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Preparation method of 4-(6-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, high price, low synthesis process yield, etc., and achieves the effects of reducing environmental pollution, reducing production cost and optimizing preparation process.

Active Publication Date: 2018-03-23
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 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 impurities. It needs to go through a silica gel column to purify, and the content of heavy metals in the product is difficult to effectively control to the level required for pharmaceutical intermediates
Therefore, on the whole, the yield of the existing synthetic process is low, difficult to purify, and the economic benefits are not good.

Method used

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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The first step: the synthesis of 4-(6-trimethylacetamido-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine

[0032] At -70°C, n-butyl lithium (37.2 mL, 93 mmol) in n-hexane (2.5 N) was slowly added to N-(5-bromo-pyridine-2-)-2,2-dimethylpropanamide ( 7.94 g, 31 mmol) in diethyl ether (80 mL), and the reaction mixture was stirred at this temperature for 1 hour. Diethyl ether (60 mL) of N-tert-butoxycarbonyl-4-piperidone (6.15 g, 31 mmol) was added to the reaction solution at -70°C and stirred for 2 hours. After the completion of the reaction monitored by TLC, the reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was spin-dried and purified by a flash silica gel column to obtain 11.01 g of a solid with a yield of 94.42%.

[0033] Detected by mass spectrometry, ESI / MS: m / z=322.3[MH] + , the solid was determined to be 4-(6-trimethylacetamido-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine.

[0034] ...

Embodiment 2

[0042] The first step: the synthesis of 4-(6-trimethylacetamido-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine

[0043]At -65°C, slowly add n-butyllithium (1.94L, 4.85mol) in n-hexane solution (2.5N) into N-(5-bromo-pyridine-2-)-2,2-dimethylpropanamide (500 g, 1.94 mol) in tetrahydrofuran (1 L), the reaction mixture was stirred at -65°C to -70°C for 1 hour. N-tert-butoxycarbonyl-4-piperidone (465 g, 2.33 mol) in tetrahydrofuran (2 L) was added to the reaction solution at -65°C and stirred for 2 hours. After the completion of the reaction monitored by TLC, the reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was spin-dried and purified by a flash silica gel column to obtain 704.6 g of solid, with a yield of 96.0%.

[0044] Detected by mass spectrometry, ESI / MS: m / z=322.3[MH] + , the solid was determined to be 4-(6-trimethylacetamido-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine.

[0045] The secon...

Embodiment 3

[0053] The first step: the synthesis of 4-(6-trimethylacetamido-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine

[0054] At -78°C, slowly add n-butyl lithium (46.6L, 116.67mol) in n-hexane solution (2.5N) into N-(5-bromo-pyridine-2-)-2,2-dimethylpropanamide (10 kg, 38.89 mol) in tetrahydrofuran (20 L), the reaction mixture was stirred at -78°C to -70°C for 1 hour. N-tert-butoxycarbonyl-4-piperidone (7.75kg, 38.89mol) in tetrahydrofuran (12L) was added to the reaction solution at -78°C and stirred for 2 hours. After the completion of the reaction monitored by TLC, the reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic layer was spin-dried and purified by a flash silica gel column to obtain 13.79 kg of solid with a yield of 93.9%.

[0055] Detected by mass spectrometry, ESI / MS: m / z=322.3[MH] + , the solid was determined to be 4-(6-trimethylacetamido-3-pyridyl)-4-hydroxy-N-tert-butoxycarbonylpiperidine.

[0056] Th...

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Abstract

The invention discloses a preparation method of 4-(6-aminopyridine-3-radical) piperidine-1-tert-butyl formate. The target product 4-(6-aminopyridine-3-radical) piperidine-1-tert-butyl formate is obtained by three steps of reactions by taking N-(5-bromine-piperidine-2-)-2, 2-dimethylacrylamide, N-t-butyloxycarboryl-4-piperidone, raney nickel and the like as raw materials. The preparation method issimple, convenient and stable in process operation, and a product in each step is easy to separate, high in yield and environmentally friendly; the comprehensive yield is 82 percent or above; comparedwith the yield of 42 percent of the existing process, the yield is obviously increased; furthermore, the raw materials are low in cost and readily available, so that the production costs of existingbiological, medical and chemical intermediates are substantially reduced; industrial large-scale production is facilitated.

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-aminopyridin-3-yl)piperidine-1-carboxylate. Background technique [0002] 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester, English name: tert-Butyl-4-(6-aMinopyridin-3-yl)piperidine-1-carboxylate, molecular formula is C15H23N3O2. White powdery solid, it is a good biological, pharmaceutical and chemical intermediate. [0003] 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester is not reported much in the open literature, and the existing synthetic techniques can be roughly divided into two categories: [0004] Method 1. Using 2-nitro-5-bromopyridine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)-5,6- Dihydropyridine-1(2-hydrogen)-tert-butyl carboxylate is coupled under the catalysis of metal palladium, and then the nitro group is simultaneously reduced while the double ...

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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