Method for preparing intermediate of 4-methoxypyrrole derivative

Abstract

The present invention relates to a method for preparing intermediates of 4-methoxypyrrole derivatives. The preparation method according to the present invention has advantages that the production cost can be lowered by using inexpensive starting materials, a high-temperature reaction is not required as a whole, inexpensive and non-explosive reagents are used instead of (trimethylsilyl)diazomethane, and further an intermediate of 4-methoxypyrrole derivatives can be prepared as a whole at a high yield.

What is claimed is: 
     
         1 . A method for preparing a compound represented by the following Chemical Formula 1, comprising the steps of:
 1) reacting a compound represented by the following Chemical Formula 1-1 with ammonium chloride, and sodium cyanide, or potassium cyanide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-2;   2) protecting a compound represented by the following Chemical Formula 1-2 with an amine protecting group (P) to prepare a compound represented by the following Chemical Formula 1-3;   3) reacting a compound represented by the following Chemical Formula 1-3 with (i) methylpotassium malonate, or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide, followed by reaction with an acid to prepare a compound represented by the following Chemical Formula 1-4;   4) reacting a compound represented by the following Chemical Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a compound represented by the following Chemical Formula 1-5;   5) reacting a compound represented by the following Chemical Formula 1-5 with dimethyl sulfate to prepare a compound represented by the following Chemical Formula 1-6; and   6) reacting a compound represented by the following Chemical Formula 1-6 with an acid to prepare a compound represented by the following Chemical Formula 1:   
       
         
           
           
               
               
           
         
       
     
     
         2 . The method according to  claim 1 , wherein
 in the step 1, the molar ratio of the compound represented by the Chemical Formula 1-1 to ammonium chloride is 10: 1 to 1:10, and   the molar ratio of the compound represented by the Chemical Formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10.   
     
     
         3 . The method according to  claim 1 , wherein
 in the step 1, the reaction with the compound represented by the Chemical Formula 1-1, ammonium chloride, and sodium cyanide or potassium cyanide is carried out at 0 to 40° C., and the reaction with an acid is carried out at 80 to 120° C.   
     
     
         4 . The method according to  claim 1 , wherein
 the acid in the step 1 is acetic acid or hydrochloric acid.   
     
     
         5 . The method according to  claim 1 , wherein,
 the amine protecting group (P) in the step 2 is tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), Tosyl, or Acyl.   
     
     
         6 . The method according to  claim 1 , wherein
 the reaction of the step 2 is carried out at 10 to 40° C.   
     
     
         7 . The method according to  claim 1 , wherein
 the magnesium halide in the step 3 is magnesium chloride or magnesium bromide.   
     
     
         8 . The method according to  claim 1 , wherein
 in the step 3, the molar ratio of the compound represented by the Chemical Formula 1-3 to methylpotassium malonate or methylsodium malonate is 10:1 to 1:10,   the molar ratio of the compound represented by the Chemical Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, and   the molar ratio of the compound represented by the Chemical Formula 1-3 to the magnesium halide is 10:1 to 1:10.   
     
     
         9 . The method according to  claim 1 , wherein
 the acid in the step 3 is hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid.   
     
     
         10 . The method according to  claim 1 , wherein
 the reaction between the compound represented by the Chemical. Formula 1-3 and (i) methylpotassium malonate or methylsodium malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide in the step 3 is carried out at 50 to 100° C., and the reaction with the acid is carried out at 0 to 40° C.   
     
     
         11 . The method according to  claim 1 , wherein
 the molar ratio of the compound represented by the Chemical Formula 1-4 to N,N-dimethylformamide dimethylacetal in the step 4 is 1:1 to 1:10.   
     
     
         12 . The method according to  claim 1 , wherein
 the reaction of the step 4 is carried out at 20 to 70° C.   
     
     
         13 . The method according to  claim 1 , wherein
 the molar ratio of the compound represented by the Chemical Formula 1-5 to dimethylsulfate in the step 5 is 10:1 to 1:10.   
     
     
         14 . The method according to  claim 1 , wherein
 the reaction of the step 5 is carried out at 20 to 60° C.   
     
     
         15 . The method according to  claim 1 , wherein
 the molar ratio of the compound represented by the Chemical Formula 1-6 to trifluoroacetic acid in the step 6 is 1:1 to 1:30.   
     
     
         16 . The method according to  claim 1 , wherein
 the reaction of the step 6 is carried out at 10 to 40° C.   
     
     
         17 . The method according to  claim 1 , wherein
 the acid of the step 6 is trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid.