A process for the synthesis of a venetoclax intermediate

Abstract

This invention discloses a method for synthesizing a venetum intermediate, specifically as follows: Step 1: In an organic solvent, 2,4-difluorobenzoic acid and 5-hydroxy-7-azaindole undergo an etherification reaction under the action of an acid-binding agent. After the reaction, post-treatment yields 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid; Step 2: 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid reacts with 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine in… An amination reaction occurs under the action of a base. After the reaction, post-treatment yields 2-(7-azaindole-5-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine-1-)benzoic acid, i.e., Venetantora intermediate III. The synthetic process provided by this invention avoids Grignard reactions and subsequent hydrolysis reactions, shortens the operation steps, simplifies the synthetic process, and provides a simple and easy-to-operate synthetic process. The raw materials are inexpensive and readily available, while avoiding the use of highly toxic raw materials. The production process is green and environmentally friendly, and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of anticancer drug synthesis, and particularly to a method for synthesizing a venetum intermediate. Background Technology

[0002] Venetoclax, developed by AbbVie and Roche, is a breakthrough anticancer drug. Its current highest development stage is market approval for the treatment of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). It is an oral B-cell lymphoma factor-2 (BCL-2) inhibitor. BCL-2 plays a crucial role in apoptosis (programmed cell death), preventing the apoptosis of some cells, including lymphocytes, and is overexpressed in certain types of cancer, contributing to drug resistance. Venetoclax aims to selectively inhibit BCL-2 function, restoring cellular communication systems and allowing cancer cells to self-destruct, thus treating tumors. This drug has shown promising clinical efficacy in treating various types of blood cancers, including CLL, diffuse large B-cell lymphoma (DLBCL) of non-myeloid leukemia (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM).

[0003] Currently, the synthesis of venetum requires intermediate III. One common method for preparing intermediate III involves reacting methyl 2,4-difluorobenzoate with compound II to generate intermediate I. Intermediate I then reacts with 1-((4''-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1''-biphenyl]-2-yl)methyl)piperazine dihydrochloride via nucleophilic and hydrolysis reactions to synthesize intermediate III. However, this method suffers from low yields because compound I has two F-substituents on its benzene ring, both of which participate in the reaction. Furthermore, the resulting mixture of 2- and 4-substituents is difficult to purify. Another drawback is that during the removal of the TIPS protecting group, the hydroxyl group in the product reacts with the N-molecule in another molecule, significantly impacting the yield. The preparation process is also cumbersome, resulting in low yields and increasing production difficulty. The synthetic route is as follows:

[0004] Formula 1 Another synthetic route uses 2-fluoro-4-bromo-1-iodobenzene as the starting material, and proceeds through Grignard reaction, nucleophilic reaction, Buchwald coupling, and hydrolysis to obtain intermediate III. This method requires Grignard reaction, and the N-alkylation reaction uses a noble metal palladium compound and ligand catalysis. Although the reaction conditions are milder than the original route, the raw material cost is high, making it unsuitable for industrial production. The synthetic route is shown in Equation 2 below:

[0005] Formula 2 Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention discloses a method for synthesizing venetouraine intermediates.

[0007] The technical solution adopted in this invention is as follows: Step s1: Prepare 2,4-difluorobenzoic acid (referred to as raw material I) and 5-hydroxy-7-azaindole (referred to as raw material II). Dissolve raw material I and raw material II in an organic solvent. Add an acid-binding agent to the mixture to induce an etherification reaction. After the reaction is completed, post-treatment is performed to obtain 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid (referred to as intermediate I). Step s2: Prepare 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine, denoted as intermediate II. Intermediate I and intermediate II are mixed in an organic solvent, and an amination reaction is carried out by adding a base. After the reaction is completed, post-treatment is performed to obtain 2-(7-azaindole-5-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine-1-)benzoic acid, i.e., venetouracil intermediate III, denoted as intermediate III.

[0008] Furthermore, in step s1, the molar ratio of raw material I to raw material II ranges from 1.2 to 1.5:1.0; the molar ratio of raw material II to acid-binding agent ranges from 1.0:2.0 to 5.0.

[0009] Furthermore, in step s1, the organic solvent is one of dioxane, methyl tert-butyl ether, diethylene glycol dimethyl ether, N,N-dimethylformamide, and dimethyl sulfoxide; the acid-binding agent is one of potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, and DIPEA.

[0010] Furthermore, in step s1, the reaction temperature range is 100℃~120℃, and the reaction time range is 3h~5h.

