Preparation method of Venoclara intermediate

Abstract

The invention provides a preparation method of a Venoclara intermediate. The intermediate is a compound with a structural formula I. The invention further provides a preparation method of the Venoclara intermediate. Taking a compound II as a raw material, and reacting with a compound III under the action of alkali to obtain a crude product of a compound IV; carrying out ester hydrolysis reaction on the crude product of the compound IV and alkali to obtain a compound I; the compound IV in the preparation method does not need to be purified and separated and can be directly used for subsequent ester hydrolysis reaction to obtain the compound I, the process operation is simplified, the production cost is reduced, the preparation method is more environment-friendly and safer, the purity of the obtained compound I is a high-purity solid with the purity larger than 99.5%, the yield is about 85%, and the preparation method is suitable for industrial large-scale production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparation, and particularly relates to a preparation method of a venetoclax intermediate. Background Art

[0002] Venetoclax (ABT-199) is a selective Bcl-2 inhibitor jointly developed by AbbVie and Genentech, and is used for the treatment of chronic lymphocytic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, multiple myeloma, etc. It entered clinical trials in 2011. The Phase I trial (NCT01328626) enrolled 84 patients with relapsed / refractory CLL / SLL and 44 patients with relapsed / refractory non-Hodgkin lymphoma. The response rate of Venetoclax in the treatment of CLL / SLL was 79% (the complete response rate was 22%), and the median duration of continuous response was 20.5 months; the response rate of Venetoclax in the treatment of non-Hodgkin lymphoma was 48% (the complete response rate was 7.5%). To date, it has obtained 3 breakthrough therapy designations from the FDA: in April 2015, the FDA granted Venetoclax breakthrough drug designation for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) with 17p deletion mutation as a single agent; in January 2016, the FDA granted Venetoclax combined with the anti-cancer drug Rituximab breakthrough drug designation for the treatment of relapsed / refractory chronic lymphocytic leukemia; shortly thereafter, the FDA granted Venetoclax combined with hypomethylating agents (HMAs) breakthrough drug designation for the treatment of previously untreated acute myeloid leukemia patients who are not suitable for standard induction therapy. In addition, in early January 2016, the FDA granted Venetoclax priority review for a new drug application (NDA) for the treatment of CLL (including 17p deletion CLL) that has previously received at least one therapy. On April 11, 2016, the US FDA approved Venetoclax for the treatment of chronic lymphocytic leukemia, making it the world's first Bcl-2 inhibitor.

[0003] Compound I is one of the key intermediates for the preparation of venetoclax. The common preparation process uses Compound II and Compound III as raw materials, and in the presence of a base and a solvent, a substitution reaction occurs at a certain temperature to obtain Compound IV. Under alkaline conditions, Compound IV undergoes an ester hydrolysis reaction to obtain Compound I. However, the common preparation processes of Compound IV all require separation and purification by column chromatography or recrystallization before the ester hydrolysis reaction can be carried out under alkaline conditions to obtain the venetoclax intermediate Compound I, with cumbersome process operations and large yield losses.

[0004] Therefore, it is necessary to explore a new preparation process that can not only obtain the intermediate compound I of venetoclax with high purity in high yield but also be suitable for large-scale industrial production. Summary of the Invention

[0005] Object of the Invention: The present invention aims to provide a method for preparing an intermediate of venetoclax, namely a method for preparing a compound of formula I.

[0006] To achieve the above object, the technical solution provided by the present invention is as follows:

[0007] The compound of the present invention having the structure shown in formula I:

[0008]

[0009] The preparation method of the compound of the present invention having the structures shown in formula I and formula II, the reaction route is as follows:

[0010]

