A method for the synthesis of a venetoclax key intermediate

Abstract

This invention proposes a method for synthesizing a key intermediate of venetoclax, specifically as follows: Under the action of a catalyst, raw material I and raw material II are dissolved in an organic solvent, and then simultaneously undergo coupling and hydrolysis reactions under alkaline aqueous conditions. After the reaction, the key intermediate of venetoclax is obtained through processing. This invention replaces the synthetic raw material 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate tert-butyl ester with 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester. Compared to Br, the reaction is less difficult with fluorine (F) and does not require stringent reaction conditions. Furthermore, by adding a certain proportion of purified water to the reaction solution, the simultaneous coupling and hydrolysis reactions under alkaline aqueous conditions avoid the demanding conditions of the Buchwald reaction, preventing anhydrous and oxygen-free conditions, simplifying the operation steps, resulting in simple operation and high yield.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for synthesizing a key intermediate of venetoclax. Background Technology

[0002] Venetoclax, developed by AbbVie and Roche, is a breakthrough anticancer drug. Currently, its highest development stage is market approval for the treatment of acute myeloid leukemia and chronic lymphocytic leukemia. On April 11, 2016, Venetoclax received FDA approval in the United States, becoming the first FDA-approved B-cell lymphoma factor-2 (BCL-2) inhibitor, and has already secured four indications in the US. On December 2, 2020, Venetoclax received approval from the China National Medical Products Administration (NMPA). Venetoclax 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 the function of BCL-2, restoring the cell's communication system and causing cancer cells to self-destruct, thereby achieving the goal of treating tumors. Venetoclax, as a monotherapy and in combination therapy, treats various types of blood cancers, including CLL, NHL (diffuse large B-cell lymphoma) (DLBCL), acute myeloid leukemia (AML), and multiple myeloma (MM). Since its launch, it has effectively alleviated the suffering of patients with the target indications. According to Evaluate Pharma, its sales are projected to reach $1.4 billion in 2020, demonstrating significant clinical value and a broad market prospect.

[0003] In the traditional process for preparing intermediate III,

[0004] The process typically involves the Buchwald reaction of 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid tert-butyl ester with a catalyst and ligands, followed by hydrolysis to synthesize 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzoic acid (III). However, the Buchwald reaction requires stringent conditions, resulting in numerous impurities, reduced yield, and increased production difficulty.

[0005] The synthetic route is shown below:

[0006] Summary of the Invention

[0007] The technical problem to be solved by this invention is to overcome the defects of the existing technology. This invention proposes a method for synthesizing key intermediates of venetoc, which avoids the harsh conditions of the Buchwald reaction, avoids anhydrous and oxygen-free conditions, simplifies the operation steps, makes the operation simple, has a high yield, thereby reducing the synthesis cost and making it suitable for industrial production.

[0008] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for synthesizing a key intermediate of venetteroc, as detailed below:

[0009] Under the action of a catalyst, raw material I and raw material II are dissolved in an organic solvent and then undergo coupling and hydrolysis reactions simultaneously under alkaline aqueous solution conditions. After the reaction is completed, the key intermediate of Venetoclax is obtained through processing.

[0010] The key intermediate of venetoclax is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid;

[0011] Raw material I is 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride; raw material II is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester; the molar ratio of raw material I to raw material II is 1:1.2-2.0;

[0012] Purified water is added to the reaction solution, and the purified water accounts for 3.0-5.0% of the total molar amount of the raw materials.

[0013] Furthermore, the catalyst is Pd(OAc)2 and AmPhos, with Pd(OAc)2 and AmPhos each accounting for 1.0-2.0% of the total molar amount of the raw materials.

[0014] Furthermore, the organic solvent is any one or a combination of two of N,N-dimethylformamide, tetrahydrofuran, and toluene.

[0015] Furthermore, the alkaline aqueous solution is either sodium hydroxide or potassium hydroxide.

[0016] Furthermore, the alkaline solute accounts for 2.0-3.0% of the total molar amount of the raw materials.

[0017] Furthermore, the reaction temperature is 30℃-80℃.

[0018] Furthermore, the post-processing includes water quenching, filtration, recrystallization with ethyl acetate and n-heptane. After the reaction is completed, the reaction process is quenched with water, and after filtration to obtain the solid reaction product, the recrystallization process is completed with ethyl acetate and n-heptane to obtain the key intermediate of Venetoclax.

