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Method for controlling palladium residue in fosaprepitant dimeglumine

A technology for fosaprepitant dimeglumine and palladium residues is applied in the field of controlling palladium residues in fosaprepitant dimeglumine, can solve problems such as unsatisfactory effects, and achieves good palladium removal effect and cheap raw materials Easy-to-obtain, high-purity effects

Inactive Publication Date: 2014-12-24
TAIZHOU EOC PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Because in the chemical reaction post-treatment process, especially related to reducing the residual problem of heavy metal palladium in the compound, there are often many solutions, including some physical and chemical methods, as disclosed in CN1255912A using cysteine ​​or N-acyl half Cystine is used as a palladium removal reagent, the effect is not ideal, and the residual palladium reaches 50ppm

Method used

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  • Method for controlling palladium residue in fosaprepitant dimeglumine
  • Method for controlling palladium residue in fosaprepitant dimeglumine
  • Method for controlling palladium residue in fosaprepitant dimeglumine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Preparation of fosaprepitant dimeglumine

[0027] 19g intermediate [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluoro Phenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid monobenzyl ester (19g, 0.027 mol), meglumine (10.3g, 0.053mol), 1g of palladium on carbon, and 400mL of methanol were put into a hydrogenation kettle, and hydrogenated at 1.5-2.0MPa for 10 hours. After the reaction is finished, filter off Pd / C, concentrate the filtrate under reduced pressure to remove part of the solvent, slowly drop it into a mixed solvent of 200 mL of absolute ethanol and 200 mL of anhydrous acetonitrile, filter, and dry in vacuum to obtain Fosaprepitant Dimeglumine.

[0028] 1 HNMR (CD3OD, 500MHz, ppm) δ: 1.43 (d, J=6.6, 3H), 2.72 (s, 6H), 2.84 (d, J=13.8, 1H), 2.94 (d, J=10.3, 1H), 3.11-3.30(m, 4H), 3.42-3.82(m, 14H), 4.19-4.24(m, 3H), 4.35(d, J=2.2, 1H), 7.03(t, J=8.5, 2H), 7.34 (s, 2H), 7.51 (brs, 2H), 7.69 (s...

Embodiment 2

[0033] Dissolve 5 g of fosaprepitant dimeglumine in 20 mL of methanol, stir to dissolve, add 1 g of activated carbon at 25 ° C, stir for 1 h, filter, and drop the filtrate into a mixed solvent of 40 mL of absolute ethanol and 40 mL of anhydrous acetonitrile, Filter and vacuum-dry to obtain a sample of fosaprepitant dimeglumine.

[0034] Get an appropriate amount of fosaprepitant dimeglumine I to measure the residual palladium, and with reference to the detection method of Example 1, it is measured by atomic absorption spectrophotometry, and the residual palladium is 0.1ppm.

[0035] ESI-MS615 (M+H, 100%).

Embodiment 3

[0037] Dissolve 5g of fosaprepitant, pepitant dimeglumine in 20mL of methanol, stir to dissolve, add 1g of diatomaceous earth at 25°C, stir for 1h, filter, and drop the filtrate into a mixed solvent of 40mL of absolute ethanol and 40mL of anhydrous acetonitrile , filtered, and vacuum-dried to obtain a sample of fosaprepitant dimeglumine.

[0038] Take an appropriate amount of fosaprepitant dimeglumine I to determine the residual palladium, and determine by atomic absorption spectrophotometry with reference to the detection method of Example 1, the residual palladium is 0.08ppm.

[0039] ESI-MS615 (M+H, 100%).

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Abstract

The invention provides a method for controlling a palladium residue in fosaprepitant dimeglumine. The fosaprepitant dimeglumine has a structure as shown in the formula (I), and the content of palladium is 0-150ppm. The method is characterized by comprising the following steps: 1) dissolving fosaprepitant dimeglumine crude product into an alcohol solution, stirring and dissolving; and 2) adding a palladium removing agent, stirring, filtering and dropwise adding filtrate into a mixed solvent of absolute ethyl alcohol and anhydrous acetonitrile, filtering, and drying in vacuum, so as to obtain a fosaprepitant dimeglumine sample. Compared with the prior art, the method provided by the invention can be used for producing high-purity product, wherein the palladium residue limit of the product is smaller than 1ppm and accords with the requirement of medicines for injection on the palladium residue limit. The method disclosed by the invention specifically comprises the steps of directly dissolving the crude product; adding the palladium removing agent; stirring and filtering; and dropwise adding the filtrate into an organic solvent, filtering and drying, thus obtaining a pure product. The method is simple and convenient to operate, is good in palladium removal effect, uses cheap and easily available raw material, and is suitable for being put into industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for controlling palladium residue in fosaprepitant dimeglumine. Background technique [0002] In industrial synthesis methods, heavy metals are widely used in the synthesis of compounds in different fields, among which palladium is particularly common. Since palladium is easy to form complexes, the biggest disadvantage in application is that a certain amount often remains in organic synthesis, thereby reducing the purity of the compound and its pharmacological activity. Therefore, it is particularly important to find an effective method for palladium removal. [0003] Fosaprepitant dimeglumine in formula (I) is developed by Merck and is mainly used to prevent and treat nausea and vomiting caused by anticancer drug chemotherapy. Its chemical name is: 1-deoxy-1-(methylamino)-D-sorbitol [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl Base)phenyl]ethoxy]-3-(...

Claims

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Application Information

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IPC IPC(8): C07F9/6558
Inventor 冀学芳汪进周韡鑫李合亭邵宪伟王成娜徐峰张孝清
Owner TAIZHOU EOC PHARMA CO LTD
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