Method for preparing CDK4/6 inhibitor key intermediate through chemical-enzymatic method

An enzymatic preparation and inhibitor technology, applied in organic chemistry, fermentation, etc., can solve the problems of high cost of palladium catalyst and high safety requirements of catalytic hydrogenation equipment, and achieve the effect of short steps, low equipment requirements and high yield

Active Publication Date: 2021-03-30
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthesis method does not require deprotection and has fewer impurities, but the cost of the palladium catalyst used is high and requires high safety requirements for catalytic hydrogenation equipment

Method used

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  • Method for preparing CDK4/6 inhibitor key intermediate through chemical-enzymatic method
  • Method for preparing CDK4/6 inhibitor key intermediate through chemical-enzymatic method
  • Method for preparing CDK4/6 inhibitor key intermediate through chemical-enzymatic method

Examples

Experimental program
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Effect test

Embodiment 1

[0037] 1): Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperidine-1-carboxylate

[0038] Under the protection of nitrogen, add 40.6g of 5-bromo-2-nitropyridine into 400ml of anhydrous THF, drop 240ml of tert-butylmagnesium chloride solution (1.0M) at -10~-20°C, and keep the reaction for 2h after dropping Get Grignard reagent. Dissolve 52.8g of N-tert-butoxycarbonyl-4-bromo-piperidine and 324mg of ferric chloride in 500ml of anhydrous THF under the protection of nitrogen, add the above-mentioned Grignard reagent dropwise, control the temperature at -10~-20°C, and keep warm for the reaction 4h, after the completion of the TLC reaction, add saturated ammonium chloride solution, extract with ethyl acetate, dry, evaporate to dryness, add 200ml of methyl tert-butyl ether to reflux for beating for 1h, drop to -5 ~ 0°C, filter with suction, and dry After drying, 55.7 g of the product was obtained, with a yield of 90.7% and a purity of 98.8%.

[0039] 2) Synthesis of tert-butyl 4-...

Embodiment 2

[0042] 1) Synthesis of 4-(6-nitropyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0043]Under the protection of nitrogen, add 60.9g of 5-bromo-2-nitropyridine into 600ml of anhydrous THF, drop 380ml of tert-butylmagnesium chloride solution (1.0M) at -10~-20°C, and keep the reaction for 2h after dropping Get Grignard reagent. Dissolve 79.2g of N-tert-butoxycarbonyl-4-bromo-piperidine and 486mg of ferric chloride in 750ml of anhydrous THF under the protection of nitrogen, add the above-mentioned Grignard reagent dropwise, control the temperature at -10~-20°C, and keep the reaction 4h, after the TLC reaction is completed, add saturated ammonium chloride solution, extract with ethyl acetate, dry, evaporate to dryness, add 300ml methyl tert-butyl ether to reflux for beating for 1h, drop to -5 ~ 0°C, filter with suction and dry After drying, 83.9 g of the product was obtained, with a yield of 91.1% and a purity of 98.9%.

[0044] 2) Synthesis of tert-butyl 4-(6-aminopy...

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Abstract

The invention discloses a method for preparing a CDK4 / 6 inhibitor key intermediate through a chemical enzyme method. The method comprises the following steps: firstly, carrying out halogen / magnesium exchange on 5-bromo-2-nitropyridine and tert-butyl magnesium chloride to generate a Grignard reagent, and then carrying out addition reaction with N-tert-butyloxycarboryl-4-bromopiperidine to obtain 4-(6-nitropyridine-3-yl)piperidine-1-tert-butyl formate; and then creatively using nitroreductase (assisted by reductive coenzyme I) to reduce the 4-(6-nitropyridine-3-yl)piperidine-tert-butyl formate into 4-(6-aminopyridine-3-yl)piperidine-1-tert-butyl formate. The method has the advantages of short steps, simple operation, mild reaction conditions, high safety, no heavy metal catalyst, environmental protection, good product quality, high yield and low cost.

Description

technical field [0001] The invention relates to a method for preparing a CDK4 / 6 inhibitor key intermediate (4-(6-aminopyridin-3-yl)piperidine-1-carboxylate tert-butyl ester) by chemical-enzymatic method, which belongs to the technical field of organic synthesis. Background technique [0002] Cyclin-dependent kinases CDKs are a class of protein kinases that play a role in cell cycle regulation and are important factors in cell cycle regulation, among which CDK4 / 6 is the human cell division and proliferation cycle (G1 phase S phase G2 phase M phase) These two kinases are hyperactive and exhibit significant activity in many malignancies. CDK4 / 6 inhibitors induce cell cycle arrest through the CDK4 / 6-Rb signaling pathway, thereby inhibiting cell proliferation and exerting anti-tumor effects. tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate has attracted much attention as a key intermediate of CDK4 / 6 inhibitors. [0003] 4-(6-aminopyridin-3-yl) piperidine-1-carboxylic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/16C07D401/04
CPCC12P17/165C07D401/04Y02P20/55
Inventor 李斌齐英超赵希伟
Owner SHANDONG BOYUAN PHARM CO LTD
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