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Preparation method of BCL-2 inhibitor venetoclax

A technology for BCL-2 and inhibitors, which is applied in the field of preparation of BCL-2 inhibitor-Vitekla, can solve the problems of unsuitable large-scale industrial production and preparation, limited drug application, poor operability, etc., and achieves simple and easy reaction, Enhanced operability and short steps

Active Publication Date: 2020-03-13
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the Vitekla synthesis process in the prior art has the disadvantages of complex routes, poor operability, and not suitable for large-scale industrial production, which limits the application of this type of drug to a certain extent.

Method used

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  • Preparation method of BCL-2 inhibitor venetoclax
  • Preparation method of BCL-2 inhibitor venetoclax

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Step 1, preparation of V1:

[0031] At room temperature, VM1 (18.1g, 105mmol, 1.05eq), 1-p-toluenesulfonyl-5-hydroxyl-7-azaindole (28.8g, 100mmol, 1.0eq), potassium carbonate ( 27.6g, 200mmol, 2.0eq) and 300mL dimethyl sulfoxide, stirred, heated to 95-100°C for reaction, and TLC monitored the reaction. After the reaction is complete, cool down to room temperature, add 1000mL of water, stir, extract with isopropyl acetate (500mL×3), combine the organic phases, wash with saturated brine (300mL×1), dry over anhydrous sodium sulfate, suction filter, and the filtrate Concentrate under reduced pressure to dryness, add 350mL of n-heptane to the residual liquid for slurry, filter with suction, and dry to obtain 40.1g of solid product V1 with a yield of 91%.

[0032] Step 2, preparation of V2:

[0033] Add intermediate V1 (40.1g, 91mmol, 1.0eq), Boc piperazine (18.6g, 100mmol, 1.1eq), potassium carbonate (25.1g, 182mmol, 2.0eq) and 500mL tetrahydrofuran in a 1000mL reaction fl...

Embodiment 2

[0043] Step 1, preparation of V1:

[0044] At room temperature, VM1 (10.3g, 60mmol, 1.2eq), 2-nitrobenzenesulfonyl-5-hydroxyl-7-azaindole (16g, 50mmol, 1.0eq), potassium phosphate ( 21.2g, 100mmol, 2.0eq) and 200mL N,N-dimethylformamide, stirred, heated up to 95-100°C for reaction, and TLC monitored the reaction. After the reaction is complete, cool down to room temperature, add 500 mL of water, stir, extract with tert-butyl acetate (200 mL×3), combine the organic phases, wash with saturated brine (200 mL×1), dry over anhydrous sodium sulfate, suction filter, and the filtrate Concentrate under reduced pressure to dryness, add 200 mL of n-hexane to the residual liquid to make a slurry, filter with suction, and dry to obtain 21.3 g of solid product V1 with a yield of 90%.

[0045] Step 2, preparation of V2:

[0046] Add intermediate V1 (21.3g, 45mmol, 1.0eq), Boc piperazine (12.6g, 68mmol, 1.5eq), triethylamine (13.6g, 135mmol, 3.0eq) and 300mL acetonitrile in 500mL reaction f...

Embodiment 3

[0056] Step 1, preparation of V1:

[0057] At room temperature, VM1 (19.4g, 113mmol, 1.5eq), 4-nitrobenzenesulfonyl-5-hydroxyl-7-azaindole (24g, 75mmol, 1.0eq), potassium phosphate ( 23.9g, 225mmol, 3.0eq) and 300mL dimethyl sulfoxide, stirred, heated to 95-100°C for reaction, TLC monitored the reaction. After the reaction is complete, cool down to room temperature, add 600 mL of water, stir, extract with tert-butyl acetate (300 mL×3), combine the organic phases, wash with saturated brine (300 mL×1), dry over anhydrous sodium sulfate, suction filter, and the filtrate Concentrate under reduced pressure to dryness, add 300mL of n-hexane to the residual liquid to make a slurry, filter with suction, and dry to obtain 31.2g of solid product V1 with a yield of 88%.

[0058] Step 2, preparation of V2:

[0059] In 500mL reaction flask, add intermediate V1 (31.2g, 66mmol, 1.0eq), Boc piperazine (22.1g, 119mmol, 1.8eq), DIPEA (25.5g, 198mmol, 3.0eq) and 300mL tetrahydrofuran, stir, be...

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Abstract

The invention discloses a preparation method of a BCL-2 inhibitor venetoclax. The method mainly comprises the following six steps: 1) VM1 and VM2 used as reaction starting materials undergo a dockingreaction under the catalytic action of an alkali to prepare an intermediate V1; 2) the intermediate V1 reacts with Boc piperazine under the catalytic action of the alkali to prepare an intermediate V2; 3) Boc protection is removed from the intermediate V2 under the action of an acid reagent to prepare an intermediate V3; 4) the intermediates V3 and VM3 are heated to react to form a Schiff base, and the Schiff base is converted into secondary amine under the action of a reducing agent to prepare an intermediate V4; 5) the intermediate V4 reacts with the intermediate VM4 under the action of a condensing agent to prepare an amide compound intermediate V5; and 6) a phenylsulfonyl protecting group is removed from the intermediate V5 under the catalysis of a catalyst to obtain the final productvenetoclax. Compared with the prior art, the preparation method has the advantages of short steps, simple and feasible reaction, and suitableness for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of BCL-2 inhibitor-Vitekla. Background technique [0002] Venetoclax is a breakthrough anticancer drug jointly developed by Abbvie and Roche. It was the first drug approved by the US Food and Drug Administration (FDA) on April 11, 2016. A B-cell lymphoma-2 gene inhibitor (BCL-2), which is mainly used for patients with chronic lymphocytic leukemia (CLL) with 17p gene deletion and who have received at least one drug therapy. [0003] BCL-2 family members are mainly involved in the regulation of mitochondrial outer membrane, such as Bad, Bax, etc. can promote apoptosis, BCL-2, MCL-1, etc. can inhibit apoptosis. The overexpression of BCL-2 family inhibits apoptosis proteins often enables tumor cells to escape apoptosis and develop resistance to a variety of antitumor drugs. Vitekla is a specific small molecule inhibitor of Bcl-2, which can specifically inhibit Bcl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 李泽标陈丹吴洪当徐晓红林燕峰
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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