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Method for synthesizing key intermediate of venetoclax

A synthesis method and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of harsh reaction conditions, high activity of Grignard reagents, and many impurities, and achieve the effects of simple operation, improved substitution reaction yield, high yield and high purity

Inactive Publication Date: 2020-11-06
NANJING POLYTECHNIC INSITUTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] When the traditional process is preparing intermediate II, the Grignard reagent triisopropylmagnesium chloride is used to catalyze 1-bromo-3-fluoro-4-iodobenzene into 4-bromo-2-fluorobenzoic acid tert-butyl ester and then carry out subsequent reactions. Because the Grignard reagent must be used under low temperature, anhydrous and oxygen-free conditions, and the high activity of the Grignard reagent leads to harsh reaction conditions, more impurities, and lower yield, which increases the difficulty of production

Method used

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  • Method for synthesizing key intermediate of venetoclax
  • Method for synthesizing key intermediate of venetoclax

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Experimental program
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Effect test

Embodiment 1

[0024] In the first step, add DMAP (0.367g, 3%) in 300mL THF solution, then add 4-bromo-2-fluorobenzoic acid (21.9g, 100mmol) and boc anhydride (26.16g, 120mmol) and stir, at 20 Reaction at ℃ for 1 hour, the solution after the esterification reaction was washed with 10% citric acid aqueous solution (200mL) and 10% sodium bicarbonate solution (200ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was tert-butyl 4-bromo-2-fluorobenzoate.

[0025] In the second step, 4-bromo-2-fluorobenzoic acid tert-butyl ester and 5-hydroxy-7-azaindole (14.74g, 110mmol) obtained from the first step reaction were dissolved in 200mL acetonitrile solution and 0.138g Potassium carbonate was reacted for 30 minutes, and the reaction temperature was 0°C. Then the solution after the reaction was quenched with water and filtered, and the filter cake was recrystallized and dried by adding ethyl acetate to obtain the key intermediate 4-bromo-2-[(1H-pyrrolo[2,3-b]pyridine of...

Embodiment 2

[0027] In the first step, add DMAP (9.16g, 50%) in 350mL THF solution, then add 4-bromo-2-fluorobenzoic acid (32.85g, 150mmol) and boc anhydride (87.2g, 400mmol) and stir, at 60 Reaction at ℃ for 1 hour, the solution after the esterification reaction was washed with 10% citric acid aqueous solution (200mL) and 10% sodium bicarbonate solution (200ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was tert-butyl 4-bromo-2-fluorobenzoate.

[0028] In the second step, 4-bromo-2-fluorobenzoic acid tert-butyl ester and 5-hydroxy-7-azaindole (14.74g, 110mmol) obtained from the first step reaction were dissolved in 200mL acetonitrile solution and 0.138g Potassium carbonate was reacted for 30 minutes, and the reaction temperature was 40°C. Then the solution after the reaction was quenched with water and filtered, and the filter cake was recrystallized and dried by adding ethyl acetate to obtain the key intermediate 4-bromo-2-[(1H-pyrrolo[2,3-b]pyridine o...

Embodiment 3

[0030] In the first step, add DMAP (9.16g, 50%) in 400mL THF solution, then add 4-bromo-2-fluorobenzoic acid (32.85g, 150mmol) and boc anhydride (163.5g, 750mmol) and stir, at 100 Reaction at ℃ for 1 hour, the solution after the esterification reaction was washed with 10% citric acid aqueous solution (200mL) and 10% sodium bicarbonate solution (200ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was tert-butyl 4-bromo-2-fluorobenzoate.

[0031] In the second step, 4-bromo-2-fluorobenzoic acid tert-butyl ester and 5-hydroxy-7-azaindole (14.74g, 110mmol) obtained from the first step reaction were dissolved in 200mL acetonitrile solution and 0.138g Potassium carbonate was reacted for 30 minutes, and the reaction temperature was 80°C. Then the solution after the reaction was quenched with water and filtered, and the filter cake was recrystallized and dried by adding ethyl acetate to obtain the key intermediate 4-bromo-2-[(1H-pyrrolo[2,3-b]pyridine...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing a key intermediate of venetoclax. The method comprises the following steps: with 4-bromo-2-fluorobenzoic acid (I) as a raw material, carrying out esterification to obtain 4-bromo-2-fluorobenzoic acid tert-butyl ester (II); and subjecting 4-bromo-2-fluorobenzoic acid tert-butyl ester (II)to a substitution reaction with 5-hydroxy-7-azaindole (III) so as to obtain the intermediate of venetoclax, namely 4-bromo-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoic acid tert-butyl ester (IV). Compared with a traditional Grignard reagent method, the method of the invention has the advantages that operation is simple, the rigorous conditions of no water and no oxygen are avoided, yield and purity are higher after the improvement, and the yield of a substitution reaction in the next step can be obviously improved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a key intermediate of venetoclax. Background technique [0002] Venetoclax is a BCl-2 selective inhibitor jointly developed by Abbvie and Genetech, which is the world's first protein-protein interaction (Protein-Protein Interaction, PPI) Inhibitors, obtained the marketing authorization of the US FDA and the EU in April 2015 and December 2016, respectively, with the previous name or number GDC-0199, and the trade name VENCLEXTA™, Vitekla, used to treat patients with 17p deletion mutations ( del17p) patients with relapsed / refractory chronic lymphocytic leukemia (R / RCLL), venetoclax has obtained three breakthrough drug qualifications (breakthrough drug designation, priority review qualification and accelerated approval qualification) and orphan drug status. Venetoclax monotherapy resulted in a clinically significant reduction in the number of cance...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 宋俊松何学军刘练朱浩然张翔赵明发吴睿
Owner NANJING POLYTECHNIC INSITUTE
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