2-3 hours. The mixture was then filtered, and the filter cake was washed with a 1:1 mixture of 10 kg of tetrahydrofuran and water and dried at 45 °C to obtain 7.8 kg of crude compound II. The crude product was added to 61.3 kg of acetonitrile, heated to 55 °C, and stirred for 30 minutes until the system was completely dissolved. Then, the temperature was slowly lowered to 20 °C, and 15.6 kg of water was slowly added dropwise. After the addition was complete, the mixture was kept at 20 °C and stirred for 3 hours. The solution was filtered and dried at 45 °C to obtain 7.1 kg of compound II, osimertinib, as a pale yellow solid powder, with a yield of 70%.

[0032] The prepared compound II 1 HMNR spectrum as follows Figure 1 As shown, 1 HNMR(400MHz,DMSO)δ2.19(s,6H),2.27(t,J=5.5Hz,2H),2.70(s,3H),2.87(t,J=5.4 Hz,2H),3.86(s,3H),3.90(s,3H),5.77(dd,1H),6.29(dd,1H),6.44(dd,1H),7.03(s ,1H),7.16(t,J=7.4Hz,1H),7.21-7.27(m,2H),7.51(d,J=8.1Hz,1H),7.91(s,1H),8 .24(d,J=7.9Hz,1H),8.34(d,J=5.3Hz,1H),8.69(s,1H),9.21(s,1H),10.22(s,1H).

[0033] The HPLC chromatogram of compound II prepared is shown below. Figure 2 As shown.

[0034] Example 2

[0035] 9.6 kg of compound I was added to 99.2 kg of 1,4-dioxane, heated to 50 °C to dissolve, then cooled to room temperature. 480 g of 5% palladium on carbon was added, and the mixture was purged with nitrogen three times, followed by hydrogen (0.1 MPa). The reaction was carried out at 30 °C for 12 hours (based on TLC monitoring). After hydrogenation, the mixture was purged with nitrogen, cooled to 10 °C, and then slowly added dropwise at 10 °C for approximately 4 hours (based on TLC monitoring). After acylation, the temperature was increased to 85 °C and the reaction was carried out for 8 hours (based on TLC monitoring). After the reaction was complete, the mixture was filtered. The filtrate was heated to 85°C, and 86 kg of water was added dropwise. After the addition was complete, the mixture was cooled to room temperature and stirred for 2-3 hours. The mixture was then filtered again, and the filter cake was washed with a 1:1 mixture of 1,4-dioxane and water. The cake was dried at 55°C to obtain 7.7 kg of crude compound II. 60.5 kg of acetonitrile was added to the crude product, and the mixture was heated to 60°C and stirred for 30 minutes until the system was completely dissolved. The temperature was then slowly lowered to 30°C, and 15.4 kg of water was added dropwise. After the addition was complete, the mixture was kept at 30°C and stirred for 3 hours. The mixture was filtered and dried at 45°C to obtain 6.9 kg of compound II, osimertinib, as a pale yellow solid powder, with a yield of 68%.

[0036] The present invention has been described in detail above through embodiments, but the content described is only an exemplary embodiment of the present invention and should not be considered as limiting the scope of the present invention. The scope of protection of the present invention is defined by the claims. Any technical solutions designed by those skilled in the art using the technical solutions described in the present invention, or designed by those skilled in the art under the inspiration of the technical solutions of the present invention, within the substance and protection scope of the present invention, to achieve the above-mentioned technical effects, or any equivalent changes and improvements made to the scope of the application, should still fall within the patent protection scope of the present invention.

Claims

1. A method for preparing osimertinib, characterized in that, The synthesis route is as follows: Includes the following steps: Step 1: In the reaction vessel, the solution of compound I undergoes a hydrogenation reduction reaction under hydrogen protection and is catalyzed by palladium on carbon to generate intermediate I; Step 2: Replace hydrogen protection with nitrogen protection, add 3-chloropropionyl chloride and an organic base to the reaction system, and obtain intermediate II after acylation. Step 3: Intermediate II undergoes an elimination reaction upon direct heating to generate compound II, osimertinib.

2. The method for preparing osimertinib according to claim 1, characterized in that, The reaction temperature for the palladium-carbon catalytic hydrogenation reduction in step one is 15-30℃.

3. The method for preparing osimertinib according to claim 1, characterized in that, The acylation reaction temperature in step two is 0-10℃.

4. The method for preparing osimertinib according to claim 1, characterized in that, The reaction temperature for the elimination reaction in step three is 75-85℃.

5. The method for preparing osimertinib according to claim 1, characterized in that, The catalyst used in the palladium-carbon hydrogenation reduction in step one is 5% palladium on carbon, and the amount used is 5%-10% of the weight of compound I.

6. The method for preparing osimertinib according to claim 1, characterized in that, The reaction solvent in step one is tetrahydrofuran or 1,4-dioxane.

7. The method for preparing osimertinib according to claim 1, characterized in that, In step two, the amount of 3-chloropropionyl chloride used is 1-1.2 molar equivalents of compound I.

8. The method for preparing osimertinib according to claim 1, characterized in that, The organic base in step two is N,N-diisopropylethylamine or triethylamine.

9. The method for preparing osimertinib according to claim 1, characterized in that, The amount of organic base used in step two is 6-10 molar equivalents of compound I.

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