Method for producing lysine derivative

Abstract

The present invention provides a method for industrially producing an optically active lysine derivative useful as a pharmaceutical intermediate. More particularly, the present invention provides a production method including protecting an amino group or an amino group and carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid with a protecting group, reducing a nitro group to synthesize a 6,6-dimethyl lysine derivative and reacting the 6,6-dimethyl lysine derivative with an acetic acid derivative.

What is claimed is:  
     
         1 . A method for producing an optically active lysine derivative of the formula (5)  
       
         
           
           
               
               
           
         
       
       wherein 
 * means an asymmetric carbon atom,  
 P 1  and P 2  are each independently an amino-protecting group or hydrogen atom where P 1  and P 2  are not hydrogen atoms at the same time, or P 1  and P 2  in combination show an amino-protecting group,  
 R 1  is alkyl group having 1 to 6 carbon atoms or aralkyl group having 7 to 12 carbon atoms, and  
 P 5  is a hydrogen atom or carboxyl-protecting group or a salt thereof, which method comprises the steps of (1) protecting an amino group or an amino group and a carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1)  
                     
 wherein * is as defined above, or a salt thereof, with a protecting group to give an optically active amino acid derivative of the formula (2)  
                     
 wherein *, P 1  and P 2  are as defined above and P 3  is a hydrogen atom or carboxyl-protecting group,  
 (2) reducing a nitro group of the derivative of the formula (2) to give an optically active 6,6-dimethyl lysine derivative of the formula (3)  
                     
 wherein *, P 1  and P 2  are as defined above and P 4  is a hydrogen atom or carboxyl-protecting group, or a salt thereof, and (3) reacting the derivative of the formula (3) or a salt thereof with an acetate derivative of the formula (4)  
                     
 wherein Y 1  is a leaving group and R 1  is as defined above.  
 
     
     
         2 . The method of  claim 1 , wherein the reduction is a catalytic reduction using a transition metal catalyst and metallic sulfate.  
     
     
         3 . The method of  claim 1 , wherein the reduction is a catalytic reduction using a palladium catalyst and ferrous sulfate.  
     
     
         4 . The method of  claim 1 , wherein either P 1  or P 2  is a tert-butoxycarbonyl group and the other is a hydrogen atom, P 3 , P 4  and P 5  are methyl groups and R 1  is a tert-butyl group.  
     
     
         5 . A method for producing an optically active 6,6-dimethyl lysine derivative of the formula (3)  
       
         
           
           
               
               
           
         
       
       wherein 
 * means an asymmetric carbon atom,  
 P 1  and P 2  are each independently an amino-protecting group or hydrogen atom where P 1  and P 2  are not hydrogen atoms an amino-protecting group, and  
 P 4  is a hydrogen atom or carboxyl-protecting group, or a salt thereof, which method comprises protecting an amino group or an amino group and a carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1)  
                     
 wherein * is as defined above, or a salt thereof, with a protecting group to give an optically active amino acid derivative of the formula (2)  
                     
 wherein *, P 1  and P 2  are as defined above and P 3  is a hydrogen atom or carboxyl-protecting group, and reducing a nitro group of the derivative of the formula (2).  
 
     
     
         6 . The method of  claim 5 , wherein the reduction is a catalytic reduction using a transition metal catalyst and metallic sulfate.  
     
     
         7 . The method of  claim 5 , wherein the reduction is a catalytic reduction using a palladium catalyst and ferrous sulfate.  
     
     
         8 . The method of  claim 5 , wherein either P 1  or P 2  is a tert-butoxycarbonyl group and the other is a hydrogen atom and P 3  and P 4  are methyl groups.  
     
     
         9 . A method for producing an optically active 6,6-dimethyl lysine derivative of the formula (3)  
       
         
           
           
               
               
           
         
       
       wherein 
 * means an asymmetric carbon atom,  
 P 1  and P 2  are each independently an amino-protecting group or hydrogen atom where P 1  and P 2  are not hydrogen atoms at the same time, or P 1  and P 2  in combination show an amino-protecting group, and  
 P 4  is a hydrogen atom or carboxyl-protecting group, or a salt thereof, which method comprises reducing an amino acid derivative of the formula (2)  
                     
 wherein *, P 1  and P 2  are as defined above and P 3  is a hydrogen atom or carboxyl-protecting group.  
 
     
     
         10 . The method of  claim 9 , wherein the reduction is a catalytic reduction using a transition metal catalyst and metallic sulfate.  
     
     
         11 . The method of  claim 9 , wherein the reduction is a catalytic reduction using a palladium catalyst and ferrous sulfate.  
     
     
         12 . The method of  claim 9 , wherein either P 1  or P 2  is a tert-butoxycarbonyl group and the other is a hydrogen atom and P 3  and P 4  are methyl groups.  
     
