Low-cost simple and convenient preparation method of 3-amino-4-methylpyridine

A picoline and nitropyridine technology, applied in the field of medicinal chemistry, can solve the problems of high price and high price of 4-picoline-3-boronic acid, and achieve the effects of low cost, easy post-processing and short process flow

Active Publication Date: 2019-07-16
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] Although the synthetic route 4 is short, the price of the raw material 4-picoline-3-boronic acid used is high, and it is necessary to prepare the corresponding Grignard reagent from 3-bromo-4-picoline through the Grignard reaction, and then react with borate ester and hydrolyze come and get, resulting in the price of 4-picoline-3-boronic acid being higher than the market supply price of 3-amino-4-picoline

Method used

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  • Low-cost simple and convenient preparation method of 3-amino-4-methylpyridine
  • Low-cost simple and convenient preparation method of 3-amino-4-methylpyridine
  • Low-cost simple and convenient preparation method of 3-amino-4-methylpyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1: the preparation of 4-methyl-3-nitropyridine

[0056] Add 10.5 grams (0.1 moles) of 3-chlorocrotonaldehyde, 30.5 grams (0.5 moles) of nitromethane, and 0.4 grams of DBU to a 250-milliliter four-neck flask connected with a stirring, thermometer, and reflux condenser, and stir at 40-45°C React for 4 hours, after the reaction is completed by gas phase detection; add 17.5 grams (0.15 moles) of N,N-dimethylformamide dimethyl acetal, raise the temperature to 100-105 °C and stir for 4 hours, while steaming out and recovering excess nitromethane , After the gas phase detection reaction is completed; cool to 30°C, add 30.0 grams of 17% ammonia water, 50 grams of dichloromethane, stir and react at 30-35°C for 4 hours, cool to 20°C, separate layers, and extract the water layer with dichloromethane 3 times, 20 grams of dichloromethane each time, combined the organic phases, dried 3.0 grams of anhydrous sodium sulfate for 3 hours, filtered, and distilled the filtrate to...

Embodiment 2

[0057] Embodiment 2: the preparation of 4-methyl-3-nitropyridine

[0058] In a 500 ml four-neck flask connected with stirring, thermometer and reflux condenser, add 15.0 g (0.1 mole) of 3-bromocrotonaldehyde, 50 g of dichloromethane, 6.7 g (0.11 mole) of nitromethane, and 0.4 g of DBU , stirred and reacted at 40-45°C for 4 hours. After the reaction was completed by gas phase detection, 17.5 grams (0.15 moles) of N,N-dimethylformamide dimethyl acetal was added, and the temperature was raised to 100-105°C and stirred for 4 hours. Recover dichloromethane and excess nitromethane. After the reaction is completed by gas phase detection, cool to 30°C, add 35.0 grams of 15% ammonia-methanol solution, stir and react at 40-45°C for 4 hours, recover methanol by distillation under reduced pressure, and cool to 20 ℃, add 100 grams of water, 50 grams of dichloromethane, separate layers, extract the aqueous layer 3 times with dichloromethane, each time 20 grams of dichloromethane, combine th...

Embodiment 3

[0059] Embodiment 3: the preparation of 4-methyl-3-nitropyridine

[0060] In the 250 milliliters four-neck flasks that are connected with stirring, thermometer, reflux condenser, add 10.5 grams (0.1 moles) 2-chlorocrotonaldehyde, 50 grams toluene, 6.7 grams (0.11 moles) nitromethane, 0.5 grams piperidine, Stir and react at 40-45°C for 4 hours. After the reaction is completed by gas phase detection, add 17.5 grams (0.15 moles) of N,N-dimethylformamide dimethyl acetal, raise the temperature to 100-105°C, stir and react for 4 hours, and evaporate to recover at the same time Dichloromethane and excess nitromethane, after the gas phase detection reaction is completed, cool to 30 ° C, add 35.0 grams of 15% ammonia-methanol solution, stir and react at 40-45 ° C for 4 hours, recover methanol and toluene by distillation under reduced pressure, and cool to 20°C, add 100 grams of water and 50 grams of dichloromethane to the residue, separate layers, extract the aqueous layer with dichlor...

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Abstract

The invention relates to a low-cost simple and convenient preparation method of 3-amino-4-methylpyridine. The method comprises the following steps: performing addition on halogenated crotonaldehyde asa raw material and nitromethane, performing methylenenation condensation, performing aminopyridine cyclization to obtain 4-methyl-3-nitropyridine, and performing reduction to prepare the 3-amino-4-methylpyridine. According to the preparation method provided by the invention, the raw materials used in the method are cheap and easy to obtain, the conditions are mild, the operation is simple, convenient and safe, the reaction selectivity is high, the product yield and purity are high, and the costs are low; and in the process, the atomic economy is high, and three waste (waste water, waste gas and solid waste) is less.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of low-cost 3-amino-4-picoline. The compound can be used to prepare anti-AIDS drugs such as nevirapine and tofacitinib, and belongs to the technical field of medicinal chemistry. Background technique [0002] 3-Amino-4-picoline is an important pyridine derivative and an important intermediate raw material for the synthesis of medicines, pesticides, pigments, etc. [0003] Nevirapine is a non-nucleoside reverse transcriptase inhibitor developed by Boehringer Ingelheim, Germany. It binds near the catalytic site of the enzyme, acts directly on reverse transcriptase, inhibits its activity, and then inhibits HIV replication. It is used clinically to inhibit AIDS mother-to-child virus transmission. Tofacitinib is a rheumatoid arthritis drug developed by Pfizer Pharmaceuticals of the United States. It was approved by the US Food and Drug Administration (FDA) on November 6, 2012 for patients ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 戚聿新鞠立柱江枭南钱余锋
Owner XINFA PHARMA
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