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Preparation method of milrinone impurities

A technology of milrinone and impurities, applied in the field of drug synthesis, to achieve the effects of controllable reaction, reasonable route design and strong operability

Inactive Publication Date: 2018-08-24
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Impurities are often related to drug safety, and in a few cases are also related to efficacy, so controlling the content of drug impurities is the key to evaluating drug quality and safety. Milrinone impurity is an impurity in the synthesis process of milrinone. Therefore, the research on the impurity of milrinone is beneficial to control the quality and safety of milrinone, but there is no report on the synthesis and research of this impurity

Method used

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  • Preparation method of milrinone impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] (1) Dissolve 24.4g of (Z)-4-ethoxy-3-(4-pyridyl)-3-ene-2-butanone in 360mL of methanol, and add 4.8g of sodium borohydride in batches , after stirring and reacting at room temperature for 3 hours, thin-layer chromatography showed that the reaction was complete, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 21g of yellow-brown oily compound B, with a yield of 85.17%;

[0020] (2) Dissolve 21g of compound B in 210mL of toluene, add diphenylphosphoryl azide, stir and react at 30°C for 4 hours, thin-layer chromatography shows that the reaction is complete, add 200mL of water to the mixture, and the product is dichloromethane Extraction, the organic phase was dried with anhydrous sodium sulfate to obtain 22g of compound C, yield 92.72%;

[0021] (3) Dissolve 16g of compound C in 320mL of methanol and 64mL of water, add 40g of triphenylphosphine, and react at 25°C for 2 hours. Thin layer chromatography shows that the ...

Embodiment 2

[0024] (1) Dissolve 24.4g of (Z)-4-ethoxy-3-(4-pyridyl)-3-ene-2-butanone in 360mL of methanol, and add 6.8g of potassium borohydride in batches , after stirring and reacting at room temperature for 3 hours, thin-layer chromatography showed that the reaction was complete, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 21g of yellow-brown oily compound B, with a yield of 85.17%;

[0025] (2) Dissolve 21g of Compound B in 210mL of toluene, add sodium azide, stir and react at 30°C for 4 hours, thin-layer chromatography shows that the reaction is complete, add 200mL of water to the mixture, and extract the product with dichloromethane. The organic phase was dried with anhydrous sodium sulfate to obtain 22 g of compound C, with a yield of 92.72%;

[0026] (3) Dissolve 16g of compound C in 320mL of ethanol and 64mL of water, add 18g of triethylphosphine, and react at 25°C for 2 hours. Thin layer chromatography shows that the r...

Embodiment 3

[0029] (1) Dissolve 24.4g of (Z)-4-ethoxy-3-(4-pyridyl)-3-ene-2-butanone in 360mL of methanol, and add 6.8g of potassium borohydride in batches After stirring and reacting at room temperature for 4 hours, thin-layer chromatography showed that the reaction was complete. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 21 g of yellow-brown oily compound B, with a yield of 85.17%;

[0030] (2) Dissolve 21g of Compound B in 210mL of toluene, add sodium azide, stir and react at 30°C for 5 hours, thin layer chromatography shows that the reaction is complete, add 200mL of water to the mixture, and extract the product with dichloromethane. The organic phase was dried with anhydrous sodium sulfate to obtain 22 g of compound C, with a yield of 92.72%;

[0031] (3) Dissolve 16g of compound C in 320mL of ethanol and 64mL of water, add 11.6g of trimethylphosphine, and react at 25°C for 2 hours. Thin layer chromatography shows that the...

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Abstract

The invention discloses a preparation method of milrinone impurities, and belongs to the field of pharmaceutical synthesis. The preparation method disclosed by the invention has the advantages of reasonable design of reaction routes and high operability. The method comprises the following steps: by using (Z)-4-ethoxyl-3-(4-pyridyl)-3-ene-2-butanone as a raw material, performing four-step reactionsynthesis including reduction, azidation, azide reduction and condensation between the raw material and cyanoacetic acid so as to synthesize a target compound. According to the method disclosed by the invention, the design of the whole route is reasonable, post-treatment is simple, and the raw material is low-cost and easy to obtain; the purity of the target product prepared by the method disclosed by the invention can reach 99.0 percent or above, and can be applied to pharmacokinetics and clinical research; moreover, a testing sample is provided for clinical research on milrinone, and the target product has an important application value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for preparing milrinone impurities. Background technique [0002] Milrinone, also known as milrinone, chemical name: 2-methyl-6-oxygen-1,6-dihydro-(3,4'-bipyridine)-5-carbonitrile; the second On behalf of the bispyridone class of positive inotropes, both peripheral vasodilators. For the treatment of refractory heart failure and heart failure patients with digitalis poisoning. It was launched in the United States in 1987, and since then intravenous milrinone has been widely used in the United States and other countries to improve the postoperative and preoperative outcomes of patients with heart failure. [0003] With the progress of the times and the improvement of the level of science and technology, people have a fuller understanding of the importance of scientific evaluation of the quality, safety and efficacy of drugs before they are marketed. Among them, the quality ...

Claims

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Application Information

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IPC IPC(8): C07D213/30C07D213/42C07D213/38C07D213/40
CPCC07D213/30C07D213/38C07D213/40C07D213/42
Inventor 宋化丰赵万年胡永铸刘春魏常青
Owner TLC NANJING PHARMA RANDD CO LTD
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