Preparation method and application of vinca impurity compound

Abstract

The invention belongs to the field of chemical drug synthesis, and particularly relates to a preparation method and application of a Venoclara impurity compound. The invention provides a method for preparing a high-purity impurity compound I and a method for preparing a high-purity impurity compound III, and the method comprises the following steps: dissolving a compound II in a solvent, and adding an oxidizing reagent for reaction to obtain the compound I; drying the compound I to obtain a compound III; the invention also provides application of the Venoclara impurity compound I or the Venoclara impurity compound III. The preparation method has the advantages that the raw materials are cheap and easy to obtain, the operation is simple, the reaction conditions are mild, the purity of the obtained impurity compound I can reach 98.67% and the yield can reach 95% after the impurity compound I is purified by adopting a column chromatography method, the purity of the impurity compound III can reach 98.68% and the yield can reach 87.4% after the impurity compound III is purified by adopting the column chromatography method, and the total reaction yield can reach 83%.

Description

Technical Field

[0001] The present invention belongs to the field of chemical drug synthesis, and particularly relates to a preparation method and application of a Venetoclax impurity compound. Background Art

[0002] Venetoclax is used for the treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and is the only Bcl-2 selective inhibitor approved for marketing globally at present. It can play a targeted role and help restore apoptosis of tumor cells.

[0003] Currently, the commonly used synthetic route of Venetoclax is as follows:

[0004]

[0005] Currently, there are many preparation methods for Venetoclax, and impurities often exist. The synthesis of these impurity compounds is difficult, which increases the difficulty of quality control of Venetoclax and further affects the quality of its preparation-related products. Impurity Compound I and Impurity Compound III (the structural formulas are as follows) are the main impurities in the import registration standard of Venetoclax. The State Drug Administration's import drug registration standard (standard number: JX20201040) stipulates that the content of Impurity Compound I and Impurity Compound III in Venetoclax tablets shall not exceed 0.50% of the labeled amount. Due to the low content of this impurity in the product, it is difficult to isolate high-purity impurity reference substances by existing technologies. Therefore, the research on the directional synthesis of this impurity is of great significance.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a preparation method and application of a Venetoclax impurity compound for preparing reference substances of high-purity Impurity Compound I and Impurity Compound III. The preparation method has cheap and easily available raw materials, a simple process, mild reaction conditions, and is easy for industrial production.

[0008] The present invention provides a preparation method of Venetoclax Impurity Compound I, including:

[0009]

[0010] In some embodiments, in the step of preparing Compound I from Compound II, the oxidation reagent is 3-chloroperoxybenzoic acid.

[0011] In some embodiments, in the step of preparing Compound I from Compound II, the molar ratio of Compound II to the oxidation reagent is 1:1 to 1.2.

[0012] In some embodiments, in the step of preparing Compound I from Compound II, the molar ratio of Compound II to the oxidation reagent is 1:1.1.

[0013] In some embodiments, in the step of preparing Compound I from Compound II, the reaction solvent is an organic solvent; the organic solvent is dichloromethane, tetrahydrofuran or ethyl acetate; the reaction temperature range is 25 - 30 °C.

[0014] A method for preparing venetoclax impurity Compound III, comprising:

[0015]

[0016] In some embodiments, in the step of preparing Compound I from Compound II, the oxidation reagent is 3-chloroperoxybenzoic acid; the molar ratio of Compound II to the oxidation reagent is 1:1 - 1.2; the reaction solvent is an organic solvent; the organic solvent is dichloromethane, tetrahydrofuran or ethyl acetate; the reaction temperature range is 25 - 30 °C.

[0017] In some embodiments, in the step of preparing Compound III from Compound I, the drying is air-blowing drying; the drying temperature range is 100 - 110 °C; the drying time range is 60 - 80 h.

[0018] In some embodiments, in the step of preparing Compound III from Compound I, the drying temperature is 100 °C and the drying time is 72 h.

[0019] An application of venetoclax impurity Compound I or Compound III, including quality research or process research of the bulk drug and preparations of venetoclax.

[0020] Beneficial effects:

[0021] The present invention provides a method for preparing venetoclax impurity compounds and their applications, for preparing reference substances of high-purity impurity Compound I and impurity Compound III, and for quality research or process research of the bulk drug and preparations of venetoclax. The preparation method of the present invention has cheap and easily available raw materials, simple operation, and mild reaction conditions. The obtained impurity Compound I can reach a purity of 98.67% and a yield of 95% by column chromatography purification, the impurity Compound III can reach a purity of 98.68% and a yield of 87.4% by column chromatography purification, and the total reaction yield can reach 83%. Specific embodiments

[0022] To enable those skilled in the art to understand the features and effects of the present invention, the following provides a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used herein shall have the ordinary meanings understood by those skilled in the art regarding the present invention. In case of conflicts, the definitions in this specification shall prevail.