[0011] Furthermore, in step s1, the post-processing includes pH crystallization, filtration and drying. After drying, crude intermediate I is obtained, which is then recrystallized with ethyl acetate and n-heptane to obtain intermediate I.

[0012] Furthermore, in step s2, the molar ratio of intermediate I to intermediate II is in the range of 1.0:1.2 to 1.5; the molar ratio of intermediate I to alkali is in the range of 1.0:2.0 to 5.0.

[0013] Furthermore, in step s2, the base is one of potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, and DIPEA.

[0014] Furthermore, in step s2, the reaction temperature range is 100℃~120℃.

[0015] Furthermore, in step s2, the reaction time is 18h to 24h.

[0016] Furthermore, in step s2, the post-processing includes extraction with ethyl acetate and water, pH adjustment, filtration and drying to obtain crude intermediate III, which is then purified by crystallization with formic acid and isopropanol to obtain venetouraine intermediate III.

[0017] The beneficial effects of this invention are as follows: 1. It avoids Grignard reactions and subsequent hydrolysis reactions, shortens the operation steps, and simplifies the synthesis process. At the same time, the introduction of the 4-position F element makes the reaction highly targeted, reduces the functional group substitution process in the intermediate reaction, reduces the number of reaction steps, and reduces the by-products generated in the intermediate process. In addition, it avoids the relatively harsh Buchwald reaction, simplifies the process, and is suitable for industrial production.

[0018] 2. In the post-processing, the existing column chromatography purification technology is avoided. By crystallizing and purifying each reaction post-processing, the purity of Venetara intermediate III reaches more than 99.0%.

[0019] 3. The raw materials used have low toxicity, meet the requirements of green and environmentally friendly processes, and are inexpensive and readily available, thus improving the economics of pharmaceutical manufacturing. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the synthetic route for synthesizing venetola intermediates.

[0021] Figure 2 This is the HPLC chromatogram of the synthesis method of venetum intermediate.

[0022] Figure 3 MS spectrum of the synthesis method of venetum intermediate.

[0023] Figure 4 The 13C NMR spectrum of the synthesis method of venetola intermediate.

[0024] Figure 5 The 1H NMR spectrum of the synthesis method of venetum intermediate. Detailed Implementation

[0025] The specific embodiments of the present invention will now be described with reference to the accompanying drawings.

[0026] Example 1:

[0027] A method for synthesizing a venetum intermediate, such as Figure 1 As shown, it includes the following steps: Step s1, synthesizing intermediate I, the specific process is as follows: 5-Hydroxy-7-azaindole (100.0 g, 0.746 mol) and labeled as starting material II, 2,4-difluorobenzoic acid (141.5 g, 0.895 mol) and labeled as starting material I, potassium phosphate (424.5 g, 1.492 mol), and 1000 ml of diethylene glycol dimethyl ether were added to a three-necked reaction flask. The mixture was heated to 120 °C and reacted for 3 h. After the reaction was completed, the temperature was lowered, the pH was adjusted to 2–3, and the mixture was stirred for 3 h. The mixture was then filtered, washed with purified water, and dried to obtain 166.5 g of crude venetum intermediate I. The crude product was dissolved in 1660 ml of ethyl acetate under reflux, and 3320 ml of n-heptane was slowly added dropwise. The mixture was slowly cooled to 5 °C and stirred for 3 h. After filtration and drying, 151.5 g of light white solid, i.e., venetum intermediate I, was obtained, with a yield of 74.6% and an HPLC purity of 98.3%.

[0028] Step s2, synthesis of intermediate III, specific process: Prepare 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine, denoted as intermediate II. To a three-necked reaction flask, intermediate I (100.0 g, 0.367 mol), intermediate II (140.6 g, 0.441 mol), DIPEA (94.8 g, 0.734 mol), and 500 ml DMSO were added. The mixture was heated to 120 °C and reacted for 18 h. After the reaction was completed, the mixture was cooled, and 500 ml purified water and 500 ml ethyl acetate were added to adjust the pH to 2–3. The mixture was stirred for 3 h, filtered, washed with purified water, and dried to obtain 190.7 g of crude venetum intermediate III. The crude product was dissolved in 190 ml formic acid by heating to 35 °C with stirring. 570 ml isopropanol was slowly added dropwise, the mixture was slowly cooled to 5 °C, stirred for 3 h, filtered, and dried to obtain 164.0 g of white solid, i.e., venetum intermediate III, with a yield of 78.3% and an HPLC purity of 99.2%.

[0029] Final substance analysis: The HPLC chromatogram of the white solid is as follows: Figure 2 As shown.

[0030] MS spectrum of white solid as follows Figure 3 As shown.

