Synthesis method of 4-(6-aminopyridine-3-yl) piperidine-1-tert-butyl formate

A technology of tert-butyl formate and carbamate, applied in the field of synthesis of 4-piperidine-1-tert-butyl carboxylate, can solve the problems of high safety risk and high equipment requirements, and achieve high safety and low equipment requirements , the effect of high yield

Inactive Publication Date: 2021-04-06
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Patent CN110540535A directly uses cheaper 2-amino-5-bromopyridine as raw material on the basis of patent CN109384767A, and undergoes palladium catalyst catalytic coupling and reduction to obtain the product without deprotection, less impurities and low cost, but still needs Palladium-carbon catalytic hydrogenation requires high equipment requirements and high safety risks

Method used

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  • Synthesis method of 4-(6-aminopyridine-3-yl) piperidine-1-tert-butyl formate
  • Synthesis method of 4-(6-aminopyridine-3-yl) piperidine-1-tert-butyl formate
  • Synthesis method of 4-(6-aminopyridine-3-yl) piperidine-1-tert-butyl formate

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Effect test

Embodiment 1

[0039] (1) Synthesis of 4-(6-fluorenylamino-3-pyridyl)-4-hydroxyl-N-tert-butoxycarbonylpiperidine

[0040] Under nitrogen protection, add 39.5g of fluorenylmethyl N-(5-bromopyridin-2-yl)carbamate into 400ml of anhydrous THF, drop 100ml of isopropylmagnesium chloride and lithium chloride at 0-5°C solution (1.3M), dropwise and keep warm for 2 hours to obtain the Grignard reagent.

[0041] Under the protection of nitrogen, 17.9g of N-tert-butoxycarbonyl-4-piperidone was dissolved in 100ml of anhydrous THF, the above-mentioned Grignard reagent was added dropwise, the temperature was controlled at 10-15°C, and the reaction was kept for 3h. After the TLC reaction is completed, add 500ml of saturated ammonium chloride solution, extract with 300ml of ethyl acetate, dry and evaporate to dryness, add 150ml of methyl tert-butyl ether to reflux for beating for 1h, drop to -5~0°C, filter with suction, and dry 41.9 g of the product was obtained with a yield of 90.3% and a purity of 98.6%. ...

Embodiment 2

[0045] (1) Synthesis of 4-(6-fluorenylamino-3-pyridyl)-4-hydroxyl-N-tert-butoxycarbonylpiperidine

[0046] Under nitrogen protection, add 59.3g of fluorenylmethyl N-(5-bromopyridin-2-yl)carbamate into 600ml of anhydrous 2-methyltetrahydrofuran, drop 145ml of isopropyl Magnesium chloride lithium chloride solution (1.3M), after dripping, keep warm for 2 hours to obtain the Grignard reagent.

[0047] Under the protection of nitrogen, dissolve 29.8g of N-tert-butoxycarbonyl-4-piperidone in 150ml of anhydrous 2-methyltetrahydrofuran, add the above-mentioned Grignard reagent dropwise, control the temperature at 5-10°C, keep the temperature for 3h, and perform TLC reaction After completion, add 750ml of saturated ammonium chloride solution, extract with 450ml of ethyl acetate, dry and evaporate to dryness, add 200ml of methyl tert-butyl ether to reflux for beating for 1 hour, drop to -5~0°C, filter with suction, and dry to obtain the product 70.3g, yield 91.1%, purity 98.7%.

[0048]...

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Abstract

The invention discloses a synthetic method of 4-(6- aminopyridine-3-yl) piperidine-1-tert-butyl formate. According to the method, fluorenylmethyl-N-(5-bromopyridine-2-yl) carbamate and isopropyl magnesium chloride lithium chloride are subjected to halogen / magnesium exchange to generate a Grignard reagent, then the Grignard reagent and N-tertbutyloxycarboryl-4-piperidone are subjected to addition, an addition product is reduced by triethylsilane, and deprotection is performed under an alkaline condition to obtain a target product. The method has the advantages of simple steps, no special reactions such as ultralow temperature, high temperature, high pressure, catalytic hydrogenation and the like, low equipment requirements, high safety, cheap and easily available raw materials, no need of expensive catalysts, high product purity, high yield and suitability for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate, which belongs to the technical field of organic synthesis. Background technique [0002] 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester is an important pharmaceutical intermediate, which can be used as a key intermediate of some pyrimidine or pyridopyridone drugs, which can be Efficient and highly selective inhibition of the activity of cell cycle-dependent kinases (CDKs) CDK4 and CDK6 to play an anti-tumor effect has attracted much attention. [0003] 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester currently has the following synthetic methods: [0004] Patent WO201324078 uses 5-bromo-2-nitropyridine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-5,6-di Hydropyridine-1(2-hydrogen)-tert-butyl carboxylate is used as the starting material, and the coupling is catalyzed under the palladium catalyst, f...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 昝金行苏曼
Owner SHANDONG BOYUAN PHARM CO LTD
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