Synthesis of polycyclic-carbamoylpyridone compounds

Abstract

Methods of making compounds of Formula I are disclosed:

We claim: 
     
         1 - 153 . (canceled) 
     
     
         154 . A process to prepare a compound of Formula I: 
       
         
           
           
               
               
           
         
         according to the following General Scheme VI 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the process comprises the following steps: 
         reacting B-1.J-1 under conditions suitable to yield C-1; 
         reacting C-1 with an alkylated formamide acetal to yield D-1; 
         reacting D-1 with K-1 to yield E-1; 
         reacting E-1 with M-1 in the presence of a base to yield F-1; 
         reacting F-1 with at least one acid to yield FF-1; 
         reacting FF-1 with N-1, or salts or co-crystals thereof, in the presence of an additive to yield G-1; 
         reacting G-1 under conditions suitable to yield a compound of Formula I; 
         wherein
 Hal is halogen, which may be the same or different, 
 n is 1, 2, or 3, 
 L is —C(R c ) 2 —, —C(R c ) 2 C(R c ) 2 —, —C(R c ) 2 C(R c ) 2 C(R c ) 2 —, or —C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 —, 
 each R c  is, independently, hydrogen, halo, hydroxyl or C 1 -C 4 alkyl, 
 each R a , R 1 , and R 2  is, independently, (C 1 -C 4 )alkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )aryl (C 1 -C 4 )alkyl; 
 each R h  is independently (C 1 -C 4 )alkyl. 
 
       
     
     
         155 . The process of  claim 154  wherein B-1.J-1 is reacted in the presence of an acid. 
     
     
         156 . The process of  claim 155  wherein the acid is selected from the group consisting of an inorganic acid, an organic acid, a halogenated organic acid, a Lewis acid and mixtures thereof. 
     
     
         157 . (canceled) 
     
     
         158 . The process of  claim 155  wherein the acid is trifluoroacetic acid. 
     
     
         159 . (canceled) 
     
     
         160 . The process of  claim 154  wherein the alkylated formamide acetal is N,N-dimethylformamide dimethyl acetal. 
     
     
         161 . The process of  claim 154  wherein C-1 is reacted with an alkylated formamide acetal in the presence of an acid. 
     
     
         162 . (canceled) 
     
     
         163 . The process of  claim 161 , wherein the acid is trifluoroacetic acid. 
     
     
         164 . (canceled) 
     
     
         165 . The process of  claim 154  wherein K-1 is aminoacetaldehyde dimethylacetal. 
     
     
         166 . (canceled) 
     
     
         167 . The process of  claim 154  wherein M-1 is dimethyl oxalate. 
     
     
         168 . The process of  claim 154  wherein E-1 is reacted with M-1 in the presence of a base selected from the group consisting of a metal hydride, an alkoxide, an inorganic carbonate, a bis(triaklylsilyl)amide base, and a mixture thereof. 
     
     
         169 . (canceled) 
     
     
         170 . The process of  claim 168 , wherein the base is sodium methoxide. 
     
     
         171 . The process of  claim 154  wherein F-1 is reacted with at least one acid selected from the group consisting of an organic acid, an inorganic acid, an organic carboxylic acids, and mixtures thereof. 
     
     
         172 . (canceled) 
     
     
         173 . The process of  claim 171  wherein the at least one acid is p-toluenesulfonic acid. 
     
     
         174 . The process of  claim 154  wherein L is —CH 2 —CH 2 —. 
     
     
         175 . The process of  claim 154  wherein N-1 is 
       
         
           
           
               
               
           
         
       
     
     
         176 . The process of  claim 154  wherein N-1 is in the form of a salt or co-crystal. 
     
     
         177 . The process of  claim 176  wherein N-1 is 
       
         
           
           
               
               
           
         
       
     
     
         178 . (canceled) 
     
     
         179 . The process of  claim 154  wherein the additive is selected from the group consisting of a carboxylate salt, an inorganic carbonate, a metal hydride, an alkoxide, a water scavenger and a mixture thereof. 
     
     
         180 . (canceled) 
     
     
         181 . The process of  claim 154  wherein the additive is potassium acetate. 
     
     
         182 . The process of  claim 154  wherein G-1 is reacted with at least one reagent selected from the group consisting of metal salts, Lewis acids, sodium ethanethiolate, sodium hexamethyldisiloxane, trifluoroacetic acid, and combinations thereof. 
     
     
         183 . (canceled) 
     
     
         184 . The process of  claim 182  wherein the at least one reagent is magnesium bromide. 
     
     
         185 . The process of  claim 154  wherein each R a , R b , R 1 , and R 2  is, independently C 1 -C 4 alkyl. 
     
     
         186 - 192 . (canceled) 
     
     
         193 . The process of  claim 154  wherein J-1 is 
       
         
           
           
               
               
           
         
       
     
     
         194 - 240 . (canceled) 
     
     
         241 . A compound having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt, or co-crystal thereof, 
         wherein
 Hal is halogen, which may be the same or different, 
 n is 1, 2, or 3, 
 L is —C(R c ) 2 —, —C(R c ) 2 C(R c ) 2 —, —C(R c ) 2 C(R c ) 2 C(R c ) 2 —, or —C(R c ) 2 C(R c ) 2 C(R c ) 2 C(R c ) 2 —, 
 each R c  is, independently, hydrogen, halo, hydroxyl or C 1 -C 4 alkyl, and 
 each R b , R d , R 1 , and R 2  is, independently, (C 1 -C 4 )alkyl, (C 6 -C 30 )aryl, or (C 6 -C 10 )aryl(C 1 -C 4 )alkyl. 
 
       
     
     
         242 . A compound having the structure: 
       
         
           
           
               
               
           
         
         or a salt, or co-crystal thereof.