Osimertinib impurity as well as preparation method and application thereof

Abstract

The invention discloses an osimertinib impurity as well as a preparation method and application thereof, and according to the preparation method, cheap and easily available raw materials are combined with an alkali catalyst, a demethylation reagent, an organic solvent and the like, and the osimertinib impurity is prepared through addition and demethylation two-step reaction. A specific base catalyst, a demethylation reagent and an organic solvent are further selected, so that the purity and the yield of the osimertinib impurity can be remarkably improved. The method is simple to operate, and is beneficial to detecting and monitoring the impurity in the osimertinib synthesis process.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine and organic chemical synthesis, and more particularly relates to an osimertinib impurity, a preparation method thereof, and an application thereof. Background Art

[0002] Osimertinib (AZD9291) is a third-generation mutant-selective epidermal growth factor receptor tyrosine kinase inhibitor developed by AstraZeneca, UK. Osimertinib can target specific proteins (tyrosine kinases) inside cancer cells, inhibit cancer cells and prevent their growth, and takes effect quickly, which can rapidly relieve the related symptoms of tumors.

[0003] The chemical name of osimertinib is N-{2-{[2-(dimethylamino)ethyl(methyl)amino]-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl}prop-2-enamide, and the molecular formula is C 28 H 33 N 7 O 2， Molecular weight: 499.62, CAS number: 1421373-65-0, and the chemical structural formula is as follows:

[0004]

[0005] During the synthesis process of osimertinib, many impurities are generated. These impurities exist in the final product and affect the quality of osimertinib API. Therefore, it is necessary to detect and monitor the impurities during the preparation process of osimertinib, so as to control the quality of osimertinib API. However, during the preparation process, many unknown impurities are generated, and the content of the impurities is very low and difficult to separate. Therefore, it is difficult to obtain a sufficient amount of high-purity impurities and lack corresponding reference substances, and there is a lack of detection and monitoring of impurities during the preparation process of osimertinib.

[0006] Therefore, there is an urgent need to provide clear osimertinib impurities, a preparation method thereof, and an application thereof. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the defects and deficiencies that there are still many unknown impurities in the existing osimertinib, that is, the impurity reference substances are unknown and it is also difficult to separate them, and to provide an osimertinib impurity and a preparation method thereof; another object of the present invention is to provide the application of the osimertinib impurity as a reference substance.

[0008] The first object of the present invention is to provide an osimertinib impurity, and the osimertinib impurity has the structure shown in formula (II):

[0009]

[0010] The second object of the present invention is to provide a preparation method of the aforesaid osimertinib impurity, and the method comprises the following steps:

[0011] Step (1): React osimertinib and a basic catalyst with a reaction reagent in an organic solvent, and after the reaction is completed, separate the product to obtain Compound I shown in Formula I;

[0012] In the preparation method of the present invention, under a preferred scheme, the organic solvent and the reaction reagent can be added in an amount in excess of osimertinib, and there is no special ratio limit.

[0013] Step (2): React Compound I with a de-R group reagent in an organic solvent to obtain Compound II;

[0014] The structural formula of the aforesaid osimertinib is:

[0015] The structural formula of Compound I is as shown in Formula I: The aforesaid R is selected from C1-4 alkyl groups, and preferably, the aforesaid R is selected from methyl, ethyl, n-propyl or n-butyl.

[0016] Further, the basic catalyst in Step (1) is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium acetate, and preferably one or more of sodium carbonate, potassium carbonate or cesium carbonate.

[0017] Further, the organic solvent and the reaction reagent in Step (1) are independently selected from C1-4 alkyl alcohols;

[0018] Preferably, the organic solvent and the reaction reagent are the same C1-4 alkyl alcohol or different C1-4 alkyl alcohols;

[0019] Preferably, the C1-4 alkyl alcohol is selected from one or more of methanol, ethanol, n-propanol or n-butanol.

[0020] Further, the molar ratio of osimertinib to the basic catalyst in Step (1) is 1:2 to 5, preferably 1:3 to 4, and more preferably 1:3.6.

[0021] Further, the reaction temperature in Step (1) is 50 to 80 °C, and the reaction time is 20 to 24 h; preferably, the reaction temperature is 60 to 70 °C.

[0022] Further, the organic solvent in Step (2) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane.

[0023] Further, the de-R group reagent in Step (2) is selected from BBr 3 、AlCl 3, one or more of hydrobromic acid and hydroiodic acid, preferably BBr 3 .

