Process for producing optically active tropinonemonocarboxylic acid ester derivative

Abstract

An optically active tropinonemonocarboxylic acid ester derivative useful as an intermediate for synthesis of optically active tropane derivatives was obtained by reacting succindialdehyde with an organic amine and acetonedicarboxylic acid ester to obtain a tropinonedicarboxylic acid ester derivative, and then subjecting this derivative to enzyme-catalyzed asymmetric dealkoxy-carbonylation. Since anhydroecgonine methyl ester derived from the optically active tropinone-monocarboxylic acid ester derivative by reduction and dehydration had the same direction of optical rotation as in the case of anhydroecgonine methyl ester obtained from natural cocaine, it was proved that the obtained optically active tropinonemonocarboxylic acid ester derivative had the same absolute configuration as that of natural cocaine. The yield of the optically active tropinonemonocarboxylic acid ester derivative from the asymmetric dealkoxycarbonylation was 30 to 50 mol %, and its optical purity was 70 to 97% ee. In addition, it was found that a crystalline optically active anhydroecgonine carboxylic acid ester derivative can be obtained by reducing and then dehydrating the optically active tropinonemonocarboxylic acid ester derivative and that its optical purity can easily be increased by recrystallization.

1 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative which comprises subjecting a tropinonedicarboxylic acid ester derivative represented by the following formula (1):  
       
         
           
           
               
               
           
         
       
       wherein R′ is an alkyl group, an aralkyl group or an amino-protecting group selected from lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R is an alkyl group or an aralkyl group, to asymmetric dealkoxycarbonylation in the presence of an enzyme to obtain an optically active tropinonemonocarboxylic acid ester derivative represented by the following formula (2):  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are as defined above.  
     
     
         2 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative according to  claim 1 , wherein the enzyme is liver esterase or baker's yeast.  
     
     
         3 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative according to  claim 1  or  2 , wherein R is an alkyl group of 1 to 6 carbon atoms and R′ is an aralkyl group, a lower aliphatic acyl group, an aromatic acyl group, an aryloxycarbonyl group or a tri-lower-alkylsilyl group; or R is an alkyl group of 2 to 6 carbon atoms and R′ is an aralkyloxycarbonyl group; or each of R and R′ is an aralkyl group.  
     
     
         4 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative according to any one of  claims 1  to  3 , wherein R is an alkyl group of 1 to 6 carbon atoms selected from methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group and hexyl group, and R′ is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group; or R is an alkyl group of 2 to 6 carbon atoms selected from ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group and hexyl group, and R′ is an aralkyloxycarbonyl group of 8 or 9 carbon atoms selected from benzyloxycarbonyl group and methoxybenzyloxycarbonyl group; or each of R and R′ is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group.  
     
     
         5 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative which comprises reacting succindialdehyde represented by the following formula (3):  
       
         
           
           
               
               
           
         
       
       with an organic amine represented by the following formula (4): 
       R″—NH 2   (4) 
       wherein R″ is an alkyl group or an aralkyl group, and an acetonedicarboxylic acid ester represented by the following formula (5):  
       
         
           
           
               
               
           
         
       
       wherein R is an alkyl group or an aralkyl group; if necessary, converting the substituent derived from the substituent R″ of the organic amine of the formula (4) to an amino-protecting group; thereby obtaining a tropinonedicarboxylic acid ester derivative represented by the following formula (1):  
       
         
           
           
               
               
           
         
       
       wherein R′ is an alkyl group, an aralkyl group or an amino-protecting group selected from lower aliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R is an alkyl group or an aralkyl group; and then subjecting the tropinonedicarboxylic acid ester derivative to asymmetric dealkoxycarbonylation in the presence of an enzyme to obtain an optically active tropinonemonocarboxylic acid ester derivative represented by the following formula (2):  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are as defined above.  
     
     
         6 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative according to  claim 5 , wherein the enzyme is liver esterase or baker's yeast.  
     
     
         7 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative according to  claim 5  or  6 , wherein in the above formula (1), R is an alkyl group of 1 to 6 carbon atoms and R′ is an aralkyl group, a lower aliphatic acyl group, an aromatic acyl group, an aryloxycarbonyl group or a tri-lower-alkylsilyl group; or R is an alkyl group of 2 to 6 carbon atoms and R′ is an aralkyloxycarbonyl group; or each of R and R′ is an aralkyl group.  
     
     
         8 . A process for producing an optically active tropinonemonocarboxylic acid ester derivative according to any one of  claims 5  to  7 , wherein R is an alkyl group of 1 to 6 carbon atoms selected from methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group and hexyl group, and R′ is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group; or R is an alkyl group of 2 to 6 carbon atoms selected from ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group and hexyl group, and R′ is an aralkyloxycarbonyl group of 8 or 9 carbon atoms selected from benzyloxycarbonyl group and methoxybenzyloxycarbonyl group; or each of R and R′ is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group.  
     
     
         9 . A process for producing an optically active anhydroecgonine carboxylic acid ester derivative which comprises converting the substituent R′ and/or substituent R of the optically active tropinonemonocarboxylic acid ester derivative of the above formula (2) to another substituent or other substituents if necessary, reducing the oxo group at the 3-position of this derivative, and then dehydrating the resulting compound to obtain an optically active anhydroecgonine carboxylic acid ester derivative represented by the following formula (6):  
       
         
           
           
               
               
           
         
       
       wherein R and R′ are as defined above.  
     
     
         10 . A process for producing an optically active anhydroecgonine carboxylic acid ester derivative according to  claim 9 , wherein a crystalline optically active anhydroecgonine carboxylic acid ester derivative is obtained by the reduction and the dehydration, and the obtained crystalline optically active anhydroecgonine carboxylic acid ester derivative is purified by recrystallization to obtain the anhydroecgonine carboxylic acid ester derivative having a high optical activity.  
     
     
         11 . A process for producing an optically active anhydroecgonine carboxylic acid ester derivative according to  claim 9  or  10 , wherein the optically active tropinonemonocarboxylic acid ester derivative of the above formula (2) is methyl (1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate, and the obtained optically active anhydroecgonine carboxylic acid ester derivative of the above formula (6) is methyl (1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate.