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Preparation method of Venetoclax intermediate and product

A technology of venetola and an intermediate, which is applied in the field of medicine, can solve the problems of unsuitability for large-scale production, low total yield, long steps and the like, and achieves a technology that is beneficial to large-scale industrial production, reduces production costs and consumes low energy. Effect

Inactive Publication Date: 2019-02-12
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, the steps of this route are too long, resulting in low overall yield, and need to use expensive rare earth metal cerium oxide, which is high in cost, and also requires the use of high temperature resistant equipment at 200°C, which is not suitable for industrial large-scale production

Method used

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  • Preparation method of Venetoclax intermediate and product
  • Preparation method of Venetoclax intermediate and product
  • Preparation method of Venetoclax intermediate and product

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Step 1: Preparation of 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (Ⅲ)

[0042]

[0043] Dissolve 5-bromo-7-azaindole (20.0g, 101.5mmol) in 200mL tetrahydrofuran, add potassium tert-butoxide (13.7g, 121.8mmol) at room temperature, raise the temperature to 60-65°C, and stir for 2 hours. The temperature was lowered to 10-20°C, and triisopropylchlorosilane (21.5g, 111.7mmol) was added dropwise. After the dropwise addition, the reaction was continued at 10-20°C for 4 hours. TLC detection showed that the reaction of the raw materials was complete. After the reaction is complete, add 100 mL of water to quench, extract once with 200 mL of ethyl acetate, wash the extract once with 200 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and spin dry, the crude product is recrystallized with 200 mL of methanol, filtered, and dried to obtain Light yellow powder 30.9g, yield 86.3%.

[0044] Step 2: Preparation of 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]...

Embodiment 2

[0051] Step 1: Preparation of 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (Ⅲ)

[0052]

[0053] Dissolve 5-bromo-7-azaindole (100.0 g, 0.51 mol) in 200 mL of tetrahydrofuran, add potassium tert-butoxide (68.5 g, 0.61 mol) at room temperature, raise the temperature to 60-65 °C, and stir for 2 hours. The temperature was lowered to 10-20°C, and 107.5 g (0.56 mol) of triisopropylchlorosilane was added dropwise. After the dropwise addition, the reaction was continued at 10-20°C for 4 hours. TLC detection showed that the reaction of the raw materials was complete. After the reaction was completed, 500 mL of water was added to quench, extracted once with 1000 mL of ethyl acetate, the extract was washed once with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried, the crude product was recrystallized with 1000 mL of methanol, filtered, and dried Yellow powder 156.7g, yield 87.5%.

[0054] Step 2: Preparation of 1-(triisopropylsily...

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Abstract

The invention discloses a preparation method of a Venetoclax intermediate. 5-bromine-7-azaindole (II) is used as a raw material; an upper protecting group generates 5-bromine-1-(Triisopropyl silicyl)-1H-pyrrolo[2,3-b]pyridine (III); a compound (III) and Triisopropyl borate react and then are oxidized to obtain 1-(Triisopropyl silicyl)-1H-pyrrolo[2,3-b]pyridine-5-alcohol (IV); and a compounds (IV)and 2,4-difluoro methylbenzoate react to generate 2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)-4-methyl 2-fluorobenzoate (I). According to the preparation method, lithium bisamide is replaced with tertiary butanol sodium / potassium, thus the production cost is lowered, trimethyl borate is replaced with the Triisopropyl borate, equipment input is less in the synthesis process, and the operation flow is simplified; and most of all, reacting under the ultra-low temperature is not needed, the reaction temperature can be minus 20-minus 10 DEG C, general equipment can all meet the requirements, energy consumption is lowered, operation is convenient, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of a venetura intermediate and a product thereof. Background technique [0002] The chemical name of Venetola is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazine-1- Base)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3 -b]pyridin-5-yloxy)benzamide, which is the first selective inhibitor targeting B-cell lymphoma factor 2 (BCL-2). B-cell lymphoma factor 2 (B-celllymphoma-2, BCL-2) in the cells of leukemia patients can promote the growth of cancer cells and is often overexpressed in B lymphocytes and other B-cell malignancies. Venetola was approved by the FDA on April 11, 2016 for chronic lymphocytic leukemia. [0003] In the prior art, a number of patent documents have disclosed the synthesis method of the venetura intermediate (I), and disclosed a number of synthesis routes. [0004] Synthetic route...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 黄雄鸠何伟彭磊唐丽昌王珑霖白栖
Owner CHONGQING SANSHENG IND CO LTD
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