Process for the preparation of tricyclic amino alcohol derivatives

Abstract

A process for the preparation of tricyclic amino alcohol derivatives including 2-[N-[2-(9H-carbazol-2-yloxy)ethyl]]amino-1-[(3-methylsulfonylamino)phenyl]ethanol useful in the treatment of diabetes, obesity, hyperlipidemia and so on; and intermediates as represented by formula (5) or (6) or the like useful in the preparation, wherein R11 is hydrogen or the like; and *1 represents an asymmetric carbon atom. 2-Halo-1-(3-nitrophenyl)ethanone derivatives and 1-(3-nitrophenyl)oxirane derivatives, which are intermediates for the preparation of tricyclic amino alcohol derivatives, are easy of purification, and particularly optically active 1-(3-nitrophenyl)oxirane derivatives are effective in enhancing the optical purities of the final products.

1 . A process for the preparation of a compound of the formula (1):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a hydrogen or halogen atom, or a hydroxyl group, R 3  represents a lower alkyl group or a benzyl group, *1 represents an asymmetric carbon atom, and A represents one of the following groups:  
       
         
           
           
               
               
           
         
       
       wherein X represents NH, O or S, R 5  represents a hydrogen atom, or a hydroxyl, amino or acetylamino group, *2 represents an asymmetric carbon atom when R 5  is not a hydrogen atom, said process comprising: 
 reducing a compound of the formula (7):  
                     
  wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, B represents a chlorine or bromine atom, to give a halohydrin of the formula (6):  
                     
  wherein R 11 , B and *1 are as defined above; and,  
 converting the halohydrin under alkaline conditions into an epoxy compound of the formula (5):  
                     
  wherein R 11  and *1 arc as defined above; and,  
 reacting the epoxy compound with a compound of the formula (9):  
                     
  wherein R 2  represents an amino-protecting group, and A′ represents one of the following groups:  
                     
  wherein X represents NH, O or S, R 5  represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group, and *2 represents an asymmetric carbon atom when R 51  is not a hydrogen atom, to give an amino alcohol of the formula (4):  
                     
  wherein R 11 , R 2 , A′ and *1 are as defined above; and,  
 reducing the nitro group to give an aniline derivative of the formula (3):  
                     
  wherein R 11 , R 2 , A′ and *1 are as defined above; and,  
 reacting the aniline derivative with a sulfonating agent to give an amino alcohol of the formula (2):  
                     
  wherein R 3 , R 11 , R 2 , A′ and *1 are as defined above; and then, simultaneously or sequentially removing the protecting groups to give the compound of the formula (1).  
 
     
     
         2 . A process for the preparation of either one of optical isomers of a halohydrin of the formula (6):  
       
         
           
           
               
               
           
         
       
       wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, and B represents a chlorine or bromine atom, and *1 represents an asymmetric carbon atom, said process comprising: 
 asymmetrically reducing a compound of the formula (7):  
                     
  wherein R 11  and B are as defined above, using an asymmetric reduction catalyst together with a hydrogen donor, said asymmetric reduction catalyst being prepared preliminarily or in situ in a reaction system from a metal complex and a ligand, said metal complex being a transition metal complex represented by MX m L n  in which M is a transition metal of ruthenium or rhodium, X represents a hydrogen or halogen atom, or a carboxyl, hydroxyl, alkoxyl group and the like, L represents a neutral ligand such as an aromatic or olefin compound, and m and n represent integers, and said ligand being an optically active amine compound, to give the compound of the formula (6).  
 
     
     
         3 . A process for the preparation of a compound of the formula (4):  
       
         
           
           
               
               
           
         
       
       wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, R 2  represents an amino-protecting group, *1 represents an asymmetric carbon atom, and A′ represents one of the following groups:  
       
         
           
           
               
               
           
         
       
       wherein X represents NH, O or S, R 51  represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group, and *2 represents an asymmetric carbon atom when R 51  is not a hydrogen atom, said process comprising: 
 reacting an epoxy compound of the formula (5):  
                     
  wherein R 11  and *1 are as defined above, with a compound of the formula (9):  
                     
  wherein R 2  and A′ are as defined above, to give the compound of the formula (4).  
 
     
     
         4 . A compound of the formula (4):  
       
         
           
           
               
               
           
         
       
       wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, R 2  represents an amino-protecting group, *1 represents an asymmetric carbon atom, and A′ represents one of the following groups:  
       
         
           
           
               
               
           
         
       
       wherein X represents NH, O or S, R 51  represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group, and *2 represents an asymmetric carbon atom when R 51  is not a hydrogen atom, or a salt thereof.  
     
     
         5 . A compound of the formula (3):  
       
         
           
           
               
               
           
         
       
       wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, R 2  represents an amino-protecting group, *1 represents an asymmetric carbon atom, and A′ represents one of the following groups:  
       
         
           
           
               
               
           
         
       
       wherein X represents NH, O or S, R 51  represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group, and *2 represents an asymmetric carbon atom when R 51  is not a hydrogen atom, or a salt thereof.  
     
