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Fosaprepitant derivative, synthesis thereof, and use thereof in long acting preparation

A technology for drugs and compounds, applied in the field of prodrugs and pharmaceutical preparations, can solve problems such as poor patient compliance

Inactive Publication Date: 2017-02-22
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Severe nausea and vomiting lead to poor patient compliance

Method used

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  • Fosaprepitant derivative, synthesis thereof, and use thereof in long acting preparation
  • Fosaprepitant derivative, synthesis thereof, and use thereof in long acting preparation
  • Fosaprepitant derivative, synthesis thereof, and use thereof in long acting preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Embodiment 1: preparation [3-[[(2R, 3S)-2-[(1R)-1-[3,5-two (trifluoromethyl) phenyl] ethoxy]-3-(4- Fluorophenyl)4-morpholinyl]methyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-2-(trimethylammonium)- ethyl phosphate

[0168] Process 1

[0169]

[0170] As shown in Scheme 1 above, choline chloride was reacted with the phosphorylating reagent cyanoethyl N,N-diisopropylamine in anhydrous dichloromethane at room temperature in the presence of N,N-diisopropylethylamine. Propyl chlorophosphoramidite reaction, followed by coupling with aprepitant, followed by oxidation with 30% aqueous hydrogen peroxide gave the crude fosaprepitant derivative in a one-step process. The cyanoethyl protecting group was cleaved with ammonium hydroxide in methanol at room temperature. The resulting phosphodiester was further converted to the corresponding ammonium phosphate zwitterion salt by reaction with aqueous sodium hydroxide (0.1M) in methanol.

Embodiment 2

[0171] Embodiment 2: Preparation of 2-(decanoyloxy) ethyl-[3-[[(2R, 3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl ]ethoxy]-3-(4-fluorophenyl)4-morpholinyl]methyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1- base] sodium phosphate

[0172] Process 2

[0173]

[0174]

[0175] As shown in Scheme 2 above, the reaction between 1-decanoyl chloride and ethylene glycol in anhydrous dichloromethane at room temperature in the presence of triethylamine affords the hydroxy ester. At room temperature, in anhydrous dichloromethane, in the presence of N, N-diisopropylethylamine, react with the phosphorylating reagent cyanoethyl N, N-diisopropylphosphoramidite chloride, followed by reaction with Aprepitant was coupled, followed by oxidation with 30% aqueous hydrogen peroxide to obtain fosaprepitant derivatives in a one-step process. The cyanoethyl protecting group was cleaved with ammonium hydroxide in methanol at room temperature. The resulting phosphodiester was further saponified by ...

Embodiment 3

[0176] Embodiment 3: Preparation [3-[[(2R, 3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4- Fluorophenyl)4-morpholinyl]methyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-2-(nonanyloxy) Sodium ethyl phosphate

[0177] Process 3

[0178]

[0179] As shown in Scheme 3 above, the reaction between 1-nonanol and ethylene glycol in refluxing toluene in the presence of p-toluenesulfonic acid gives the hydroxy ether. The resulting hydroxyl ether was reacted with the phosphorylating reagent cyanoethyl N,N-diisopropylphosphoramidite chloride in the presence of N,N-diisopropylethylamine in anhydrous dichloromethane at room temperature The reaction, followed by coupling with aprepitant, followed by oxidation with 30% aqueous hydrogen peroxide gave the fosaprepitant derivative in a one-step process. The cyanoethyl protecting group was cleaved with ammonium hydroxide in methanol at room temperature and the resulting phosphodiester was converted to the sodium salt by reaction w...

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PUM

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Abstract

The invention relates to a Fosaprepitant derivative, a synthesis thereof, and a use thereof in a long acting preparation. The invention relates to a compound of formula (I), and a salt, an N-oxide, a quaternary ammonium and a stereoisomer thereof. R<1> to R<8> in the formula (I) are as defined in claims. The invention also relates to an intermediate for preparing the compound of formula (I), and a method for preparing the compound of formula (I). The invention further relates to a use of the compound of formula (I) as a drug especially used for preventing chemotherapy induced acute and late nausea and vomiting.

Description

technical field [0001] The present invention relates to organic chemistry, particularly prodrugs and drug formulations. Background technique [0002] Fosaprepitant dimeglumine (Fosaprepitant dimeglumine) was developed by Merck, and another drug of the company, Aprepitant (Aprepitant), is clinically used as an adjuvant drug in the treatment of brain tumors to prevent chemotherapy-induced acute and delayed nausea and vomiting. Fosaprepitant and aprepitant belong to the class of neurokinin-1 (NK-1) receptor antagonists or substance P antagonists, which mainly work by blocking the nausea and vomiting signals in the brain. The NK-1 receptor is the binding site for tachykinin (NKA) substance P (SP), located in the brainstem vomiting center and the gastrointestinal tract. Animal experiments have proved that SP can induce vomiting, and drugs that specifically block this receptor can prevent vomiting caused by all emetogenic stimuli (including cisplatin). [0003] Fosaprepitant di...

Claims

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Application Information

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IPC IPC(8): C07F9/6558C07F9/14C07J63/00A61K31/675A61P1/08C07D413/06
Inventor 陆华龙
Owner HC SYNTHETIC PHARMA CO LTD
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