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Dofetilide-d3 drug and preparation method thereof

A technology of -d3 and medicine, which is applied in the field of dofetilide-d3 medicine and its preparation, can solve the problems of easy introduction of by-products and toxicity, so as to avoid highly toxic reagents and high-risk reagents, reduce costs and reduce pollution and the effect of wasting

Pending Publication Date: 2020-07-10
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a kind of Dophyllite-d 3 The drug and its preparation method aim to solve the problem that the traditional method uses toxic or carcinogenic alkylating reagents, and often requires multiple steps to obtain the target drug molecule, which is easy to bring in by-products

Method used

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  • Dofetilide-d3 drug and preparation method thereof
  • Dofetilide-d3 drug and preparation method thereof
  • Dofetilide-d3 drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: take p-chlorophenol as raw material, synthesize compound III

[0057]

[0058] 10.3 g of p-chlorophenol and 3.84 g of sodium hydroxide were respectively weighed into a 250 mL reaction flask, and 60 mL of ethanol was added. Then 44.8 g of 1,2-dibromoethane were slowly added dropwise at room temperature. After the dropwise addition was completed, the reaction was refluxed. After 24 hours, cool, spin dry the ethanol, and add water and ethyl acetate to the bottle. It was extracted three times with ethyl acetate, and the organic phases were combined and washed with water and saturated brine successively. The solvent was removed by rotary evaporation, and then the pure target product was obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate) in a yield of 51%.

Embodiment 2

[0059] Example 2: Synthesis of Compound I

[0060]

[0061] 3.5 g of compound III, 3.5 g of p-chlorophenethylamine and 4.14 g of potassium carbonate were respectively weighed, and 15 mL of anhydrous acetonitrile was added. Then react at 80°C. After 24 hours, the solvent was directly evaporated by rotary evaporation, and then the pure target product was obtained by column chromatography (developing solvent: dichloromethane / methanol), such as figure 1 shown, by 1 The structure was confirmed by HNMR and other tests, and the yield was 91%.

Embodiment 3

[0062] Example 3: Synthesis of Compound II

[0063]

[0064] Weigh 0.4 mmol of compound I, 25.0 mg of Pd / KPCN photocatalyst and 40 mg of aluminum trichloride into a 5.0 mL reaction flask, add 2.0 mL of anhydrous acetonitrile, and add deuterium water / d 4 - a mixed solution of deuterated methanol (1.0mL / 0.6mL), replace the reaction system with an argon protection state, then place the reaction flask under a 420nm light source for 24 hours of light reaction, remove the light source after the reaction, and place the reaction mixture pad Celite filter, then with 5.0mL CH 2 Cl 2 After extraction, the extract was dried over anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The solvent was removed by rotary evaporation, and then the pure target product was obtained by column chromatography (developing solvent: dichloromethane / methanol). 1 The structure was confirmed by HNMR, C-NMR and other tests, the yield was 96%, and the deuteration rate was >95%.

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Abstract

The invention discloses a dofetilide-d3 drug and a preparation method thereof. The preparation method comprises the following steps: reacting p-chlorophenol with 1, 2-dibromoethane in ethanol at the temperature of 100 DEG C in the presence of sodium hydroxide serving as alkali to obtain a compound III; reacting the compound III with 4-chlorophenylethylamine in a second solvent at 80 DEG C in the presence of alkali to obtain a compound I; reacting the compound I with deuterium sources under the catalysis of a light source and a photocatalyst to obtain a compound II, wherein the deuterium sources comprise deuterium water and d4-deuterated methanol; and reacting the compound II with methanesulfonamide under the catalysis of a palladium catalyst to obtain the docetaxel-d3 drug. According to the preparation method, more environment-friendly and cheap deuterium water and d4-deuterated methanol are used as deuterium sources, the d4-deuterated methanol is used as a deuterium methyl source, andselective N-deuterium methylation reaction on a prodrug amine compound is realized at normal temperature and normal pressure under the action of photocatalysis of a photocatalyst, so that the docetaxel-d3 drug is prepared.

Description

technical field [0001] The present invention relates to Dofetilide-d 3 The technical field of drug synthesis, in particular to a kind of dofetilide-d 3 Medicine and preparation method thereof. Background technique [0002] Dofetilide is a new class 3 antiarrhythmic drug, mainly used for the treatment of atrial fibrillation and atrial flutter, and provides a new drug for clinical treatment of atrial fibrillation and atrial flutter. Dofetilide was approved by the European Medicines Commission in December 1999 for the treatment of atrial fibrillation and atrial flutter. This drug is easily metabolized to N-demethylated products. The stability of carbon-deuterium bonds is more stable than that of carbon-hydrogen bonds, so the corresponding deuterated drugs often have better biological properties, such as pharmacokinetics, pharmacokinetics and metabolic stability. Therefore, in order to enhance the metabolic stability of the drug, about dofetilide-d 3 The synthesis of drug m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/32C07C303/36A61P9/06
CPCC07C303/36C07C213/08C07C41/01A61P9/06C07B2200/05C07C311/32C07C217/26C07C43/247
Inventor 苏陈良张钊飞李瑛
Owner SHENZHEN UNIV
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