     
         6 . A process for the preparation of a compound of the formula (1):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a hydrogen or halogen atom, R 3  represents a lower alkyl group or a benzyl group, *1 represents an asymmetric carbon atom, and A represents one of the following groups:  
       
         
           
           
               
               
           
         
       
       wherein X represents NH, O or S, R 5  represents a hydrogen atom, or a hydroxyl, amino or acetylamino group, and *2 represents an asymmetric carbon atom when R 5  is not a hydrogen atom, said process comprising: 
 chlorinating a compound of the formula (18):  
                     
  wherein R 14  represents a hydrogen or halogen atom, R 13  represents nitro, and both R and R′ represent a hydrogen atom, with sulfuryl chloride in an ether solvent, to give a compound of the formula (19):  
                     
  wherein R 13 , R 14 , R and R′ are as defined above; and,  
 reducing the chlorinated compound to give a halohydrin of the formula (6):  
                     
  wherein R 11  represents a hydrogen or halogen atom, B represents a chlorine atom, and *1 is as defined above; and,  
 converting the halohydrin under alkaline conditions into an epoxy compound of the formula (5):  
                     
  wherein R 11  and *1 are as defined above; and,  
 reacting the epoxy compound with a compound of the formula (9):  
                     
  wherein R 2  represents an amino-protecting group, and A′ represents one of the following groups:  
                     
  wherein X represents NH, O or S, R 51  represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group, and *2 represents an asymmetric carbon atom when R 51  is not a hydrogen atom, to give an amino alcohol of the formula (4):  
                     
  wherein R 11 , R 2 , A′ and *1 are as defined above; and,  
 reducing the nitro group to give an aniline derivative of the formula (3):  
                     
  wherein R 11 , R 2 , A′ and *1 are as defined above; and,  
 reacting the aniline derivative with a sulfonating agent to give an amino alcohol of the formula (2):  
                     
  wherein R 3 , R 11 , R 2 , A′ and *1 are as defined above; and then,  
 simultaneously or sequentially removing the protecting groups to give the compound of the formula (1).  
 
     
     
         7 . A process for the preparation of an α-chloroacetophenone derivative of the formula (17):  
       
         
           
           
               
               
           
         
       
       wherein n represents 1 to 5, R 12  represents a hydrogen or halogen atom, or acyloxy, acylamino, NR 6 SO 2 R 3 , cyano, trifluoromethyl or nitro, and when n is 2 or more, R 12  represents same or different substituents as defined above, and R and R′ may be same or different from each other and represent a hydrogen atom, or a lower alkyl group or an aryl group, and wherein R 6  represents a hydrogen atom or an amino-protecting group, and R 3  represents a lower alkyl group or a benzyl group, said process comprising: 
 chlorinating a compound of the formula (16):  
                     
  wherein n, R 12 , R and R′ are as defined above, with sulfuryl chloride in an ether solvent to give the compound of the formula (17).  
 
     
     
         8 . A process for the preparation of an α-chloroacetophenone derivative of the formula (19):  
       
         
           
           
               
               
           
         
       
       wherein R 14  represents a hydrogen or halogen atom, R 13  represents nitro, and both R and R′ represent a hydrogen atom, said process comprising: 
 chlorinating a compound of the formula (18):  
                     
 
     
     
         9 . The process of  claim 7 , wherein the ether solvent used is diisopropyl ether or methyl t-butyl ether.  
     
     
         10 . The process of  claim 8 , wherein the ether solvent used is diisopropyl ether or methyl t-butyl ether.  
     
     
         11 . A process for the preparation a compound of the formula (1):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a hydrogen or halogen atom, or a hydroxyl group, R 3  represents a lower alkyl group or a benzyl group, *1 represents an asymmetric carbon atom, and A represents one of the following groups:  
       
         
           
           
               
               
           
         
          wherein X represents NH, O or S, R 5  represents a hydrogen atom, or a hydroxyl, amino or acetylamino group, *2 represents an asymmetric carbon atom when R 5  is not a hydrogen atom, said process comprising:  
         reacting an epoxy compound of the formula (5):  
         
           
             
             
                 
                 
             
           
         
          wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, and *1 has the same meaning as defined above, with a compound of the formula (9):  
         
           
             
             
                 
                 
             
           
         
          wherein R 2  represents a protective group for the amino group, and A′ represents one of the following groups:  
         
           
             
             
                 
                 
             
           
         
          wherein X represents NH, O or S, R 51  represents a hydrogen atom, a hydroxyl group protected by a protective group, an amino group protected by a protective group or an acetylamino group, and *2 represents an asymmetric carbon atom when R 51  is not a hydrogen atom, to give an amino alcohol of the formula (4):  
         
           
             
             
                 
                 
             
           
         
          wherein R 11 , R 2 , A′ and *1 are as defined above; and,  
         reducing the nitro group to give an aniline derivative of the formula (3):  
         
           
             
             
                 
                 
             
           
         
          wherein R 11 , R 2 , A′ and *1 are as defined above; and,  
         reacting the aniline derivative with a sulfonating agent to give an amino alcohol of the formula (2):  
         
           
             
             
                 
                 
             
           
         
          wherein R 3 , R 11 , R 2 , A′ and *1 are as defined above; and then,  
         simultaneously or sequentially removing the protective groups to give the compound of the formula (1).  
       
     
     
         12 . An optical isomer of a compound of the formula (6):  
       
         
           
           
               
               
           
         
       
       wherein R 11  represents a hydrogen or halogen atom, or a protected hydroxyl group, B represents a chlorine atom, and *1 represents an asymmetric carbon atom.