[0031] white solid 13 C NMR spectra as follows Figure 4 As shown.

[0032] white solid 1 HNMR spectra as follows Figure 5 As shown.

[0033] The diffraction peak data obtained from the test were consistent with the standard for venetum intermediate III, confirming that venetum intermediate III had been obtained.

[0034] Example 2:

[0035] A method for synthesizing a venetum intermediate, such as Figure 1 As shown, it includes the following steps: Step s1, synthesizing intermediate I, the specific process is as follows: 5-hydroxy-7-azaindole (50.0 g, 0.373 mol), 2,4-difluorobenzoic acid (88.5 g, 0.559 mol), potassium phosphate (395.9 g, 1.86 mol), and 500 ml of diethylene glycol dimethyl ether were added to a three-necked reaction flask. The mixture was heated to 120 °C and reacted for 3 h. After the reaction was completed, the temperature was lowered, the pH was adjusted to 2–3, and the mixture was stirred for 3 h. The mixture was then filtered, washed with purified water, and dried to obtain 81.1 g of crude venetum intermediate I. The crude product was dissolved in 810 ml of ethyl acetate under reflux, and 1620 ml of n-heptane was slowly added dropwise. The mixture was slowly cooled to 5 °C and stirred for 3 h. After filtration and drying, 72.4 g of a light white solid, namely venetum intermediate I, was obtained, with a yield of 71.4% and an HPLC purity of 99.1%.

[0036] Step s2, synthesis of intermediate III, specific process: Add intermediate I (50.0 g, 0.184 mol), intermediate II (88.0 g, 0.276 mol), DIPEA (118.9 g, 0.92 mol), and 250 ml DMSO to a three-necked reaction flask obtained in the above steps. Heat to 120 °C and react for 24 h. After the reaction is complete, cool down, add 250 ml purified water and 250 ml ethyl acetate, adjust the pH to 2-3, stir for 3 h, filter, wash with purified water, and dry to obtain 91.2 g of crude venetum intermediate III. Dissolve the crude product in 90 ml formic acid by heating to 35 °C and stirring. Slowly add 270 ml isopropanol, slowly cool to 5 °C, stir for 3 h, filter, and dry to obtain 81.3 g of light white solid, i.e., venetum intermediate III, with a yield of 77.4% and an HPLC purity of 98.7%.

[0037] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0038] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing a venetum intermediate, characterized in that, Includes the following steps: Step s1: Prepare 2,4-difluorobenzoic acid (referred to as raw material I) and 5-hydroxy-7-azaindole (referred to as raw material II). Dissolve raw material I and raw material II in an organic solvent. Add an acid-binding agent to the mixture to induce an etherification reaction. After the reaction is completed, post-treatment is performed to obtain 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid, referred to as intermediate I. Step s2: Prepare 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine, denoted as intermediate II. Intermediate I and intermediate II are mixed in an organic solvent, and an amination reaction is carried out by adding a base. After the reaction is completed, post-treatment is performed to obtain 2-(7-azaindole-5-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine-1-)benzoic acid, i.e., vernetotora intermediate III, denoted as intermediate III; In step s1, the molar ratio of raw material I to raw material II ranges from 1.2 to 1.5:1.0; the molar ratio of raw material II to acid-binding agent ranges from 1.0:2.0 to 5.

0. In step s1, the reaction temperature range is 100℃~120℃, and the reaction time range is 3h~5h; In step s1, the post-processing includes pH crystallization, filtration and drying. After drying, crude intermediate I is obtained, and then it is recrystallized with ethyl acetate and n-heptane to obtain intermediate I. In step s2, the molar ratio of intermediate I to intermediate II is in the range of 1.0:1.2 to 1.5; the molar ratio of intermediate I to alkali is in the range of 1.0:2.0 to 5.

0. In step s2, the reaction temperature range is 100℃~120℃; In step s2, the reaction time is 18h to 24h; In step s2, the post-processing includes extraction with ethyl acetate and water, pH adjustment, filtration and drying to obtain crude intermediate III, which is then purified by crystallization with formic acid and isopropanol to obtain venetouraine intermediate III.

2. The method for synthesizing a venetum intermediate according to claim 1, characterized in that: In step s1, the organic solvent is one of dioxane, methyl tert-butyl ether, diethylene glycol dimethyl ether, N,N-dimethylformamide, and dimethyl sulfoxide; the acid-binding agent is one of potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, and DIPEA.

3. The method for synthesizing a venetum intermediate according to claim 1, characterized in that: In step s2, the base is one of potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, and DIPEA.

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