     
         13 . A method for producing an optically active lysine derivative of the formula (5)  
       
         
           
           
               
               
           
         
       
       wherein 
 * means an asymmetric carbon atom,  
 P 1  and P 2  are each independently an amino-protecting group or hydrogen atom where P 1  and P 2  are not hydrogen atoms at the same time, or P 1  and P 2  in combination show an amino-protecting group,  
 R 1  is alkyl group having 1 to 6 carbon atoms or aralkyl group having 7 to 12 carbon atoms, and  
 P 5  is a hydrogen atom or carboxyl-protecting group, or a salt thereof, which method comprises reacting an optically active 6,6-dimethyl lysine derivative of the formula (3)  
                     
 wherein *, P 1  and P 2  are as defined above and P 4  is a hydrogen atom or carboxyl-protecting group, or a salt thereof, with an acetate derivative of the formula (4)  
                     
 wherein Y 1  is a leaving group and R 1  is as defined above.  
 
     
     
         14 . The method of  claim 13 , wherein either P 1  or P 2  is a tert-butoxycarbonyl group and the other is a hydrogen atom, P 4  and P 5  are methyl groups and R 1  is a tert-butyl group.  
     
     
         15 . The method of  claim 1 , wherein the optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1) is produced by the following steps (a)-(c): 
 (a) reacting a 4-methyl-4-nitropentane derivative of the formula (6)                          wherein Y 2  is a leaving group, with 2-acylaminomalonic diester of the formula (7)                          wherein R 2  and R 3  are each independently alkyl group having 1 to 6 carbon atoms or aralkyl group having 7 to 12 carbon atoms, to give 2-acylamino-2-(4-methyl-4-nitropentyl)malonic diester of the formula (8)                          wherein R 2  and R 3  are as defined above;    (b) subjecting 2-acylamino-2-(4-methyl-4-nitropentyl)malonic diester of the formula (8) to hydrolysis and decarboxylation to give 2-acetylamino-6-methyl-6-nitroheptanoic acid (racemate) of the formula (9)                          ; and    (c) having acylase act on 2-acetylamino-6-methyl-6-nitroheptanoic acid (racemate) of the formula (9) to give optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1) or a salt thereof.    
     
     
         16 . The method of  claim 1 , wherein the optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1) is produced by the following steps (d)-(g): 
 (d) reducing 5-(4-methyl-4-nitropentylidene)hydantoin of the formula (10)                          to give 5-(4-methyl-4-nitropentyl)hydantoin of the formula (11)                          ;    (e) hydrolyzing 5-(4-methyl-4-nitropentyl)hydantoin of the formula (11) to give 2-amino-6-methyl-6-nitroheptanoic acid (racemate) of the formula (12)                          ;    (f) acylating an amino group of 2-amino-6-methyl-6-nitroheptanoic acid of the formula (12) to give 2-acylamino-6-methyl-6-nitroheptanoic acid (racemate) of the formula (13)                          wherein R 4  is methyl group or phenyl group; and    (g) having acylase act on 2-acylamino-6-methyl-6-nitroheptanoic acid (racemate) of the formula (13) to give optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1) or a salt thereof.    
     
     
         17 . A compound of any of the formulas (14)-(18), a salt thereof, an optically active substance thereof or a racemate thereof:  
       
         
           
           
               
               
           
         
       
       wherein P 1  and P 2  are each independently an amino-protecting group or hydrogen atom where P 1  and P 2  are not hydrogen atoms at the same time, or P 1  and P 2  in combination show an amino-protecting group except phthaloyl group, P 3 a is a carboxyl-protecting group and P 4  is a hydrogen atom or a carboxyl-protecting group.  
     
     
         18 . A compound of any of the formulas (19)-(23):  
       
         
           
           
               
               
           
         
       
       or a salt thereof.  
     
     
         19 . A compound of any of the formulas (6), (8), (10), (11) and 5 (24) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein Y 2  is a leaving group except chlorine atom, R 4  is methyl group or phenyl group, and R 2  and R 3  are each independently alkyl group having 1 to 6 carbon atoms or aralkyl group having 7 to 12 carbon atoms, and wherein the compounds of the formulas (8) and (24) comprise their optically active substances and racemates.  
     
     
         20 . The method of  claim 1 , wherein the optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1) is produced via the following step (h): 
 (h) enantio-selectively hydrolyzing 5-(4-methyl-4-nitropentyl)hydantoin of the formula (11)                          using at least one member selected from the group consisting of a microorganism, a treated product of a microorganism, hydantoinase and N-carbamyl-amino-acid hydrolase to give optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1) or a salt thereof.    
     
     
         21 . The method of  claim 20 , wherein said microorganism, and the origin of said treated product of a microorganism, said hydantoinase and said N-carbamyl-amino-acid hydrolase are bacteria of the genus Agrobacterium, the genus Bacillus or the genus Microbacterium.  
     
     
         22 . The method of  claim 20 , wherein said microorganism, and the origin of said treated product of a microorganism, said hydantoinase and said N-carbamyl-amino-acid hydrolase are bacteria of the genus Agrobacterium, and the optically active 2-amino-6-methyl-6-nitroheptanoic acid or a salt thereof is D-2-amino-6-methyl-6-nitroheptanoic acid or a salt thereof.  
     
     
         23 . The method of  claim 20 , wherein said microorganism, and the origin of said treated product of a microorganism, said hydantoinase and said N-carbamyl-amino-acid hydrolase are bacteria of the genus Bacillus or the genus Microbacterium, and the optically active 2-amino-6-methyl-6-nitroheptanoic acid or a salt thereof is L-2-amino-6-methyl-6-nitroheptanoic acid or a salt thereof.