Preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate

A technology of tert-butyl formate and aminopyridine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of many reaction impurities, low synthesis process yield, high price and the like, and achieves the advantages of reducing environmental pollution, optimizing preparation process and reducing production cost. Effect

Active Publication Date: 2018-03-06
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In the above two methods, the raw materials used are expensive, the amount of catalyst used is as high as 0.1 equivalent, and the yield after the reaction is low. To a large extent, it is related to the partial complexation of the biborate and pyridinamine generated during coupling, resulting in a lot of reaction impuritie

Method used

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  • Preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate
  • Preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate
  • Preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The first step: the synthesis of 4-(6-fluoro-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine

[0038] Under the protection of nitrogen, in the reaction flask, add 2-fluoro-5-bromopyridine (8.80g, 0.05mol) and tetrahydrofuran (24mL), control the temperature from -10°C to 0°C, and add tetrahydrofuran of isopropylmagnesium bromide dropwise The solution (60mL, 0.06mol) was exchanged at room temperature for 4 hours after dropping, the reaction was completed, and the Grignard reagent was generated. N-tert-butoxycarbonyl-4-piperidone (9.96 g, 0.05 mol) was dissolved in 50 ml of tetrahydrofuran, and the above Grignard reagent was added dropwise, and reacted at 60° C. for 24 hours. TLC monitors the completion of the reaction and adds saturated ammonium chloride to convert Grignard salt into alcohol. After the reaction is completed, extract with ether, dry and spin dry, and purify with ether to obtain 4-(6-fluoro-3-pyridyl)-4-hydroxyl-N- 12.40 g of tert-butoxycarbonylpiperi...

Embodiment 2

[0049] The first step: the synthesis of 4-(6-fluoro-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine

[0050] Under the protection of nitrogen, add 2-fluoro-5-bromopyridine (880g, 5mol) and tetrahydrofuran (2.4L) into the reaction flask, control the temperature from -10°C to 0°C, and add isopropylmagnesium bromide solution in tetrahydrofuran dropwise (10L, 10mol, 1M), exchange at room temperature for 4 hours after dropping, the reaction is complete, and Grignard reagent is generated. N-tert-butoxycarbonyl-4-piperidone (796.8 g, 4 mol) was dissolved in 5 L of tetrahydrofuran, and the above-mentioned Grignard reagent was added dropwise, and reacted at 60°C for 24 hours. TLC monitors the completion of the reaction and adds saturated ammonium chloride to convert Grignard salt into alcohol. After the reaction is completed, extract with ether, dry and spin dry, and purify with ether to obtain 4-(6-fluoro-3-pyridyl)-4-hydroxyl-N- tert-butoxycarbonylpiperidine 1235g, yield 83.4%....

Embodiment 3

[0060] The first step: the synthesis of 4-(6-fluoro-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine

[0061] Under the protection of nitrogen, in the reaction kettle, add 2-fluoro-5-bromopyridine (8.80kg, 50mol) and tetrahydrofuran (24L), control the temperature from -10°C to 0°C, and add the tetrahydrofuran solution of isopropylmagnesium bromide dropwise (75L, 75mol, 1M), exchange at room temperature for 4 hours after dropping, the reaction is complete, and Grignard reagent is generated. Dissolve N-tert-butoxycarbonyl-4-piperidone (8.96 kg, 45 mol) in 50 L of tetrahydrofuran, add the above-mentioned Grignard reagent dropwise, and react at 60° C. for 24 hours. TLC monitors the completion of the reaction and adds saturated ammonium chloride to convert Grignard salt into alcohol. After the reaction is completed, extract with ether, dry and spin dry, and purify with ether to obtain 4-(6-fluoro-3-pyridyl)-4-hydroxyl-N- tert-butoxycarbonylpiperidine 12.29kg, yield 83.04%.

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Abstract

The invention discloses a preparation method of 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate. The method is characterized in that 2-fluoro-5-bromopyridine, N-t-butyloxycarboryl-4-piperidone, raney nickel, etc. are used as the raw materials and subjected to three-step reaction to prepare the target product that is 4-(6-substituted aminopyridine-3-radical) piperidine-1-tert-butyl formate. The method is simple, convenient and stable in process and operation; the product obtained in each step is easily separated and high in yield; the environment is protected; the rawmaterials are low in price and easy to obtain, so that the production cost of existing biological, medical and chemical intermediates can be greatly decreased; and the method is beneficial for industrial massive production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of tert-butyl 4-(6-substituted aminopyridin-3-yl)piperidine-1-carboxylate. Background technique [0002] 4-(6-substituted aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester is an important pharmaceutical intermediate, for example, when the substituted amino group is NH2, 4-(6-aminopyridine-3- Base) tert-butyl piperidine-1-carboxylate, is synthetic 3-Acetyl-1-cyclopentyl-4-methyl-7-[[5-[1-[2-(methylsulfonyl)ethyl]-4-piperidinyl]-2 The key intermediate of -pyridinyl]amino]-1,6-naphthyridin-2(1H)-one drug can selectively inhibit the dependent protein kinases CFK4 and CDK6 for the treatment of malignant tumors. [0003] The structural formula is as follows: [0004] [0005] 4-(6-substituted aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester is not much reported in the open literature, and the existing s...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 王治国宋艳红马秀娟田贝贝李世江李超李强李涛张欣
Owner SHANGHAI ZAIQI BIO TECH
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