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Synthesis method for BCL-2 inhibitor Venetoclax

A synthetic method, BCL-2 technology, applied in the direction of organic chemistry, etc., can solve the problems of no commercial large-scale supply, no industrial production, difficult to scale up the reaction, etc., achieve important industrial application value, low synthesis cost, high yield Effect

Inactive Publication Date: 2017-08-25
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

[0011] The raw material 2-fluoro-4-nitrobenzoic acid methyl ester used in the above patent is more expensive than 2,4-difluorobenzoic acid methyl ester, and there is no commercial supply in large quantities; moreover, all compounds in this synthetic route are purified by column chromatography Purification, it is difficult to scale up the reaction, so it cannot be produced industrially

Method used

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  • Synthesis method for BCL-2 inhibitor Venetoclax
  • Synthesis method for BCL-2 inhibitor Venetoclax
  • Synthesis method for BCL-2 inhibitor Venetoclax

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1Ven-16 synthesis:

[0034] Add 100g of 5-hydroxy-7-azaindole (746mmol), 141g of methyl 2,4-difluorobenzoate (821mmol), 237g of potassium phosphate (1.12mol) and 500mL of diethylene glycol dimethyl to the three-necked flask Ether, reacted at 110°C for 24h (the reaction of 5-hydroxy-7-azaindole was completely monitored by HPLC). The reaction solution was concentrated to dryness, stirred by adding 2L of ethyl acetate and 2L of water, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was heated to reflux with 1260mL ethyl acetate until it was cleared, slowly added dropwise 1260mL of petroleum ether, and the dripping was completed after 1h, and continued to stir under reflux for 1h, slowly cooled to 25°C, filtered, and dried to obtain 163g of a light white solid. The rate is 76.5%. HPLC purity 98%.

[0035] The reaction formula is as follows:

[0036]

Embodiment 2Ve

[0037] Embodiment 2 Ven-17 synthesis:

[0038]Add 30g Ven-16 (104.9mmol), 600mL DMSO, 23.4g (125.9mmol) N-Boc-piperazine and 35.9g (157.4mmol) dipotassium hydrogen phosphate to the reaction flask, raise the temperature to 120°C and react for 24h (monitored by TLC Ven-16 reaction is complete), add 900mL ethyl acetate and 900mL water and stir for 30min, then separate the liquids, wash the organic phase with 2×900mL water, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain 66g of light yellow solid. directly into the next reaction.

[0039] The reaction formula is as follows:

[0040]

Embodiment 3Ve

[0041] Embodiment 3 Ven-18 synthesis:

[0042] Add 40g Ven-17 (88mmol) and 400mL tetrahydrofuran to the reaction flask, add dropwise 500mL of 10% sodium hydroxide aqueous solution, heat up to 65°C for 24h, TLC monitors that the reaction of the raw materials is complete, cool to room temperature, add 400mL of methyl tert-butyl Stir the ether, separate the phase of methyl tert-butyl ether, adjust the pH to 4-5 with 10% hydrochloric acid solution, a solid precipitates, continue to stir for 1 h, filter, and dry at 45 ° C to obtain 39 g of white powdery solid, yield 100 %.

[0043] The reaction formula is as follows:

[0044]

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Abstract

The invention discloses a new synthesis method for a BCL-2 inhibitor Venetoclax. The synthesis method includes the steps that 2,4-difluoro methyl benzoate serves as a raw material, the 2,4-difluoro methyl benzoate and 5-hydroxy-7-azaindole are subjected to a condensation reaction, Ven-16 is obtained, and 4-substituted isomer and other impurities are removed through recrystallization; the product and N-Boc-piperazine are reacted and hydrolyzed, and Ven-18 is obtained; Ven-18 and Ven-21 are condensed, Boc of trifluoroacetic acid is removed, and Ven-20 is obtained; the product and Ven-7 are reacted, reaction intermediates in all the steps have the good crystal forms, purification can be carried out through crystal to achieve the center control requirements of the technology, and a final product Venetoclax can also be subjected to recrystallization to obtain the product Venetoclax, wherein the HPLC purity of the Venetoclax is larger than 99.5%, and the individual impurity of the Venetoclax is smaller than 0.1%; the Venetoclax has the industrialized application value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing BCL-2 inhibitor Venetoclax. Background technique [0002] The Bcl-2 protein was first discovered 30 years ago in 1986 and is expressed by the Bcl-2 gene. The Bcl-2 gene is a proto-oncogene, and the protein it expresses is called the Bcl-2 family protein. The Bcl-2 family protein is an important protein in the apoptosis pathway, and plays a key role in the occurrence and metastasis of tumors. By dimerizing with Bax and dimerizing itself, Bcl-2 protein plays an important role in the regulation of apoptosis: when Bcl-2 protein is inhibited, it dimerizes with Bax, leading to apoptosis. When the Bcl-2 protein is overexpressed, the heterodimer formed with Bax increases, and the apoptosis is inhibited. The balance between Bcl-2 and Bax proteins at cell death signaling checkpoints determines whether cells survive or die. Due to their high expression in cancer c...

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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