[0019] Compared with the prior art, the beneficial effects of the present invention include:

[0020] By replacing the raw material tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate with tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate, the reaction is made easier with fluorine (F) compared to br, and no harsh reaction conditions are required. In addition, by adding a certain proportion of purified water to the reaction solution, the coupling and hydrolysis reactions can be carried out simultaneously under alkaline aqueous conditions, avoiding the harsh conditions of the Buchwald reaction and the need for anhydrous and oxygen-free conditions. This simplifies the operation steps, making the operation simple and the yield high. Attached Figure Description

[0021] The disclosure of this invention is illustrated with reference to the accompanying drawings. It should be understood that the drawings are for illustrative purposes only and are not intended to limit the scope of protection of this invention. In the drawings, the same reference numerals are used to refer to the same parts. Wherein:

[0022] Figure 1 The schematic diagram illustrates the synthetic route for the synthesis of the key intermediate of Venetok. Detailed Implementation

[0023] It is readily understood that, based on the technical solution of this invention, those skilled in the art can propose various interchangeable structural methods and implementations without altering the essential spirit of the invention. Therefore, the following detailed embodiments and accompanying drawings are merely illustrative examples of the technical solution of this invention and should not be considered as the entirety of the invention or as limitations or restrictions on the technical solution of this invention.

[0024] A method for synthesizing a key intermediate of venetoclax, the synthetic route of which is as follows: Figure 1As shown, using 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride as raw material I and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester as raw material II, under the catalysis of Pd(OAc)2 and AmPhos, raw material I and raw material II were dissolved in an organic solvent and then simultaneously subjected to coupling and hydrolysis reactions under alkaline aqueous solution conditions. After the reaction was completed, post-treatment yielded the key intermediate of venetoclax, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1-yl)benzoic acid.

[0025] In the aforementioned reaction process, the molar ratio of raw material I to raw material II is 1:1.2-2.0. An alkaline purified aqueous solution is added to the aforementioned reaction solution, wherein the purified water accounts for 3.0-5.0% of the total molar amount of the raw materials, and the alkaline solute accounts for 2.0-3.0% of the total molar amount of the raw materials, so that the hydrolysis reaction occurs simultaneously during the coupling reaction process. In the aforementioned reaction process, the reaction temperature is 30℃-80℃.

[0026] In the aforementioned reaction process, Pd(OAc)2 and AmPhos each account for 1.0-2.0% of the total molar amount of the raw materials. By using such amounts of Pd(OAc)2 and AmPhos as catalysts, the reaction can proceed well. The organic solvent is any one or a combination of two of N,N-dimethylformamide, tetrahydrofuran, and toluene. The alkaline aqueous solution is any one of sodium hydroxide and potassium hydroxide, wherein the alkaline solute accounts for 2.0-3.0% of the total molar amount of the raw materials, and purified water accounts for 3.0-5.0% of the total molar amount of the raw materials.

[0027] After the reaction was completed, water was added to quench the reaction process, the pH of the system was adjusted to 3-4, and the solid reaction product was obtained by filtration. The product was then recrystallized with ethyl acetate and n-heptane to obtain the key intermediate of venetoc. The purity of the obtained key intermediate of venetoc was 96.1%-99.1%, and the reaction yield was 83.4%-87.5%.

[0028] The technical effects of the present invention will be further explained below with reference to the embodiments.

[0029] Example 1

[0030] In a 250 ml reaction flask, add 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride (I) (5.0 g, 0.0128 mol), 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester (6.19 g, 0.0189 mol), catalyst Pd(OAc)2 (0.035 g, 0.000157 mol), and AmPhos (0.042 g, 0.000157 mol), then add 20 ml of DMF, stir until dissolved at room temperature, and add sodium hydroxide solution. The solution (sodium hydroxide 1.26 g, 0.0314 mol, purified water 1.16 g, 0.064 mol) was heated to 80 °C and reacted for 4 h. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid, and the solid was obtained by filtration. The purity of the main product was 87.6% by liquid chromatography. The obtained solid was recrystallized from ethyl acetate and n-heptane to give 3.1 g of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid, with a purity of 96.1% and a reaction yield of 83.4%.

[0031] Example 2

[0032] In a 250 ml reaction flask, add 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride (I) (5.0 g, 0.0128 mol), 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester (7.73 g, 0.0235 mol), catalyst Pd(OAc)2 (0.035 g, 0.000157 mol), and AmPhos (0.042 g, 0.000157 mol), then add 20 ml of DMF, stir at room temperature until dissolved, and then add sodium hydroxide aqueous solution. (Sodium hydroxide 1.02 g, 0.0256 mol, purified water 0.70 g, 0.038 mol), heated to 30 °C, reacted for 7 h. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid, filtered to obtain a solid, and the purity of the main product was 89.2% as determined by liquid chromatography. The obtained solid was recrystallized from ethyl acetate and n-heptane to obtain 6.40 g of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid, with a purity of 99.1% and a reaction yield of 87.5%.

