Method for synthesizing Venetoclax key intermediates

A synthesis method and intermediate technology, applied in the field of drug synthesis, can solve the problems of not obtaining 5-hydroxy-7-azaind, etc., and achieve the effect of avoiding column chromatography purification operation, avoiding production conditions, and low synthesis cost

Inactive Publication Date: 2017-08-11
杭州科耀医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, after trying various methods of debenzylation, 5-hydroxy-7-azaindole was not obtained

Method used

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  • Method for synthesizing Venetoclax key intermediates
  • Method for synthesizing Venetoclax key intermediates
  • Method for synthesizing Venetoclax key intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Synthesis of 7-azaindole-5-pinacol borate: add 11g 5-bromo-7-azaindole, 20g double pinacol borate, 15g potassium acetate into a three-necked flask , 110mL dioxane, nitrogen replacement, add 30mg Pd(dppf)Cl 2 , The temperature was raised to 100°C and reacted for 24h (HPLC monitoring of 5-bromo-7-azaindole reaction was complete). The reaction solution was concentrated to dryness, 220mL ethyl acetate and 220mL water were added and stirred, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a theoretical product, which was directly put into the next step reaction.

[0032] (2) Synthesis of 5-hydroxy-7-azaindole: Add the above 7-azaindole-5-pinacol borate, 220mL tetrahydrofuran, 220mL 2M sodium hydroxide solution and 17.5g tetrahydrofuran to the reaction flask. Sodium perborate, react at room temperature for 2h (TLC monitors that the reaction of 7-azaindole-5-pinacol borate is complete), separate the organic phase, ad...

Embodiment 2

[0034] (1) Synthesis of 7-azaindole-5-pinacol borate: add 11g 5-bromo-7-azaindole, 20g double pinacol borate, 15g potassium acetate into a three-necked flask , 110mL dioxane, nitrogen replacement, add 30mg Pd (PPh 3 ) 4 , The temperature was raised to 100°C and reacted for 24h (HPLC monitors that the reaction of 5-bromo-7-azaindole is complete, and the bromine product 7-azaindole accounts for about 4.3%). The reaction solution was concentrated to dryness, 220mL ethyl acetate and 220mL water were added to stir, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated to dryness, and put into the next step reaction directly according to the theoretical amount of product.

[0035] (2) Synthesis of 5-hydroxy-7-azaindole: Add the above 7-azaindole-5-pinacol borate, 220mL tetrahydrofuran, 220mL 2M sodium hydroxide solution and 17.5g tetrahydrofuran to the reaction flask. Sodium perborate, react at room temperature for 2h (TLC monitors that the reaction of 7-az...

Embodiment 3

[0037] (1) Synthesis of 7-azaindole-5-pinacol borate: add 11g 5-bromo-7-azaindole, 20g double pinacol borate, 15g potassium acetate into a three-necked flask , 110mL dioxane, nitrogen replacement, add 30mg Pd (PPh 3 ) 2 Cl 2 , The temperature was raised to 100°C and reacted for 24h (HPLC monitors that the reaction of 5-bromo-7-azaindole is complete, and the bromine product 7-azaindole accounts for about 6.5%). The reaction solution was concentrated to dryness, 220mL ethyl acetate and 220mL water were added and stirred, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated to dryness, and put into the next step reaction directly according to the theoretical amount of product.

[0038] (2) Synthesis of 5-hydroxy-7-azaindole: add the above 7-azaindole-5-pinacol borate, 220mL tetrahydrofuran, 220mL 2M sodium hydroxide solution and 17.5g tetrahydrofuran to the reaction flask. Sodium perborate, react at room temperature for 2h (TLC monitors 7-azaindole-5-pi...

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Abstract

The invention discloses a method for synthesizing Venetoclax key intermediates. The method includes steps of (1), carrying out coupling reaction on 5-bromine-7-azaindole and bisdiboron in solvents under the effects of organic palladium catalysts and alkali, and carrying out after-treatment after the reaction is completely carried out so as to obtain 7-azaindole-5-pinacol borate; (2), carrying out hydrolysis reaction on the 7-azaindole-5-pinacol borate obtained at the step (1) under the effect of sodium perborate, and carrying out after-treatment after the reaction is completely carried out so as to obtain the Venetoclax key intermediates. The method has the advantages that the method is easy to implement, highly toxic reagents can be omitted, and the HPLC (high-performance liquid chromatography) purity of the Venetoclax key intermediates which are products obtained by the aid of the method is higher than 99%.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for synthesizing a key intermediate of Venetoclax. Background technique [0002] Venetoclax (ABT-199) is a selective Bcl-2 inhibitor jointly developed by AbbVie and Genentech for the treatment of chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, small lymphocytic lymphoma, diffuse large B Cell lymphoma and multiple myeloma. Up to now, a total of three breakthrough drug qualifications have been granted by the FDA: In April 2015, the FDA granted Venetoclax a breakthrough drug qualification for single-drug treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) with 17p deletion mutations. ; In January 2016, the FDA granted Venetoclax combined with the anticancer drug Rituximab (Rituximab, Rituximab) the breakthrough drug qualification for the treatment of relapsed / refractory chronic lymphocytic leukemia; shortly thereafter, the FDA granted Venetoclax an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 周军明
Owner 杭州科耀医药科技有限公司
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