[0023] The theories or mechanisms described and disclosed herein, whether correct or incorrect, shall in no way limit the scope of the present invention, that is, the content of the present invention can be implemented without being limited by any specific theory or mechanism.

[0024] In this article, all features defined in the form of numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are only for the sake of brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be regarded as having covered and specifically disclosed all possible sub-ranges and individual numerical values within the ranges (including integers and fractions).

[0025] In this article, for the sake of concise description, all possible combinations of all technical features in each embodiment or example are not described. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each embodiment or example can be combined arbitrarily, and all possible combinations should be considered as being within the scope described in this specification.

[0026] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0027] Conventional instrument equipment in the art is used in the following embodiments. For the experimental methods without specific conditions noted in the following embodiments, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Various raw materials are used in the following embodiments. Unless otherwise stated, commercially available products are used, and their specifications are conventional specifications in the art. In the specification of the present invention and the following embodiments, unless otherwise specified, "%" represents weight percentage, "parts" represents weight parts, and the ratios represent weight.

[0028] The following further describes a preparation method and application of a venetoclax impurity compound provided by this application in conjunction with specific embodiments.

[0029] Example 1

[0030] Preparation of Compound I:

[0031]

[0032] Add compound Ⅱ (50 g, 0.058 mol, 1.0 e.q.), 3-chloroperbenzoic acid with a content of 85% (12.79 g, 0.063 mol, 1.1 e.q.), and dichloromethane (2000 mL) into a 500 mL four-necked flask. Start stirring and keep the reaction at 25 - 30 °C for 3 h. Add water (1000 mL), stir for 5 min, separate the aqueous phase, and concentrate the organic phase to dryness under reduced pressure at 50 °C to obtain the crude product of compound Ⅰ.

[0033] Purify compound Ⅰ by column chromatography with a yield of 95% and a purity of 98.67%. 1 H NMR (400 MHz, Chloroform-d) δ 12.20 (s, 1H), 8.89 (dd, J = 4.5, 2.4 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.18 (t, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.43 (s, 1H), 7.34–7.27 (m, 1H), 6.99 (d, J = 7.9 Hz, 2H), 6.91 (dd, J = 9.4, 4.6 Hz, 1H), 6.54 (s, 1H), 6.48–6.42 (m, 1H), 6.01 (s, 1H), 5.32 (s, 1H), 4.19 (s, 2H), 4.14 (q, J = 7.2 Hz, 0H), 4.09–4.00 (m, 2H), 3.56 (d, J = 12.3 Hz, 3H), 3.45 (q, J = 11.8, 11.3 Hz, 3H), 3.27 (t, J = 6.2 Hz, 4H), 2.85 (d, J = 13.7 Hz, 2H), 2.71 (s, 2H), 2.07 (d, J = 5.1 Hz, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.49–1.41 (m, 4H), 1.28 (t, J = 7.1 Hz, 0H), 0.98 (s, 6H). m / z [M] + : 884.66.

[0034] Preparation of compound Ⅲ:

[0035]

[0036] Put compound Ⅰ into a forced-air drying oven and dry it at 100 °C for 72 h to generate compound Ⅲ. Purify compound Ⅲ by column chromatography with a yield of 87.4% and a purity of 98.68%. 11H NMR (400 MHz, Chloroform-d) δ 10.17 (s, 1H), 9.58 (d, J = 2.7 Hz, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.55 (t, J = 5.5 Hz, 1H), 8.29–8.16 (m, 2H), 8.01 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 3.5, 2.5 Hz, 1H), 7.31–7.20 (m, 3H), 7.13–7.05 (m, 2H), 6.94 (d, J = 9.3 Hz, 1H), 6.64–6.55 (m, 2H), 6.04 (d, J = 2.3 Hz, 1H), 4.05 (ddd, J = 11.8, 4.8, 1.7 Hz, 2H), 3.93 (s, 2H), 3.45 (td, J = 11.8, 2.0 Hz, 3H), 3.29 (dd, J = 6.9, 5.5 Hz, 2H), 3.10 (s, 2H), 2.88 (s, 2H), 2.59 (s, 2H), 2.22 (dq, J = 9.2, 5.0 Hz, 2H), 2.02 (s, 2H), 1.98 (dq, J = 8.1, 3.8 Hz, 0H), 1.76 (ddd, J = 12.7, 4.0, 1.9 Hz, 2H), 1.54–1.38 (m, 4H), 1.28 (t, J = 7.1 Hz, 0H), 0.96 (s, 6H). m / z [[M]] + : 884.61.

[0037] Example 2

[0038] Preparation of Compound I:

[0039]

[0040] Add Compound II (50 g, 0.058 mol, 1.0 e.q.), 3-chloroperbenzoic acid (11.77 g, 0.058 mol, 1 e.q.) with a content of 85%, and tetrahydrofuran (1000 mL) to a 500 mL four-necked flask. Start stirring and keep the reaction at 25 - 30 °C for 2 h.

[0041] Add water (1000 mL), stir for 5 min, separate the aqueous phase, and concentrate the organic phase to dryness under reduced pressure at 50 °C to obtain the crude product of Compound I. Purify it by column chromatography to obtain Compound I with a yield of 90% and a purity of 98.56%. 11H NMR (400 MHz, Chloroform-d) δ 12.20 (s, 1H), 8.89 (dd, J = 4.5, 2.4 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.18 (t, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.43 (s, 1H), 7.34–7.27 (m, 1H), 6.99 (d, J = 7.9 Hz, 2H), 6.91 (dd, J = 9.4, 4.6 Hz, 1H), 6.54 (s, 1H), 6.48–6.42 (m, 1H), 6.01 (s, 1H), 5.32 (s, 1H), 4.19 (s, 2H), 4.14 (q, J = 7.2 Hz, 0H), 4.09–4.00 (m, 2H), 3.56 (d, J = 12.3 Hz, 3H), 3.45 (q, J = 11.8, 11.3 Hz, 3H), 3.27 (t, J = 6.2 Hz, 4H), 2.85 (d, J = 13.7 Hz, 2H), 2.71 (s, 2H), 2.07 (d, J = 5.1 Hz, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.49–1.41 (m, 4H), 1.28 (t, J = 7.1 Hz, 0H), 0.98 (s, 6H). m / z [[M]] + : 884.66.

[0042] Preparation of Compound Ⅲ:

[0043]

[0044] Put Compound Ⅰ into a forced-air drying oven and dry it at 100 °C for 60 h to generate Compound Ⅲ. Purify Compound Ⅲ by column chromatography. The yield is 86.3% and the purity is 98.12%. 11H NMR (400 MHz, Chloroform-d) δ 10.17 (s, 1H), 9.58 (d, J = 2.7 Hz, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.55 (t, J = 5.5 Hz, 1H), 8.29–8.16 (m, 2H), 8.01 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 3.5, 2.5 Hz, 1H), 7.31–7.20 (m, 3H), 7.13–7.05 (m, 2H), 6.94 (d, J = 9.3 Hz, 1H), 6.64–6.55 (m, 2H), 6.04 (d, J = 2.3 Hz, 1H), 4.05 (ddd, J = 11.8, 4.8, 1.7 Hz, 2H), 3.93 (s, 2H), 3.45 (td, J = 11.8, 2.0 Hz, 3H), 3.29 (dd, J = 6.9, 5.5 Hz, 2H), 3.10 (s, 2H), 2.88 (s, 2H), 2.59 (s, 2H), 2.22 (dq, J = 9.2, 5.0 Hz, 2H), 2.02 (s, 2H), 1.98 (dq, J = 8.1, 3.8 Hz, 0H), 1.76 (ddd, J = 12.7, 4.0, 1.9 Hz, 2H), 1.54–1.38 (m, 4H), 1.28 (t, J = 7.1 Hz, 0H), 0.96 (s, 6H). m / z [[M]] + : 884.61.

[0045] Example 3

[0046] Preparation of Compound I:

[0047]

[0048] Add Compound II (50 g, 0.058 mol, 1.0 e.q.), 3-chloroperoxybenzoic acid (14 g, 0.069 mol, 1.2 e.q.), and ethyl acetate (1500 mL) to a 500 mL four-necked flask. Start stirring and maintain the reaction at 25–30 °C for 6 h.

