Process for the preparation of opioid modulators

Abstract

The present invention is directed to novel processes for the preparation of opioid modulators (agonists and antagonists) and intermediates in their synthesis. The opioid modulators are useful for the treatment and prevention of as pain and gastrointestinal disorders.

1 . A process for the preparation of a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
     
     
       
         
         
             
             
         
       
        is C 6-10 aryl or a heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl, isoquinolinyl and quinazolinyl; 
       each R 41P  is independently selected from C 1-6 alkyl, C 1-6 alkoxy or fluoro; 
       R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; 
       Pg 1  is a nitrogen protecting group;
 comprising 
 
     
     
       
         
         
             
             
         
       
       reacting a compound of formula (X), wherein X P  is selected from OH, CN, —CO 2 H, —C(O)—Cl or —C(O)—OC 1-4 alkyl and wherein Y P  is selected from Br, Cl or I, to yield the corresponding compound of formula (XII); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XII) with a compound of formula (XVIII); in the presence of palladium catalyst; in the presence of an organic or inorganic base; in an organic solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XIX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIX) with hydrogen or a source of hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XX); 
     
     
       
         
         
             
             
         
       
       
         reacting the compound of formula (XX) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (I). 
       
     
   
   
       2 . A process for the preparation of a compound of formula (I) 
     
       
         
         
             
             
         
       
       wherein 
     
     
       
         
         
             
             
         
       
        is C 6-10 aryl or a heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl, isoquinolinyl and quinazolinyl; 
       each R 41P  is independently selected from C 1-6 alkyl, C 1-6 alkoxy or fluoro; 
       R J  and R K  are each independently selected from hydrogen or C 1-4 alkyl; alternatively, R J  and R K  are taken together with the nitrogen atom to which they are bound to form a five to seven membered heterocyclyl; 
       Pg 1  is a nitrogen protecting group; 
       comprising 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XIX) with hydrogen or a source of hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater than about room temperature; to yield the corresponding compound of formula (XX); 
     
     
       
         
         
             
             
         
       
       reacting the compound of formula (XX) with an aqueous base; in an organic solvent; to yield the corresponding compound of formula (I). 
     
   
   
       3 .- 18 . (canceled)