Methods for the preparation of ribosides

Abstract

Provided are methods of preparing compounds and pharmaceutical compositions for treating Filoviridae virus infections The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.

1 .- 42 . (canceled) 
     
     
         43 . A method of preparing a compound of Formula (VIII) having structure: 
       
         
           
           
               
               
           
         
       
       the method comprising:
 (a) (i) forming a first reaction mixture having BCl 3 , dichloromethane, and a compound of Formula (XI-a): 
 
       
         
           
           
               
               
           
         
       
       and
 (ii) combining K 2 CO 3  with the first reaction mixture to prepare the compound of Formula (XI-b): 
 
       
         
           
           
               
               
           
         
         (b) forming a second reaction mixture having acetone, 2,2-dimethoxypropane, sulfuric acid, and the compound of Formula (XI-b) to prepare a compound of Formula (XI-c): 
       
       
         
           
           
               
               
           
         
       
       and
 (c) forming a third reaction mixture having: (i) MgCl 2 , (ii) diisopropylethylamine, (iii) the compound of Formula (XI-c), and (iv) a compound of Formula (X) having structure: 
 
       
         
           
           
               
               
           
         
       
       to prepare the compound of Formula (VIII). 
     
     
         44 . The method of  claim 43 , further comprising preparing the compound of Formula (XI-a) by a method comprising:
 forming a reaction mixture with a cyanating agent, a Lewis acid, a Brønsted acid, a solvent, and a compound of Formula (V-a) or Formula (V-b) having structure:   
       
         
           
           
               
               
           
         
       
       to prepare the compound of Formula (XI-a). 
     
     
         45 . The method of  claim 44 , wherein the cyanating agent is TMSCN, TBSCN, TESCN, HCN, KCN, NaCN, 4-toluenesulfonyl cyanide, CuCN, CuCN*LiCl, LiCN, Zn(CN) 2 , K 4  [Fe(CN) 6 ], tetrabutylammonium cyanide, tetramethylammonium cyanide, tetraethylammonium cyanide, tetrabutylammonium cyanide, tetraalkylammonium cyanide with alkyl independently being Me, Et, Pr, iPr, Bu, iBu, tertBu, Pent, Hex, tributyltin cyanide, trimethyltin cyanide, triethyltin cyanide, tripropyltin cyanide, trialkyltin cyanide with alkyl independently being Me, Et, Pr, iPr, Bu, iBu, tertBu, Pent, Hex, 2-hydroxy-2-methylpropanenitrile; or combinations thereof. 
     
     
         46 . The method of  claim 44 , wherein the Lewis acid is TMSOTf, TMSOTf, TBSOTf, TESOTf, BF 3 , BF 3 -OEt 2 , BCl 3 , BF 3 -THF, MgCl 2 , MgI 2 , MgBr 2 , MgBr 2 -OEt 2 , ZnCl 2 , ZnBr 2 , ZnI 2 , LiCl, LiBr, LiI, AlCl 3 , AlBr 3 , AlI 3 , Me 2 Si(OTf) 2 , Et 2 Si(OTf) 2 , Pr 2 Si(OTf) 2 , iPr 2 Si(OTf) 2 , (tBu) 2 Si(OTf) 2 , (C 6 F 5 ) 3 B, MeSiCl 3 , Me 2 SiCl 2 , SiCl 4 , TMSCl, TMSI, TMSVr, TBSCl, TBSBr, TBSI, TESCl, TESBr, TESI, SmCl 3 , SmBr 3 , SmI 2 , SmI 3 , ScI 3 , ScBr 3 , ScI 3 , Sm(OTf) 3 , Sc(OTf) 3 , TiCl 4 , Ti(OiPr) 4 , Ti(OiPr) 3 Cl, Ti(OiPr) 2 Cl 2 , Ti(OiPr)Cl 3 , Zn(BF 4 ) 2 , LiBF 4 , Mg(BF 4 ) 2 , ZrCl 4 , FeCl 2 , FeCl 3 , FeBr 2 , FeBr 3 , FeI 2 , FeI 3 , Cu(OTf), Cu(OTf) 2 , 4-toluenesulfonylchloride, benzenesulfonylchloride, 4-toluenesulfonyl triflate, benzenesulfonyl triflate, methyl sulfonyl chloride, methylsulfonic anhydrate, InCl 3 , InBr 3 , InI 3 , In(OTf) 3 , Mg(SO 4 ) 2 , NaSO 4 ; or combinations thereof. 
     
     
         47 . The method of  claim 44 , wherein the Brønsted acid is TFA, benzenesulfonic acid, HCl, 4-toluenesulfonic acid, triflic acid, trifluoroacetic acid, 4-nitrobenzoic acid, methylsoulfonic acid, sulfuric acid, phosphoric acid, HBr, acetic acid, formic acid, HI, trifluoromethylsulfonic acid, 4-fluorobenzoic acid, pivalic acid, HBF 4 , nitric acid, 4-chloro-benzoic acid, pentafluorophenol, HPF 6 , Camphorsulfonic acid; or combinations thereof. 
     
