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The preparation method of dalfonpyridine

A technology for pyridine and amino resin, which is applied in the field of preparation of 4-aminopyridine, can solve the problems of medium yield and is not suitable for industrial production, and achieves the effects of mild synthesis conditions, environmental friendliness and high product purity

Inactive Publication Date: 2019-02-26
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses the heavy metal oxide cuprous oxide, the yield is moderate, and it is not suitable for industrial production

Method used

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  • The preparation method of dalfonpyridine
  • The preparation method of dalfonpyridine
  • The preparation method of dalfonpyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of embodiment 1 isonicotinic acid amide resin

[0030]

[0031] Weigh 10 g of Rink Amide-AM resin with a substitution degree of 3.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, deprotect DBLK for 6 minutes + 8 minutes, and wash it with DMF 6 times . Weigh 7.38g (60mmol) isonicotinic acid and 8.9g (66mmol) HOBT dissolved in DMF, add 12mL (72mmol) DIPCDI under ice-water bath to activate for 3min, then add the mixed solution into the reaction column, react at room temperature for 2 hours, and indene Triketone detection reaction end point (if the resin is colorless and transparent, stop the reaction; if the resin develops color, extend the reaction for 1 hour). After the reaction was completed, the resin was washed with DMF for 3 times, and methanol shrunk to obtain 13.5 g of isonicotinic acid amide resin with a yield of 99%.

Embodiment 2

[0032] The preparation of embodiment 2 isonicotinic acid amide

[0033]

[0034] Add 13.5 grams of the peptide resin obtained in Example 1 into a 250mL single-necked bottle, add pre-configured TFA:H 2 O: 150 mL of a mixed solution of DCM=90:2:8, react at room temperature for 2 hours, filter the resin, and collect the filtrate. The resin was washed with a small amount of TFA, and the filtrates were combined. The filtrate was slowly added to 1500ml glacial ether for precipitation. Centrifuged, washed 5 times with glacial ether, and dried under reduced pressure to obtain 3.5 g of isonicotinic acid amide with a yield of 97% and a purity of 96% by HPLC.

Embodiment 3

[0035] The preparation of embodiment 3 isonicotinic acid amide

[0036] Add 13.5 g of the peptide resin obtained in Example 1 into a 250 mL single-necked bottle, add 150 mL of a pre-prepared TFA:DCM=90:10 mixed solution, react at room temperature for 2 hours, filter the resin, and collect the filtrate. The resin was washed with a small amount of TFA, and the filtrates were combined. The filtrate was slowly added to 1500ml glacial ether for precipitation. Centrifuged, washed 5 times with glacial ether, and dried under reduced pressure to obtain 3.0 g of isonicotinic acid amide with a yield of 90% and a purity of 96% by HPLC.

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Abstract

The invention relates to a preparation method for dalfampridine. The preparation method comprises the following steps: 1) preparing isonicotinic acid amide resin from amino resin and isonicotinic acid through a coupler; 2) removing the resin by virtue of a lysis solution and preparing isonicotinic acid amide; and 3) performing Hofmann degradation on isonicotinic acid amide obtained in the step 2) through a degrading reagent and alkali to obtain dalfampridine.

Description

technical field [0001] The present invention relates to the preparation method of 4-aminopyridine. Background technique [0002] Darfonpyridine, that is, 4-aminopyridine, is often used as an intermediate in pesticides, medicines and dyes. It is an intermediate in the synthesis of antibiotics such as 4-acetamidopiperidine acetate. The raw material of antiulcer drug, antispasmodic drug mirverine and the new antihypertensive drug pinacidil. Since its discovery in 1902, there have been many synthetic methods related to 4-aminopyridine. [0003] The most typical preparation method is pyridine nitronitroxidation method, and the synthetic route is shown in Reaction Formula 1. In this method, pyridine is used as the starting material, which is oxidized to produce pyridine nitrogen oxide, then nitrated with mixed acid to produce 4-nitropyridine nitrogen oxide, and finally reduced to obtain 4-aminopyridine. This method will use strong acid and strong alkali, which will increase the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 陈学明姚志军宓鹏程陶安进袁建成
Owner HYBIO PHARMA