[0049] Add water (1000 mL), stir for 5 min, separate the aqueous phase, and concentrate the organic phase under reduced pressure at 50 °C to dryness to obtain the crude product of Compound I. Purify it by column chromatography to obtain Compound I with a yield of 96% and a purity of 98.44%. 11H NMR (400 MHz, Chloroform-d) δ 12.20 (s, 1H), 8.89 (dd, J = 4.5, 2.4 Hz, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.18 (t, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.43 (s, 1H), 7.34–7.27 (m, 1H), 6.99 (d, J = 7.9 Hz, 2H), 6.91 (dd, J = 9.4, 4.6 Hz, 1H), 6.54 (s, 1H), 6.48–6.42 (m, 1H), 6.01 (s, 1H), 5.32 (s, 1H), 4.19 (s, 2H), 4.14 (q, J = 7.2 Hz, 0H), 4.09–4.00 (m, 2H), 3.56 (d, J = 12.3 Hz, 3H), 3.45 (q, J = 11.8, 11.3 Hz, 3H), 3.27 (t, J = 6.2 Hz, 4H), 2.85 (d, J = 13.7 Hz, 2H), 2.71 (s, 2H), 2.07 (d, J = 5.1 Hz, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.49–1.41 (m, 4H), 1.28 (t, J = 7.1 Hz, 0H), 0.98 (s, 6H). m / z [[M]] + : 884.66.

[0050] Preparation of Compound III:

[0051]

[0052] Put Compound I into a forced-air drying oven and dry it at 100 °C for 80 h to generate Compound III. Purify Compound III by column chromatography. The yield is 85.8% and the purity is 98.07%. 11H NMR (400 MHz, Chloroform-d) δ 10.17 (s, 1H), 9.58 (d, J = 2.7 Hz, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.55 (t, J = 5.5 Hz, 1H), 8.29–8.16 (m, 2H), 8.01 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 3.5, 2.5 Hz, 1H), 7.31–7.20 (m, 3H), 7.13–7.05 (m, 2H), 6.94 (d, J = 9.3 Hz, 1H), 6.64–6.55 (m, 2H), 6.04 (d, J = 2.3 Hz, 1H), 4.05 (ddd, J = 11.8, 4.8, 1.7 Hz, 2H), 3.93 (s, 2H), 3.45 (td, J = 11.8, 2.0 Hz, 3H), 3.29 (dd, J = 6.9, 5.5 Hz, 2H), 3.10 (s, 2H), 2.88 (s, 2H), 2.59 (s, 2H), 2.22 (dq, J = 9.2, 5.0 Hz, 2H), 2.02 (s, 2H), 1.98 (dq, J = 8.1, 3.8 Hz, 0H), 1.76 (ddd, J = 12.7, 4.0, 1.9 Hz, 2H), 1.54–1.38 (m, 4H), 1.28 (t, J = 7.1 Hz, 0H), 0.96 (s, 6H). m / z [[M]] + : 884.61.

[0053] Although the present invention has been disclosed above in preferred embodiments, it is not intended to limit the present invention. Anyone familiar with this technology can make various modifications and refinements without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the claims.

Claims

1. A preparation method of venetoclax impurity compound I, characterized in that, Comprising:

2. The preparation method of a venetoclax impurity compound I according to claim 1, characterized in that, In the step of preparing Compound I from Compound II, the oxidizing reagent is 3-chloroperoxybenzoic acid.

3. The preparation method of a venetoclax impurity compound I according to claim 1, wherein, In the step of preparing Compound I from Compound II, the molar ratio of Compound II to the oxidizing reagent is 1:1 to 1.

2.

4. The preparation method of a venetoclax impurity compound I according to claim 3, wherein, In the step of preparing Compound I from Compound II, the molar ratio of Compound II to the oxidizing reagent is 1:1.

1.

5. The preparation method of a venetoclax impurity compound I according to claim 1, characterized in that, In the step of preparing Compound I from Compound II, the reaction solvent is an organic solvent; the organic solvent is dichloromethane, tetrahydrofuran or ethyl acetate; the reaction temperature range is 25 to 30 °C.

6. A preparation method of Venetoclax impurity compound III, characterized in that, Comprising:

7. The preparation method of a venetoclax impurity compound III according to claim 6, wherein In the step of preparing Compound I from Compound II, the oxidizing reagent is 3-chloroperoxybenzoic acid; the molar ratio of Compound II to the oxidizing reagent is 1:1 to 1.2; the reaction solvent is an organic solvent; the organic solvent is dichloromethane, tetrahydrofuran or ethyl acetate; the reaction temperature range is 25 to 30 °C.

8. The preparation method of a venetoclax impurity compound III according to claim 6, characterized in that, In the step of preparing Compound III from Compound I, the drying is air drying; the drying temperature range is 100 to 110 °C; the drying time range is 60 to 80 h.

9. The preparation method of a venetoclax impurity compound III according to claim 6, wherein, In the step of preparing Compound III from Compound I, the drying temperature is 100 °C and the drying time is 72 h.

10. Use of the venetoclax impurity compound I or compound III according to claim 1 or 6, characterized in that, Including quality research or process research on the active pharmaceutical ingredient and preparation of venetoclax.

Images