Method for dehydro-aromatization of dihydropyridine compound and application to drug detection

A technology for dehydroaromatization and dihydropyridine, which is applied in the fields of organic chemistry, drug combination, material testing products, etc., and can solve the problems of cumbersome, complicated, and many by-products in post-processing.

Active Publication Date: 2018-12-18
BEIJING INST FOR DRUG CONTROL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the experimental conditions of most dihydropyridine dehydroaromatization reactions are harsh, and a large amount of oxidants are usually used, the by-products are many and complex, the post-treatment is cumbersome and the environment is seriously polluted.

Method used

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  • Method for dehydro-aromatization of dihydropyridine compound and application to drug detection
  • Method for dehydro-aromatization of dihydropyridine compound and application to drug detection
  • Method for dehydro-aromatization of dihydropyridine compound and application to drug detection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: Dehydroaromatization of dihydropyridine compounds

[0048] (1) Dihydropyridine compounds (usually 200mg amount of feeding) are placed in the reaction flask, and acid-containing aqueous solution (hydrochloric acid; the amount of dihydropyridine compounds in every 100ml acid-containing aqueous solution is 1.2g; the acid concentration is 0.5 mol / L), stirring and dissolving;

[0049] (2) Add nickel (elemental nickel; per 100 parts by weight of dihydropyridine compounds, the amount of nickel added is 3 parts by weight as nickel; add in the form of 40 mesh fine particles) in the reaction flask, stir at room temperature to make the reaction Complete (6 hours);

[0050] (3) Add alkali (sodium hydroxide; 1.2M) to adjust the pH to 8.0, extract three times with dichloromethane (each with the same volume as the aqueous phase), combine the organic layers, wash with saturated sodium chloride, and collect the organic layers;

[0051] (4) Add anhydrous sodium sulfate ...

Embodiment 2

[0056] Embodiment 2: Dehydroaromatization of dihydropyridine compounds

[0057] (1) Dihydropyridine compounds (usually 200mg amount of feeding) are placed in the reaction flask, and acid-containing aqueous solution (hydrochloric acid; the amount of dihydropyridine compounds in every 100ml acid-containing aqueous solution is 1g; the acid concentration is 0.7mol / L), stirring and dissolving;

[0058] (2) Add nickel (elemental nickel; per 100 parts by weight of dihydropyridine compounds, the amount of nickel added is 4 parts by weight as nickel; add in the form of 30 mesh fine particles) in the reaction flask, stir at room temperature to make the reaction Complete (10 hours);

[0059] (3) Add alkali (sodium hydroxide; 2M) to adjust the pH value to 8.5, extract three times with dichloromethane (each with the same volume as the aqueous phase), combine the organic layers, wash with saturated sodium chloride, and collect the organic layers;

[0060] (4) Add anhydrous sodium sulfa...

Embodiment 3

[0065] Example 3: Dehydroaromatization of dihydropyridines

[0066] (1) Dihydropyridine compounds (usually 200mg amount of feeding) are placed in the reaction flask, and acid-containing aqueous solution (hydrochloric acid; the amount of dihydropyridine compounds in every 100ml acid-containing aqueous solution is 2g; the acid concentration is 0.3mol / L), stirring and dissolving;

[0067] (2) Add nickel (elemental nickel; per 100 parts by weight of dihydropyridine compounds, the amount of nickel added is 2.5 parts by weight as nickel; add in the form of 60 mesh fine particles), stir at room temperature to make the reaction Complete (4 hours);

[0068] (3) Add alkali (sodium hydroxide; 1M) to adjust the pH value to 7.5, extract three times with dichloromethane (each with the same volume as the aqueous phase), combine the organic layers, wash with saturated sodium chloride, and collect the organic layers;

[0069] (4) Add anhydrous sodium sulfate to dry (10 hours), filter, con...

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Abstract

The invention relates to a method for dehydro-aromatization of a dihydropyridine compound and application to drug detection. The compound is selected from a group consisting of nifedipine, amlodipine,cilnidipine, lacidipine, felodipine, nicardipine, nitrendipine, nimodipine, barnidipine and the like. The method comprises a first step of an oxidation reaction in an acidic aqueous solution in the presence of a nickel-containing catalyst and a second step of purification. The method can prepare an impurity reference substance for detection and quality monitoring of drugs of the kind, can also beused for providing a reference for designing of instruments like a dissolution tester used in the quality detection process of the drugs, provides a reference for designing of a drug synthetic process and a preparation production process to avoid introduction of impurities through a process channel, and further can provide a reference for designing of a relevant synthetic process route of the dihydropyridine compound. According to the invention, a dehydro-aromatization reaction can be carried out in the acidic aqueous solution by using a proper oxidizing agent (such as air) in the presence ofnickel at a normal temperature and a normal pressure; and the method for dehydro-aromatization of the dihydropyridine compound provided by the invention has the advantages of mild reaction conditions, high target compound conversion rate, simple and convenient operation, few by-products and less pollution to the environment, and is a completely environmentally-friendly preparation process.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for dehydroaromatization of dihydropyridine compounds, in particular to, for example, nifedipine, amlodipine, cilnidipine, lacidipine, felodipine, nicardipine, nifedipine A method for the dehydroaromatization reaction of dihydropyridine compounds of quindipine, nimodipine and barnidipine, as a class of high-efficiency and novel reactions, the method can be used for the preparation of drugs for the detection and quality control of such drugs Impurity reference substances such as amlodipine I, etc., can also be used to provide reference for the design of instruments involved in the process of drug quality testing, such as those used in dissolution tests, and can also provide reference for the related synthesis process and preparation production process of dihydropyridine drugs. The design provides a reference to avoid the introduction of impurities through process channels, a...

Claims

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Application Information

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IPC IPC(8): C07D211/90C07D401/12A61P9/10A61P9/04A61P9/12A61P9/00G01N33/15
CPCA61P9/00A61P9/04A61P9/10A61P9/12C07D211/90C07D401/12G01N33/15
Inventor 付晖尹光贾伯阳王铁松杨文良张喆胡琴段永生
Owner BEIJING INST FOR DRUG CONTROL
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