Process for preparing spiro[2.5]octane-5,7-dione

Abstract

Disclosed is a method for the synthesis of spiro[2.5]octane-5,7-dione useful as intermediate in the manufacture of pharmaceutically active ingredients. Also disclosed are novel intermediates used in the synthesis of this compound.

1 . A method of preparing spiro[2.5]octane-5,7-dione having the formula 
       
         
           
           
               
               
           
         
       
       said method comprising cyclizing a [1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester, having the formula 
       
         
           
           
               
               
           
         
       
       wherein R is preferably C 1 -C 6  alkyl, preferably C 1 -C 4  alkyl, more preferably C 1 -C 3  alkyl or even more preferably C 1 -C 2  alkyl, particularly methyl, to form spiro[2.5]octane-5,7-dione. 
     
     
         2 . A process for the manufacture of spiro[2.5]octane-5,7-dione having the formula 
       
         
           
           
               
               
           
         
       
       said process comprising the following reaction steps (wherein R is preferably C 1 -C 6  alkyl, preferably C 1 -C 4  alkyl, more preferably C 1 -C 3  alkyl or even more preferably C 1 -C 2  alkyl, particularly methyl): 
       
         
           
           
               
               
           
         
       
     
     
         3 . A process for the manufacture of spiro[2.5]octane-5,7-dione having the formula 
       
         
           
           
               
               
           
         
       
       said process comprising the following reaction steps, via route I or via route II, wherein R is preferably C 1 -C 6  alkyl, preferably C 1 -C 4  alkyl, more preferably C 1 -C 3  alkyl or even more preferably C 1 -C 2  alkyl, particularly methyl: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound useful as intermediate selected from a group consisting of:
 (1-Carboxymethyl-cyclopropyl)-acetic acid,   6-Oxa-spiro[2.5]octane-5,7-dione,   (1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid,   (1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester,   [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester,   [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid, and   {1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid,   or a tautomer or salt thereof.   
     
     
         5 . 6-Oxa-spiro[2.5]octane-5,7-dione having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . (1-Methoxycarbonylmethyl-cyclopropyl)-acetic acid having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . (1-Chlorocarbonylmethyl-cyclopropyl)-acetic acid methyl ester having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid methyl ester having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . [1-(2-Oxo-propyl)-cyclopropyl]-acetic acid having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . {1-[(Methoxy-methyl-carbamoyl)-methyl]-cyclopropyl}-acetic acid having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound of the following general formula 
       
         
           
           
               
               
           
         
       
       wherein R is C 1 -C 6  alkyl, preferably C 1 -C 4  alkyl. 
     
     
         12 . A compound according to  claim 4  in a salt form. 
     
     
         13 . A compound according to  claim 4 , either in isolated form or in solution. 
     
     
         14 . One or more of the reaction steps of  claim 2 , or any combination of two or more successive steps. 
     
     
         15 . One or more of the reaction steps of  claim 3 , or any combination of two or more successive steps. 
     
     
         16 . The method according to  claim 1  wherein the [1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester, particularly [1-(2-oxo-propyl)-cyclopropyl]-acetic acid methyl ester, is subjected to condensation conditions using a suitable base such as e.g. the respective sodium alcoholate, particularly sodium methanolate in a suitable solvent such as e.g. comprising tetrahydrofuran at a suitable reaction temperature for cyclization to form spiro[2.5]octane-5,7-dione. 
     
     
         17 . Use of a [1-(2-oxo-propyl)-cyclopropyl]-acetic acid ester to prepare spiro[2.5]octane-5,7-dione.