[0011] Wherein, in the step of preparing compound IV, compound II, compound III, base 1, and an organic solvent are added, and the reaction is carried out under heat preservation, and then post-treatment is carried out to obtain the crude product of compound IV; in the step of preparing compound I, the crude product of compound IV, an organic solvent, and base 2 are added, and the reaction is carried out under heat preservation, and then post-treatment and purification are carried out to obtain compound I. In the step of preparing compound IV, the molar ratio of compound II: compound III: base 1 ranges from 1:1 to 1.5:2.5 to 3, and base 1 is anhydrous dipotassium hydrogen phosphate, triethylamine or N,N-diisopropylethylamine. The temperature for the heat preservation reaction is 85 - 95 °C, the organic solvent is dimethyl sulfoxide or N-methylpyrrolidone, and the heat preservation reaction time is 16 - 24 h. In the step of preparing compound I, the molar ratio of compound II: base 2 ranges from 1:2 to 3, the mass fraction of base 2 is 20% - 30%, and base 2 is an aqueous sodium hydroxide solution. The heat preservation reaction temperature ranges from 40 - 50 °C, the organic solvent is dimethyl sulfoxide, and the reaction time is 3 - 5 h. In the step of preparing compound IV, the post-treatment step is to add water and ethyl acetate to the reaction solution, stir at room temperature, stand still, separate the layers, and concentrate the organic phase to obtain the crude product of compound IV. In the step of preparing compound I, the post-treatment and purification steps are to add an acid to the reaction solution, precipitate a solid, stand still, filter to obtain the solid, and then slurry the solid in an organic solvent by heating and filter to obtain compound I. The molar ratio of compound II: acid ranges from 1:4 to 5, the mass fraction of the acid is 30% - 36%, and the acid is an aqueous hydrochloric acid solution. The organic solvent for slurrying is tetrahydrofuran or dimethyl sulfoxide, and the slurrying temperature is 25 - 35 °C.

[0012] Beneficial effects: In the preparation method of the present invention, the compound IV does not need to be purified and separated, and the crude product of compound IV can be obtained and directly used for the subsequent ester hydrolysis reaction, which simplifies the process operation and reduces the production cost. Moreover, the obtained product is a high-purity solid with a purity greater than 99.5%, and the yield is about 85%, which is more suitable for large-scale industrial production. Description of the Drawings

[0013] Appendix Figure 1 is the 1H NMR spectrum of the intermediate compound I;

[0014] Appendix Figure 2 is the MS spectrum of the intermediate compound I. Detailed Embodiments

[0015] The following specific examples are used to further clarify the present invention. These examples are implemented on the premise of the technical solution of the present invention. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention.

[0016] Example 1

[0017] Synthesis of Compound I:

[0018]

[0019] Add 20 g (0.07 mol, 1.0 eq) of compound II, 22.32 g (0.07 mol, 1.0 eq) of compound III, 30.48 g (0.175 mol, 2.5 eq) of anhydrous dipotassium hydrogen phosphate, and dimethyl sulfoxide (60 mL) into a 500 mL four-necked flask. Start stirring and keep the reaction at 85 - 95 °C for 24 h. Cool down, add ethyl acetate (200 mL) and water (200 mL), stir for 5 min, separate the aqueous phase, concentrate the organic phase to dryness under reduced pressure at 60 °C, add dimethyl sulfoxide (220 mL) to dissolve it clearly, add 20% sodium hydroxide aqueous solution (31.2 g), stir and react at 40 - 50 °C for 3 h, adjust the acidity with 30% concentrated hydrochloric acid (31.2 g), dropwise add the precipitated solid, filter, add the filter cake to tetrahydrofuran (200 mL), stir at 25 - 35 °C, filter to obtain 35.6 g of the intermediate compound I. The 1H spectrum of the intermediate compound 1 is as Figure 1 , and the mass spectrum of the intermediate compound I is as Figure 2 shown, with a yield of 84% and a purity of 99.82%.

[0020] Example 2

[0021] Synthesis of Compound I:

[0022]

[0023] Add 100 g (0.35 mol, 1.0 eq) of Compound II, 112 g (0.35 mol, 1.0 eq) of Compound III, 106.25 g (1.05 mol, 3.0 eq) of triethylamine, and N-methylpyrrolidone (300 mL) into a 2000 mL four-necked flask. Start stirring, maintain the reaction temperature at 85 - 95 °C for 16 h. After cooling, add ethyl acetate (1000 mL) and water (1000 mL), stir for 5 min, separate the aqueous phase, concentrate the organic phase to dryness under reduced pressure at 60 °C, add dimethyl sulfoxide (1100 mL) to dissolve it clearly, add 30% aqueous sodium hydroxide solution (104 g), stir and react at 40 - 50 °C for 3 h, adjust the acidity with 36% concentrated hydrochloric acid (130 g), dropwise add to precipitate a solid, filter, add the filter cake to tetrahydrofuran (1000 mL), slurry at 25 - 35 °C, filter to obtain 182.5 g of intermediate Compound I, with a yield of 86% and a purity of 99.64%.