[0024] Furthermore, in step (2), the molar ratio of compound I to the R-group removing reagent is 1:1 to 2, preferably 1:1.1 to 1.5, more preferably 1:1.2 to 1.4, and most preferably 1:1.3.

[0025] Furthermore, the reaction temperature in step (2) is 20-30°C; the reaction time is 3-5 h.

[0026] The third object of the present invention is to provide the application of the aforementioned osimertinib impurity in the quality control of osimertinib.

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

[0028] The present invention discovers a new osimertinib impurity and provides a preparation method for this impurity. Using osimertinib as the starting material, the osimertinib impurity is prepared through two steps of methoxylation and demethylation. The reagents used are cheap and easily available, the operation method is simple, and the molar conversion rate is high. It is beneficial to detect and monitor this impurity during the synthesis of osimertinib. Description of the Drawings

[0029] Figure 1 It is the mass spectrum of compound I prepared in Example 1 of the present invention.

[0030] Figure 2 It is the mass spectrum of compound II prepared in Example 1 of the present invention.

[0031] Figure 3 It is the 1H NMR spectrum of compound I prepared in Example 1 of the present invention.

[0032] Figure 4 It is the 1H NMR spectrum of II prepared in Example 1 of the present invention.

[0033] Figure 5 It is the HPLC chromatogram of the osimertinib API, and the chromatographic peak with a retention time of 18.28 is the chromatographic peak of compound II of this application. Detailed Embodiments

[0034] The following examples are used to further explain the present invention, but the examples do not limit the present invention in any form.

[0035] The synthesis route of the examples of the present invention is:

[0036]

[0037] Example 1:

[0038] (1) Preparation of Compound I:

[0039] Add 10.00 g (20.02 mmol) of osimertinib and 100.0 ml of methanol to the reaction flask. Dissolve 10.00 g of K 2 CO 3 (72.35 mmol) in 50 ml of water and add it dropwise. After adding, heat the mixture to 66 °C and react for 22 h. After monitoring the completion of the reaction by TLC, add 50.0 ml of water, cool the mixture to 25 °C for crystallization for 2.5 h, filter, and dry to obtain about 9.50 g of dry Compound I;

[0040] Take 20 mg of it, purify it by thin-layer chromatography, and perform MS and NMR analyses; The mass spectrum of Compound I is as shown in Figure 1 shown, and the 1H NMR spectrum is as shown in Figure 3 shown.

[0041] [M + H] + = 532.3, and the theoretical value is 532.30.

[0042] 1 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), δ 9.17 (s, 1H), δ 8.73 (s, 1H), δ 8.35 - 8.37 (m, 2H), δ 7.93 (s, 1H), δ 7.54 (m, 1H), δ 7.24 - 7.26 (m, 3H), δ 7.04 (s, 1H), δ 3.87, 3.95 (s, 6H), δ 3.70 (m, 2H), δ 3.30 (s, 3H), δ 2.92 (m, 2H), δ 2.72 (s, 3H), δ 2.61 (m, 2H), δ 2.30 (s, 2H), δ 2.22 (s, 6H).

[0043] (2) Preparation of Compound II:

[0044] Add 9.50 g of Compound I (17.88 mmol) to the reaction flask and dissolve it in 95.0 ml of dichloromethane (DCM). Add 24 ml of BBr 3 (1 M) solution (24 mmol) dropwise at 20 °C. After adding, react at 20 - 30 °C for 4 h and check the completion of the reaction by TLC.

[0045] Add 190 ml of water and adjust the pH to 7 - 8 with 10% Na 2 CO 3 solution. Take the DCM phase, concentrate it under reduced pressure to obtain an oily substance, and purify it by column chromatography using DCM:MeOH = 25:1 as the eluent to obtain about 8.0 g of dry Compound II; The mass spectrum of Compound II is as shown in Figure 2 shown, and the 1H NMR spectrum is as shown in Figure 4 shown.

[0046] [M+H] + = 518.3, the theoretical value is 518.28.

[0047] 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (S, 1H), δ 9.08 (S, 1H), δ 8.70 (S, 1H), δ 8.26 - 8.35 (M, 2H), δ 7.91 (S, 1H), δ 7.54 - 7.56 (M, 1H), δ 7.17 - 7.29 (M, 3H), δ 7.03 (S, 1H), δ 3.94 (S, 3H), δ 3.87 (S, 3H), δ 3.78 - 3.80 (M, 2H), δ 2.96 - 2.99 (M, 2H), δ 2.70 (S, 3H), δ 2.52, 2.56 (M, 3H), δ 2.45 (S, 2H), δ 2.32 (S, 6H).

