Method of making (s)-3-(aminomethyl) -5- methylhexanoic acid

Abstract

A method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with to form primarily reacting the with a cyanide source to form decarboxylating the to form hydrolyzing the with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)- 3 -(aminomethyl)- 5 -methylhexanoic acid, wherein R 1 and R 2 are the same or different and are hydrogen, C 1 -C 6 alkyl, aryl, benzyl, or C 3 -C 6 cycloalkyl. The present invention also provides a method of making (±)- 3 -(aminomethyl)- 5 -methylhexanoic acid that comprises condensing isovaleraldehyde with to form primarily reacting the with a cyanide source to form decarboxylating the to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)- 3 -(aminomethyl)- 5 -methylhexanoic acid.

1 . The compound having the formula  
                   
       wherein R 1  and R 2  are the same or different and are hydrogen, C 1 -C 6  alkyl, aryl, benzyl or C 3 -C 6  cycloalkyl.  
     
     
         2 . The compound of    claim 1    wherein R 1  and R 2  are ethyl.  
     
     
         3 . The compound having the formula  
                   
       wherein M is hydrogen, an alkali metal, or an alkaline earth metal and R 1  is C 1 -C 6  alkyl, aryl, benzyl, or C 3 -C 6  cycloalkyl.  
     
     
         4 . The compound of    claim 3    wherein M is sodium or potassium.  
     
     
         5 . The compound that is the mandelic acid salt of 3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         6 . The compound of    claim 5    wherein the mandelic acid is (S)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (S)-3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         7 . The compound of    claim 5    wherein the mandelic acid is (R)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (R)-3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         8 . The compound of    claim 5    wherein the mandelic acid is (R)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (S)-3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         9 . The compound of    claim 5    wherein the mandelic acid is (S)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (R)-3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         10 . A method for obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising: 
 a. combining (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol;  
 b. allowing a precipitate to form;  
 c. introducing the precipitate into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry; and  
 d. collecting the solid from the slurry.  
 
     
     
         11 . The method of    claim 10    wherein the (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid are combined in a 3% v/v solution of water in isopropyl alcohol.  
     
     
         12 . The method of    claim 10    wherein the (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid are combined in methanol and isopropanol.  
     
     
         13 . The method of    claim 10    wherein the polar aprotic solvent is dimethylsulfoxide.  
     
     
         14 . The method of    claim 10    wherein the polar aprotic solvent is tetrahydrofuran.  
     
     
         15 . A method of making (±)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising: 
 a. condensing isovaleraldehyde with  
                 
 
 to form primarily  
                 
 
 b. reacting the  
                 
 
 with a cyanide source to form  
                 
 
 c. decarboxylating the  
                 
 
 to form  
                 
 
 d. hydrolyzing the  
                 
 
 with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and  
 e. hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid, wherein R 1  and R 2  are the same or different and are hydrogen, C 1 -C 6  alkyl, aryl, benzyl, or C 3 -C 6  cycloalkyl.  
 
     
     
         16 . The method of    claim 15    wherein R 1  and R 2  of  
                 
 
       are ethyl.  
     
     
         17 . The method of    claim 15    wherein the isovaleraldehyde and  
                 
 
       are condensed in the presence of di-n-propylamine and acetic acid.  
     
     
         18 . The method of    claim 15    wherein the cyanide source is potassium cyanide.  
     
     
         19 . The method of    claim 15    wherein the alkali metalhydroxide is potassium hydroxide.  
     
     
         20 . The method of    claim 15    wherein the hydrogenation is carried out in the presence of hydrogen and sponge nickel.  
     
     
         21 . The method of    claim 15    which further comprises the step of resolving the (±)-3-(aminomethyl)-5-methylhexanoic acid to obtain (S)-3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         22 . The method of    claim 21    wherein the resolution step comprises: 
 a. combining (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol;  
 b. allowing a precipitate to form;  
 c. introducing the precipitate into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry; and  
 d. collecting the solid from the slurry.  
 
     
     
         23 . A method of making (±)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising: 
 a. condensing isovaleraldehyde with  
                 
 
 to form primarily  
                 
 
 b. reacting the  
                 
 
 with a cyanide source to form  
                 
 
 c. decarboxylating the  
                 
 
 to form an alkali or alkaline earth metal carboxylate salt; and  
 d. hydrogenating the alkali or alkaline earth metal. carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid.  
 
     
     
         24 . The method of    claim 23    wherein R 1  and R 2  of  
                 
 
       are ethyl.  
     
     
         25 . The method of    claim 23    wherein the isovaleraldehyde and  
                 
 
       are condensed in the presence of di-n-propylamine and acetic acid.  
     
     
         26 . The method of    claim 23    wherein the cyanide compound is potassium cyanide.  
     
     
         27 . The method of    claim 23    wherein the hydrogenation is carried out in the presence of hydrogen and sponge nickel.  
     
     
         28 . The method of    claim 23    which further comprises the step of resolving the (±)-3-(aminomethyl)-5-methylhexanoic acid to obtain (S)-3-(aminomethyl)-5-methylhexanoic acid.  
     
     
         29 . The method of    claim 28    wherein the resolution step comprises: 
 a. combining (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol;  
 b. allowing a precipitate to form;  
 c. introducing the precipitate into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry; and  
 d. collecting the solid from the slurry.