[0024] Example 3

[0025] Synthesis of Compound I:

[0026]

[0027] Add 1000 g (3.50 mol, 1.0 eq) of Compound II, 1120 g (3.50 mol, 1.0 eq) of Compound III, 1131 g (8.75 mol, 2.5 eq) of N,N-diisopropylethylamine, and dimethyl sulfoxide (3 L) into a 20 L four-necked flask. Start stirring, maintain the reaction temperature at 85 - 95 °C for 24 h. After cooling, add ethyl acetate (10 L) and water (10 L), stir for 5 min, separate the aqueous phase, concentrate the organic phase to dryness under reduced pressure at 60 °C, add dimethyl sulfoxide (2.2 L) to dissolve it clearly, add 26% aqueous sodium hydroxide solution (1200 g), stir and react at 40 - 50 °C for 3 h, adjust the acidity with 36% concentrated hydrochloric acid (1300 g), dropwise add to precipitate a solid, filter, add the filter cake to tetrahydrofuran (10 L), slurry at 25 - 35 °C, filter to obtain 1803.4 g of intermediate Compound I, with a yield of 85% and a purity of 99.73%.

[0028] The above specific embodiments have further elaborated on the purpose, technical solutions, and beneficial effects of the present application. It should be understood that the above are only specific embodiments of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent replacements, improvements, etc. made on the basis of the technical solutions of the present application should be included within the protection scope of the present application.

Claims

1. A method for preparing a venetoclax intermediate, comprising: Wherein, in the step of preparing Compound IV, Compound II, Compound III, Base 1, and an organic solvent are added, and the reaction is carried out under heat preservation, followed by post-treatment to obtain the crude product of Compound IV; in the step of preparing Compound I, the crude product of Compound IV, an organic solvent, and Base 2 are added, and the reaction is carried out under heat preservation, followed by post-treatment and purification to obtain Compound I.

2. The preparation method of a venetoclax intermediate according to claim 1, wherein In the step of preparing Compound IV, the molar ratio range of Compound II∶Compound III∶Base 1 is 1∶1~1.5∶2.5~3, and the Base 1 is dipotassium hydrogen phosphate anhydrous, triethylamine or N,N-diisopropylethylamine.

3. The preparation method of a venetoclax intermediate according to claim 1, wherein, In the step of preparing Compound IV, the temperature of the heat preservation reaction is 85~95 °C, the organic solvent is dimethyl sulfoxide or N-methylpyrrolidone, and the heat preservation reaction time is 16~24 h.

4. The preparation method of a venetoclax intermediate according to claim 1, characterized in that, In the step of preparing Compound I, the molar ratio range of Compound II∶Base 2 is 1∶2~3, the mass fraction of Base 2 is 20%~30%, and the Base 2 is an aqueous sodium hydroxide solution.

5. The preparation method of a venetoclax intermediate according to claim 1, characterized in that, In the step of preparing Compound I, the heat preservation reaction temperature range is 40~50 °C, the organic solvent is dimethyl sulfoxide, and the reaction time is 3~5 h.

6. The preparation method of a venetoclax intermediate according to claim 1, characterized in that, In the step of preparing Compound IV, the post-treatment steps are as follows: water and ethyl acetate are added to the reaction solution, stirred at room temperature, allowed to stand, separated into layers, and the organic phase is concentrated to obtain the crude product of Compound IV.

7. The preparation method of a venetoclax intermediate according to claim 1, characterized in that, In the step of preparing Compound I, the post-treatment steps are as follows: an acid is added to the reaction solution, a solid precipitates, allowed to stand, and the solid is filtered to obtain a solid. The purification step is as follows: the solid is slurried in an organic solvent by heating and filtered to obtain Compound I.

8. The preparation method of a venetoclax intermediate according to claim 7, characterized in that, Wherein the molar ratio range of Compound II∶acid is 1∶4~5, the mass fraction of the acid is 30%~36%, and the acid is an aqueous hydrochloric acid solution.

9. The preparation method of a venetoclax intermediate according to claim 7, characterized in that, The organic solvent for slurrying is tetrahydrofuran or dimethyl sulfoxide, and the temperature of slurrying is 25~35 °C.

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