[0048] Example 2:

[0049] (1) Preparation of Compound I: Add 10.00 g of osimertinib and 100 ml of methanol to a reaction flask, dissolve 7.65 g of Na 2 CO 3 dissolved in 50 ml of water and add dropwise. After adding, heat to 65 °C and react for 20 h. After checking the reaction is complete by TLC, add 50 ml of water, cool to 20 °C and crystallize for 2.5 h, filter, and dry to obtain about 9.00 g of dry Compound I.

[0050] The mass spectrometry and 1H NMR characterization data are basically the same as those in Example 1.

[0051] (2) Preparation of Compound II: Add 9.00 g of Compound I to a reaction flask, dissolve it in 90 ml of DCM, and add 22 ml of BBr 3 (1 M) solution dropwise at 20 °C. After adding, react at 30 °C for 4 h. Check the reaction is complete by TLC. Add 180 ml of water and adjust the pH to 7 - 8 with 10% Na 2 CO 3 solution. Take the DCM phase, concentrate under reduced pressure to obtain an oily substance, and purify it by column chromatography using DCM:MeOH = 25:1 as the eluent. Obtain about 7.30 g of dry Compound II.

[0052] The mass spectrometry and 1H NMR characterization data are basically the same as those in Example 1.

[0053] HPLC detection of osimertinib bulk drug in Example 3:

[0054] Sample concentration: 1 mg / ml;

[0055] Chromatographic column: Phenylsilane-bonded silica gel as the packing material (Waters XBridge Phenyl, 4.6 mm × 150 mm, 3.5 μm);

[0056] Mobile phase A: Trifluoroacetic acid - water (1:2000); Mobile phase B: Trifluoroacetic acid - methanol - acetonitrile (1:1000:1000), volume ratio of mobile phase A to mobile phase B: 4:6; Flow rate: 0.8 ml / min;

[0057] Injection volume: 5 μl;

[0058] Column temperature: 40 °C;

[0059] Detection wavelength: 375 nm.

[0060] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. An osimertinib impurity, characterized in that, the osimertinib impurity has the structure shown in formula (II):

2. A method for preparing the osimertinib impurity according to claim 1, characterized in that, the method comprises the following steps: Step (1): React osimertinib and a basic catalyst with a reaction reagent in an organic solvent to obtain compound I shown in formula I; Step (2): React compound I with a de-R group reagent in an organic solvent to obtain compound II; The structural formula of osimertinib is as follows: The structural formula of Compound I is shown in Formula I: The R is selected from C1-4 alkyl groups. Preferably, the R is selected from methyl, ethyl, n-propyl or n-butyl.

3. The method for preparing the osimertinib impurity according to claim 2, characterized in that, the basic catalyst in step (1) is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium acetate, preferably one or more of sodium carbonate, potassium carbonate or cesium carbonate.

4. The method for preparing the osimertinib impurity according to claim 2, characterized in that, the organic solvent and the reaction reagent in step (1) are independently selected from C1-4 alkyl alcohols; Preferably, the organic solvent and the reaction reagent are the same C1-4 alkyl alcohol or different C1-4 alkyl alcohols; Preferably, the C1-4 alkyl alcohol is selected from one or more of methanol, ethanol, n-propanol or n-butanol.

5. The method for preparing the osimertinib impurity according to claim 4, characterized in that, the molar ratio of osimertinib to the basic catalyst in step (1) is 1:2 to 5, preferably 1:3 to 4, more preferably 1:3.

6.

6. The method for preparing the osimertinib impurity according to claim 2, characterized in that, the reaction temperature in step (1) is 50 to 80 °C, and the reaction time is 20 to 24 h; preferably, the reaction temperature is 60 to 70 °C.

7. The method for preparing the osimertinib impurity according to claim 2, characterized in that, the organic solvent in step (2) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane.

8. The method for preparing the osimertinib impurity according to claim 2, characterized in that, The de-R group reagent described in step (2) is selected from BBr 3 , AlCl 3 , hydrobromic acid, hydroiodic acid, or one or more of them, preferably BBr 3 .

9. The method for preparing the osimertinib impurity according to claim 2, characterized in that, the molar ratio of compound I to the de-R group reagent in step (2) is 1:1 to 2, preferably 1:1.1 to 1.5, more preferably 1:1.2 to 1.4, most preferably 1:1.

3.

10. The method for preparing the osimertinib impurity according to claim 2, characterized in that, the reaction temperature in step (2) is 20 to 30 °C; the reaction time is 3 to 5 h.

11. Use of the osimertinib impurity according to claim 1 in the quality control of osimertinib.

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