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Refined palladium removing process for fosaprepitant

A fosaprepitant dimeglumine and solvent technology, applied in the field of medicinal chemistry, can solve problems such as potential safety hazards, and achieve the effects of low adsorption, low price, and simple removal

Active Publication Date: 2017-09-19
HANGZHOU JIUYUAN GENE ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After removing palladium, first concentrate 4 times and then use acetonitrile as an anti-solvent for recrystallization. This method has a better palladium removal effect (less than 1ppm), and the palladium residue of palladium removal by tributylphosphine and triphenylphosphine has decreased by 10% compared with that alone. However, the residual triphenylphosphine and tributylphosphine are still 0.02-0.11%. Considering the intravenous infusion of fosaprepitant dimeglumine, this method still has certain potential safety hazards

Method used

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  • Refined palladium removing process for fosaprepitant
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  • Refined palladium removing process for fosaprepitant

Examples

Experimental program
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Effect test

Embodiment 1

[0034] The preparation of embodiment 1 fosaprepitant dimeglumine

[0035] Put 15.0g of fosaprepitant dibenzyl ester, 9.2g of meglumine, 4.7g of 10% Pd / C, 24mL of Mili-Q water, and 300mL of methanol into the hydrogenation kettle, and hydrogenate at 0.38-0.42Mpa at 18-22°C 2 hours. After the reaction, the hydrogenation solution was filtered through a 0.22 μm polytetrafluoroethylene filter membrane, 15 g of JYG-01-II (purchased from Suboco Energy Co., Ltd.) was added, and stirred at 25° C. for 18 hours. After palladium removal is completed, the palladium removal solution is filtered through a 0.22 μm polytetrafluoroethylene filter membrane and washed with an appropriate amount of methanol. Methanol and water were distilled off under reduced pressure to obtain a concentrated solution, which was then dissolved in 80 mL of methanol, added dropwise to 400 mL of acetone under nitrogen protection, separated from solid and liquid, and dried in vacuum to obtain 16.0 g of fosaprepitant d...

Embodiment 2

[0051] The preparation of embodiment 2 fosaprepitant dimeglumine

[0052] Add 15.0g fosaprepitant dibenzyl ester, 9.2g meglumine, 4.7g 10% Pd / C, 24mL Mili-Q water, 300mL methanol into the hydrogenation kettle, 0.38~0.42Mpa, 18~22℃ Hydrogenate for 2 hours. After the reaction, the hydrogenation solution was filtered through a 0.22 μm polytetrafluoroethylene filter membrane, 15 g of JYG-01-II was added, and stirred at 25° C. for 24 hours. After palladium removal is completed, the palladium removal solution is filtered through a 0.22 μm polytetrafluoroethylene filter membrane and washed with an appropriate amount of methanol. Methanol and water were distilled off under reduced pressure, then dissolved in 80 mL of methanol, added dropwise to 400 mL of acetone under nitrogen protection, separated from solid and liquid, and dried in vacuum to obtain 16.0 g of fosaprepitant dimeglumine finished product. Take an appropriate amount of fosaprepitant dimeglumine sample, and determine th...

Embodiment 3

[0053] The preparation of embodiment 3 fosaprepitant dimeglumine

[0054] Add 15.0g fosaprepitant dibenzyl ester, 9.2g meglumine, 4.7g 10% Pd / C, 24mL Mili-Q water, 300mL methanol into the hydrogenation kettle, 0.38~0.42Mpa, 18~22℃ Hydrogenate for 2 hours. After the reaction, the hydrogenation solution was filtered through a 0.22 μm polytetrafluoroethylene filter membrane, 15 g of JYG-01-II was added, and stirred at 30° C. for 18 hours. After palladium removal is completed, the palladium removal solution is filtered through a 0.22 μm polytetrafluoroethylene filter membrane and washed with an appropriate amount of methanol. Methanol and water were distilled off under reduced pressure, then dissolved in 80 mL of methanol, added dropwise to 400 mL of acetone under nitrogen protection, separated from solid and liquid, and dried in vacuum to obtain 16.0 g of fosaprepitant dimeglumine finished product. Take an appropriate amount of fosaprepitant dimeglumine sample, and determine th...

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Abstract

The invention provides a method of reducing the content of palladium in fosaprepitant dimeglumine. The method comprises the following steps: preparing a fosaprepitant dimeglumine solution; adding a sulfhydryl silica gel palladium removing agent, stirring and filtering and then carrying out vacuum distillation concentration; adding a proper amount of solvent into a concentrated solution containing the fosaprepitant for dissolving, and then dropwise adding a mixed solution into an antisolvent; standing, crystallizing and drying to obtain a finished product of fosaprepitant dimeglumine. The palladium removing method provided by the invention is higher in efficiency; the palladium residues in a finished product of the fosaprepitant can be reduced from an original high ppm value to below 5ppm, which conforms to the limit requirements of drugs for injection on the palladium content. Compared with an organic phosphorus reagent, a palladium removing agent provided by the invention has the advantages of safety and low toxicity; in addition, the palladium removing agent can be removed from the solution by simple filtering. The process has a significant cost advantage and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the category of medicinal chemistry, and in particular relates to a method for reducing palladium content in fosaprepitant dimeglumine Background technique [0002] Fosaprepitant, also known as Fosaprepitant, English name Fosaprepitant. FDA approved Fosaprepitant dimeglumine, the Chinese name is Fosaprepitant Dimeglumine, and it was approved for marketing on January 25, 2008. It is used for the treatment of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. The specifications are 115mg and 150mg , packaged in vials, the dosage form is powder injection for injection, the trade name is EMEND, which is the same as the trade name of aprepitant. At the same time, fosaprepitant dimeglumine is also on the market in Sweden, the Czech Republic, Portugal and the UK under the trade name IVEMEND. [0003] The chemical name of fosaprepitant dimeglumine is deoxy-1-(methylamino)-D-sorbitol[3-[[(2R,3S)-2-[(1R)-1-...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
Inventor 白传伟翁文锃王炎江郭旺明
Owner HANGZHOU JIUYUAN GENE ENG
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