     
         48 . The method of  claim 44 , wherein the solvent is DCM, THF, MeTHF, Et 2 O, MeCN, EtCN, toluene, benzene, chlorobenzene, nitrobenzene, fluorobenzene, methanol, ethanol, 2-propanol, propanol, butanol, MTBE, EtOAc, iPrOAc, Me 2 O, (TMS) 2 O, acetone, 2-butanone, chloroform, 1,2-dichloroethane, diglyme, dioxane, acetic acid, formic acid, trifluoroacetic acid, methylisobutylketone, DMAc, DMF, NMP, DMSO; or combinations thereof. 
     
     
         49 . The method of  claim 44 , further comprising preparing the compound of Formula (V-a) or Formula (V-b) by a method comprising:
 forming the reaction mixture with TMSCl, PhMgCl, iPrMgCl, an additive, a compound of Formula (VI-a) having structure:   
       
         
           
           
               
               
           
         
         and a compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         to prepare the compound of Formula (V-a) or Formula (V-b), 
         wherein 
         the additive is BF 3 -OEt 2 , Sm(OTf) 3 , Sc(OTf) 3 , FeCl 3 , LiCl, LiBr, TiCl(OiPr) 3 , ScCl 3 , Bu 4 NBr+LaCl 3 -2LiCl, nLaCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, LaCl 3 +2LiCl, Sm(OTf) 3 +LiCl, SmCl 3 , Bis[2-(N,N-dimethylamino)ethyl] ether, TMEDA, NdCl 3 , NdCl 3 +CsCl, nNdCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, NdCl 3 +2LiCl, NdCl 3 +LiBr, NdCl 3 +LiI, NdBr 3 , NdBr 3 +CsCl, nNdBr 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, NdBr 3 +2LiCl, NdBr 3 +LiBr, NdBr 3 +LiI, Nd(OTf) 3 , CeCl 3 , CeCl 3 +CsCl, nCeCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, CeCl 3 +2LiCl, CeCl 3 +LiBr, CeCl 3 +LiI, CeBr 3 , Ce(OTf) 3 , YCl 3 , YCl 3 +CsCl, nYCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, YCl 3 +2LiCl, YCl 3 +LiBr, YCl 3 +LiI, YBr 3 , YBr 3 +CsCl, nYBr 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, YBr 3 +2LiCl, YBr 3 +LiBr, YBr 3 +LiI, Y(OTf) 3 , LaCl 3 , La(OTf) 3 , MgCl 2 , TiCl 4 , SnCl 4 , AlCl 3 , Bu 4 NCl, Diethyleneglycol diethylether (DGDE), DGDE+Bu 4 NCl, DGDE+Bu 4 NBr, DGDE+Bu 4 NI, CaCl 2 , CaBr 2 , CaI 2 , Ca(OTf) 2 , YCl 3 , YCl 3 -2LiCl, YCl 3 —LiCl or a combination thereof. 
       
     
     
         50 . The method of  claim 49 , wherein the additive is LaCl 3 -2LiCl, YCl 3 , CeCl 3 , NdCl 3 , or LaCl 3 . 
     
     
         51 . A method of preparing a compound of Formula V-a or V-b: 
       
         
           
           
               
               
           
         
       
       the method comprising:
 forming a reaction mixture comprising a deprotonating agent, a silylating agent, a coupling agent, an additive, a compound of Formula VI-a: 
 
       
         
           
           
               
               
           
         
         and a compound of Formula VII: 
       
       
         
           
           
               
               
           
         
         to prepare the compound of Formula V-a or V-b, 
       
       wherein
 each R b  is independently benzyl (Bn) or tert-butyldimethylsilyl (TBS); 
 alternatively, two R b  groups on adjacent carbons can be combined to form a —C(Me) 2 — group; and 
 R 10  is H or a silyl group; 
 wherein 
 the additive is BF 3 -OEt 2 , Sm(OTf) 3 , Sc(OTf) 3 , FeCl 3 , LiCl, LiBr, TiCl(OiPr) 3 , ScCl 3 , Bu 4 NBr+LaCl 3 -2LiCl, nLaCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, LaCl 3 +2LiCl, Sm(OTf) 3 +LiCl, SmCl 3 , Bis[2-(N,N-dimethylamino)ethyl] ether, TMEDA, NdCl 3 , NdCl 3 +CsCl, nNdCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, NdCl 3 +2LiCl, NdCl 3 +LiBr, NdCl 3 +LiI, NdBr 3 , NdBr 3 +CsCl, nNdBr 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, NdBr 3 +2LiCl, NdBr 3 +LiBr, NdBr 3 +LiI, Nd(OTf) 3 , CeCl 3 , CeCl 3 +CsCl, nCeCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, CeCl 3 +2LiCl, CeCl 3 +LiBr, CeCl 3 +LiI, CeBr 3 , Ce(OTf) 3 , YCl 3 , YCl 3 +CsCl, nYCl 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, YCl 3 +2LiCl, YCl 3 +LiBr, YCl 3 +LiI, YBr 3 , YBr 3 +CsCl, nYBr 3 +mLiCl, wherein m is 0.5 to 50, n is 1 to 100, YBr 3 +2LiCl, YBr 3 +LiBr, YBr 3 +LiI, Y(OTf) 3 , LaCl 3 , La(OTf) 3 , MgCl 2 , TiCl 4 , SnCl 4 , AlCl 3 , Bu 4 NCl, Diethyleneglycol diethylether (DGDE), DGDE+Bu 4 NCl, DGDE+Bu 4 NBr, DGDE+Bu 4 NI, CaCl 2 , CaBr 2 , CaI 2 , Ca(OTf) 2 , YCl 3 , YCl 3 -2LiCl, YCl 3 —LiCl or a combination thereof. 
 