[0033] Example 3

[0034] In a 250 ml reaction flask, add 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride (I) (5.0 g, 0.0128 mol), 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester (8.40 g, 0.0256 mol), catalyst Pd(OAc)2 (0.057 g, 0.000256 mol), and AmPhos (0.070 g, 0.000256 mol), then add 20 ml of DMF, stir at room temperature until dissolved, and then add sodium hydroxide solution. The solution (sodium hydroxide 1.28 g, 0.032 mol, purified water 1.16 g, 0.064 mol) was heated to 60 °C and reacted for 4 h. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid, and the solid was obtained by filtration. The purity of the main product was 85.4% by liquid chromatography. The obtained solid was recrystallized from ethyl acetate and n-heptane to give 6.20 g of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid, with a purity of 98.1% and a reaction yield of 85.1%.

[0035] Examples of traditional processes

[0036] Add 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride (I) (5.5 g, 0.0141 mol) and 75 ml of toluene to a 200 ml three-necked flask. Adjust the pH to 8-9 by adding 20.0% K3PO4 at room temperature and stir for 30 min. Allow to stand and separate the layers, then collect the organic phase. Wash the organic layer with 20 ml of saturated sodium chloride solution, dry with 10.00 g of anhydrous sodium sulfate for 30 min, filter, and rinse the filter cake with 10 ml of toluene. Combine the organic phases and concentrate under reduced pressure at 40-50 °C until no liquid drips out. Add 10 ml of toluene and stir for 5 min. A tetrahydrofuran solution of sodium tert-butoxide (11.00 g sodium tert-butoxide dissolved in 110 ml tetrahydrofuran) was added to the reaction solution from the previous step, and the mixture was bubbled with nitrogen for 45 min to form an alkaline solution of 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine.

[0037] Add Pd2dba3 (0.23 g, 0.000251 mol), Amphos (0.13 g, 0.000489 g), and tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (5.5 g, 0.0141 mol) to the second reaction flask. After purging with nitrogen, slowly add a prepared alkaline solution of 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine. Rinse the flask walls with 10 ml of tetrahydrofuran and purge with nitrogen. Maintain the temperature at 50℃~55℃ and react for 3 h.

[0038] The mixture was cooled to 0℃~20℃, and saturated brine and tetrahydrofuran were added. Extraction and separation were performed, and the organic phase was concentrated under reduced pressure. Liquid chromatography showed the main product purity to be 76.2%. The obtained product was recrystallized from ethyl acetate and n-heptane to yield 6.30 g of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate with a purity of 93.4% and a reaction yield of 71.3%.

[0039] Add the product from the previous step (6.30 g, 0.010 mol), potassium tert-butoxide (7.46 g, 0.066 mol), 100 ml of 2-methyltetrahydrofuran, and 0.82 g of water to a 200 ml three-necked flask, and purge with nitrogen. React at 50-55 °C for 2 h. Cool to a lower temperature, adjust the pH to 3-4, filter, and recrystallize the resulting filter cake from ethyl acetate and n-heptane to obtain 5.14 g of the Venetoclax intermediate 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid, purity 94.7%, reaction yield 90.2%. Overall yield of the two steps: 63.9%.

[0040] The technical scope of this invention is not limited to the content described above. Those skilled in the art can make various modifications and variations to the above embodiments without departing from the technical concept of this invention, and all such modifications and variations should fall within the protection scope of this invention.

Claims

1. A process for the synthesis of a key intermediate of Venetoclax, characterized in that, Specifically as follows: Under the action of a catalyst, raw material I and raw material II are dissolved in an organic solvent and then undergo coupling and hydrolysis reactions simultaneously under alkaline aqueous solution conditions. After the reaction is completed, the key intermediate of Venetoclax is obtained through processing. The key intermediate of venetoclax is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4''-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid; Raw material I is 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride; raw material II is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate tert-butyl ester; the molar ratio of raw material I to raw material II is 1:1.2-2.0; Purified water is added to the reaction solution, and the purified water accounts for 3.0-5.0 times the total molar amount of the raw materials. The catalysts are Pd(OAc)2 and AmPhos, with Pd(OAc)2 and AmPhos accounting for 1.0%-2.0% of the total molar amount of the raw materials, respectively.

2. The process for synthesis of Venetoclax key intermediate as claimed in claim 1 wherein, The organic solvent is any one or a combination of two of N,N-dimethylformamide, tetrahydrofuran, and toluene.

3. The process for synthesis of Venetoclax key intermediate as claimed in claim 1, wherein, The alkaline aqueous solution is either sodium hydroxide or potassium hydroxide.

4. The process for synthesis of Venetoclax key intermediate as claimed in claim 3 wherein, The alkaline solute accounts for 2.0-3.0 times the total molar amount of the raw materials.

5. The method for synthesizing the key intermediate of venetoc according to claim 1, characterized in that, The reaction temperature is 30℃-80℃.

6. The method for synthesizing the key intermediate of venetoc according to claim 1, characterized in that, The post-processing includes water quenching, filtration, recrystallization with ethyl acetate and n-heptane. After the reaction is completed, water is added to quench the reaction process, and after filtration to obtain the solid reaction product, the recrystallization process is completed with ethyl acetate and n-heptane to obtain the key intermediate of Venetoclax.

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