Synthesis of heterocyclic compounds

Abstract

Methods for the synthesis of heterocyclic compounds including N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide and pharmaceutically acceptable salts thereof.

1 . A method for preparing a compound of formula (c) comprising reacting a compound of formula (a) with a compound of formula (b): 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is selected from the group consisting of OH and OR 2 , where R 2  is substituted or unsubstituted alkyl; 
       R 3  is selected from the group consisting of H, OH, halogen, and —OCHR 4 R 5 , wherein R 4  and R 5  are each independently selected from the group consisting of H, and halogen; and 
       R 6  and R 7  are each independently selected from the group consisting of OH and halogen. 
     
   
   
       2 . (canceled) 
   
   
       3 . The method of  claim 1 , wherein the reaction is performed in the presence of a solvent selected from the group consisting of dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and combinations thereof. 
   
   
       4 . The method of  claim 1 , wherein the reaction is performed in the presence of a halide salt. 
   
   
       5 . The method of  claim 4 , wherein the halide salt is potassium fluoride. 
   
   
       6 . The method of  claim 1 , wherein the reaction is performed in the presence of an inorganic base. 
   
   
       7 . The method of  claim 6 , wherein the inorganic base is sodium carbonate. 
   
   
       8 - 10 . (canceled) 
   
   
       11 . A compound of formula (c): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein 
       R 3  is selected from the group consisting of H, OH, halogen and —OCHR 4 R 5 , wherein R 4  and R 5  are each independently selected from the group consisting of H and halogen; and 
       R 6  is selected from the group consisting of OH and halogen. 
     
   
   
       12 - 53 . (canceled) 
   
   
       54 . A compound according to  claim 11 , wherein R 3  is —OCHR 4 R 5 . 
   
   
       55 . A compound according to  claim 54 , wherein R 3  is —OCHF 2 . 
   
   
       56 . A compound according to  claim 11 , wherein R 6  is halogen 
   
   
       57 . A compound according to  claim 11 , wherein R 3  is —OCHF 2  and R 6  is Br. 
   
   
       58 . The method of  claim 1 , wherein R 3  is —OCHR 4 R 5 . 
   
   
       59 . The method of  claim 58 , wherein R 3  is —OCHF 2 . 
   
   
       60 . The method of  claim 1 , wherein R 1  is OH. 
   
   
       61 . The method of  claim 1 , wherein R 6  and R 7  are each, independently, halogen. 
   
   
       62 . The method of  claim 61 , wherein R 6  is Br and R 7  is F. 
   
   
       63 . The method of  claim 1 , wherein R 1  is OH, R 3  is —OCHF 2 , R 6  is Br and R 7  is F. 
   
   
       64 . The method of  claim 1 , wherein compound (a) is 4-difluoromethoxy-3-hydroxybenzaldehyde. 
   
   
       65 . The method of  claim 1 , wherein compound (a) is 4-difluoromethoxy-3-hydroxybenzaldehyde and compound (b) is 2-bromo-1-fluoro-4-nitrobenzene. 
   
   
       66 . The method of  claim 1 , further comprising the step of cyclizing a compound of formula (c) to form a compound of formula (d): 
     
       
         
         
             
             
         
       
     
   
   
       67 . The method of  claim 66 , wherein R 3  is —OCHF 2 . 
   
   
       68 . The method of  claim 66 , wherein the reaction is performed in the presence of a catalyst. 
   
   
       69 . The method of  claim 66 , wherein the catalyst is a transition metal complex. 
   
   
       70 . The method of  claim 69 , wherein the transition metal complex is palladium acetate. 
   
   
       71 . The method of  claim 66 , wherein the cyclization step is performed in the presence of a solvent selected from the group consisting of dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and combinations thereof. 
   
   
       72 . The method of  claim 66 , further comprising the step of oxidizing a compound of formula (d) to produce a compound of formula (e): 
     
       
         
         
             
             
         
       
     
   
   
       73 . The method of  claim 72 , wherein R 3  is —OCHF 2 . 
   
   
       74 . The method of  claim 72 , wherein the reaction is performed in the presence of an oxidizing agent selected from the group consisting of potassium permanganate, sulfamic acid, sodium chlorite, hydrogen peroxide, silver oxide, ruthenium chloride and combinations thereof. 
   
   
       75 . The method of  claim 74 , wherein the oxidizing agent comprises a combination of sulfamic acid and sodium chlorite. 
   
   
       76 . The method of  claim 75 , wherein the sulfamic acid to sodium chlorite ratio is between approximately 1:2 and approximately 2:1. 
   
   
       77 . The method of  claim 75 , wherein the sulfamic acid to sodium chlorite ratio is between approximately 2:3 and approximately 3:2. 
   
   
       78 . The method of  claim 72 , wherein the reaction is performed in the presence of glacial acetic acid. 
   
   
       79 . The method of  claim 72 , further comprising the step of reacting a compound of formula (e) with a compound of formula (f) to produce a compound of formula (g): 
     
       
         
         
             
             
         
       
       wherein 
       R 8  is selected from the group consisting of H and alkyl; and 
       R 9  and R 10  are each, independently, selected from the group consisting of H, OH and halogen. 
     
   
   
       80 . The method of  claim 79 , wherein R 3  is —OCHF 2 . 
   
   
       81 . The method of  claim 79 , wherein R 9  and R 10  are each, independently, halogen. 
   
   
       82 . The method of  claim 79 , wherein the reaction is performed in the presence of an inorganic acid halide. 
   
   
       83 . The method of  claim 82 , wherein the inorganic acid halide is selected from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride and pyridine. 
   
   
       84 . The method of  claim 83 , wherein the inorganic acid halide is thionyl chloride. 
   
   
       85 . The method of  claim 84 , wherein the thionyl chloride is added in the presence of a catalytic amount of dimethylformamide. 
   
   
       86 . The method of  claim 79 , wherein the reaction is performed in the presence of a base. 
   
   
       87 . The method of  claim 86 , wherein the base is selected from the group consisting of potassium tertiary butoxide, sodium tertiary butoxide and lithium tertiary butoxide. 
   
   
       88 . The method of  claim 79 , wherein compound (g) is N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide. 
   
   
       89 . The method of  claim 88 , further comprising the step of reducing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide in the presence of a reducing agent to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo [b,d]furan-1-carboxamide. 
   
   
       90 . The method of  claim 89 , wherein the reducing agent is selected from the group consisting of zinc, indium, iron, tin, Raney-nickel and sodium borohydride. 
   
   
       91 . The method of  claim 89 , further comprising the step of reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide with methanesulfonyl chloride in a solvent in the presence of a base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide. 
   
   
       92 . The method of  claim 91 , wherein the solvent is selected from the group consisting of tetrahydrofuran, dioxane and toluene. 
   
   
       93 . The method of  claim 91 , wherein the base is selected from the group consisting of pyridine, 2,6-lutidine and triethylamine. 
   
   
       94 . The method of  claim 91 , further comprising the step of converting the N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide to a sodium salt thereof. 
   
   
       95 . The method of  claim 94 , wherein the N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide is reacted with sodium hydride in the presence of a solvent. 
   
   
       96 . The method of  claim 95 , wherein the solvent is tetrahydrofuran. 
   
   
       97 . N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide prepared by a process according to  claim 91 . 
   
   
       98 . N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide sodium salt prepared by a process according to  claim 94 .