     
     
         52 . The method of  claim 51 , wherein the deprotonating agent is sodium hydride (NaH), isopropylmagnesium chloride (iPrMgCl), tert-butylmagnesium chloride (tBuMgCl), phenylmagnesium chloride (PhMgCl), phenylmagnesium bromide (PhMgBr), butyllithium (BuLi), methyllithium (MeLi), methylmagnesium chloride (MeMgCl), methylmagnesium bromide (MeMgBr), tert-butyllithium (tBuLi), isopropyllithium (iPrLi), phenyllithium (PhLi), lithium hydride (LiH), potassium hydride (KH), ethyllithium (EtLi), ethylmagnesium bromide (EtMgBr), ethylmagnesium chloride (EtMgCl), propyllithium (PrLi), propylmagnesium bromide (PrMgBr), propylmagnesium chloride (PrMgCl), cyclohexanelithium (cyHexLi), cyclohexanemagnesium bromide (cyHexMgBr), cyclohexanemagnesium chloride (cyHexMgCl), or combinations thereof. 
     
     
         53 . The method of  claim 51 , wherein the coupling agent is n-butyllithium (nBuLi), magnesium chloride (MgCl 2 ), isopropylmagnesium chloride (iPrMgCl), isopropylmagnesium chloride-lithium chloride (iPrMgCl—LiCl), tert-butylmagnesium chloride (tBuMgCl), phenylmagnesium chloride (PhMgCl), methyllithium (MeLi), methylmagnesium chloride (MeMgCl), methylmagnesium bromide (MeMgBr), tert-butyllithium (tBuLi), isopropyllithium (iPrLi), phenyllithium (PhLi), lithium hydride (LiH), potassium hydride (KH), sodium hydride (NaH), ethyllithium (EtLi), ethylmagnesium bromide (EtMgBr), ethylmagnesium chloride (EtMgCl), propyllithium (PrLi), propylmagnesium bromide (PrMgBr), propylmagnesium chloride (PrMgCl), cyclohexanelithium (cyHexLi), cyclohexanemagnesium bromide (cyHexMgBr), cyclohexanemagnesium chloride (cyHexMgCl), or combinations thereof. 
     
     
         54 . The method of  claim 51 , wherein the silylating agent is a tri-substituted silyl chloride, a tri-substituted silyl bromide, a tri-substituted silyl iodide, or a tri-substituted silyl fluoride. 
     
     
         55 . The method of  claim 51 , wherein
 the deprotonating agent is PhMgCl; and   the coupling agent is iPrMgCl or iPrMgCl—LiCl.   
     
     
         56 . The method of  claim 51 , wherein
 the deprotonating agent is PhMgCl;   the silylating agent is TMSCl;   the coupling agent is iPrMgCl; and   R b  is benzyl.   
     
     
         57 . The method of  claim 51 , wherein the compound of Formula (V-a) or Formula (V-b) has the structure: 
       
         
           
           
               
               
           
         
       
       the method comprising:
 forming the reaction mixture comprising TMSCl, PhMgCl, iPrMgCl, the additive, the compound of Formula (VI-a) having structure: 
 
       
         
           
           
               
               
           
         
         and the compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         to prepare the compound of Formula (V-a) or Formula (V-b). 
       
     
     
         58 . The method of  claim 51 , wherein the compound of Formula (V-a) has the structure: 
       
         
           
           
               
               
           
         
       
       the method comprising:
 forming the reaction mixture comprising TMSCl, PhMgCl, iPrMgCl—LiCl, the additive, the compound of Formula (VI-a) having structure: 
 
       
         
           
           
               
               
           
         
         and the compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         to prepare the compound of Formula (V-a). 
       
     
     
         59 . The method of  claim 51 , wherein the additive is LaCl 3 -2LiCl, LaCl 3 , CeCl 3 , NdCl 3 , or YCl 3 . 
     
     
         60 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.