Isomorphs of remdesivir and methods for synthesis of same

Abstract

A new isoform of 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate (Remdesivir) having increased water solubility is disclosed, along with methods for making the same. Also disclosed are solid and liquid pharmaceutical compositions suitable for treating viral infections such as Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, or Paramyxoviridae viral infections which contain an effective amount of Remdesivir prepared according to the inventive method and the use of those compositions for treating such viral infections.

What is claimed is: 
     
         1 . A method for the synthesis of Remdesivir, which comprises:
 (a) reacting (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one with a halo-pyrazole in presence of boron trichloride in an organic solvent at room temperature;   (b) cyanating (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol;   (c) hydrolysing (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile in presence of boron trichloride; and   (d) condensing (3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile with 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate.   
     
     
         2 . The method according to  claim 1 , wherein (d) is replaced by:
 (d1) reacting (3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile with 2,2 dimethoxy propane in presence of PTSA and isopropylacetate; and   (d2) reacting (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[5 3,4-d][1,3]dioxole-4-carbonitrile with t-BuMgCl in presence of 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate.   
     
     
         3 . The method of  claim 1 , wherein the halo-pyrazole in (a) is iodopyrazole or bromopyrazole. 
     
     
         4 . Remdesivir prepared according to the method of  claim 1 . 
     
     
         5 . A pharmaceutical composition comprising Remdesivir according to  claim 4  as the active ingredient. 
     
     
         6 . A method of treating a viral infection in a mammal comprising administering a therapeutically effective amount of a pharmaceutical composition according to  claim 5  to a mammal in need thereof. 
     
     
         7 . The method of  claim 6 , wherein said administering is parenteral administration. 
     
     
         8 . The method of  claim 6 , wherein said mammal is a human. 
     
     
         9 . The method of  claim 6 , wherein said viral infection is caused by SARS-CoV-2. 
     
     
         10 . The method of  claim 2 , wherein the halo-pyrazole in (a) is iodopyrazole or bromopyrazole. 
     
     
         11 . Remdesivir prepared according to the method of  claim 2 .