Preparation of trans-fused 3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan derivatives

Abstract

The present invention concerns processes for the preparation of each of the 4 diastereomers of formula (I) in stereochemically pure form from either of two enantiomerically pure precursors. The tetracyclic ringsystem having trans-fused five and seven membered rings is formed in an acid-catalysed cyclization reaction. The invention further relates to the thus obtained cis-fused tetracyclic alcohol intermediates, the methanamine end-products, the methanamine end-products for use as a medicine, in particular as CNS active medicines.

1 . A process for preparing each individual diastereoisomer of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein the substituents on carbon atoms 3a and 12b have the trans configuration, the substituent on carbon atom 2 may have the R or the S configuration, comprising the step of cyclizing a compound of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein R represents C 1-3  alkylcarbonyl; 
 OR 1  represents a leaving group and the substituents —OR and —CH 2 —CHOH—CH 2 OR 1  have the cis configuration, in a reaction inert solvent in the presence of an acid, whereby  
                                       
 
     
     
         2 . A process according to  claim 1  wherein each individual diastereomer of formula (I) is converted further into a target compound of formula (III) comprising the further steps of reacting the intermediate compound of formula (I) with aqueous or gaseous methylamine in an organic solvent at an elevated temperature, thus yielding  
       
         
           
           
               
               
           
         
       
     
     
         3 . A process according to  claim 1  wherein the compound of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein 
 OR 1  is a leaving group  
 and the substituents —OR and —CH 2 —CHOH—CH 2 —OR 1  have the cis configuration  
 is prepared from a diol of formula  
                     
 wherein the substituents —OR and —CH 2 —CHOH—CH 2 —OH have the cis configuration by selective conversion of the primary hydroxyl group into a leaving group, through reaction with a sulfonylchloride in a reaction-inert solvent, in the presence of an excess of base, and optionally in the presence of dimethylaminopyridine and/or dibutyl(oxo)stannane.  
 
     
     
         4 . A process according to  claim 3  wherein the intermediate diol of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein the substituents have the cis configuration is prepared from a ketone of formula (V)  
       
         
           
           
               
               
           
         
       
       by the following series of reaction steps 
 (a) reduction of the ketone to the cis-oriented hydroxyl group by reaction with lithium or sodium borohydride in a mixture of an organic solvent and an aqueous buffer having a pH of about 7 at a temperature below ambient temperature;  
 (b) acylation of the hydroxyl group following art-known procedures; and  
 (c) deacetalisation in an organic solvent in the presence of an acid, whereby  
                                       
 
     
     
         5 . A process according to  claim 4  wherein the ketone of formula (V)  
       
         
           
           
               
               
           
         
       
       is prepared from a pro-chiral ketone of formula (VIII) and (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde or (4R)-2,2-dimethyl-1,3-dioxylane-4-carboxaldehyde (VII) in an aldol reaction,  
       
         
           
           
               
               
           
         
       
       yielding unsaturated ketone (VI) and reducing said unsaturated ketone to a mixture of epimeric ketones (V-a) and (V-c) or (V-b) and (V-d), and optionally converting (V-c) into (V-a), or (V-b) into (V-d) by treatment with a base in a suitable solvent at a temperature in the range of 35° C.-45° C.  
     
     
         6 . An intermediate compound of formula (I) having the formula  
       
         
           
           
               
               
           
         
       
       wherein OR 1  represents a leaving group.  
     
     
         7 . A compound of formula (III) having the formula  
       
         
           
           
               
               
           
         
       
       in free base form or a pharmaceutically acceptable acid addition salt form thereof.  
     
     
         8 . A compound of formula (II) according to  claim 7  for use as a medicine.  
     
     
         9 . A compound according to  claim 8  for use as a CNS active medicine.