Synthesis of n-[n-(3,3-dimethylbutyl)-l-alpha-aspartyl]-l-phenylalanine 1-methyl ester using 3,3-dimethylbutyraldehyde precursors

Abstract

N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is produced by hydrogenation of L-α-aspartyl-L-phenylalanine 1-methyl ester and 3,3-dimethylbutyraldehyde produced in situ by the hydrolysis or cleavage of a 3,3-dimethylbutyraldehyde precursor. The production method is efficient and low cost, as compared with conventional N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester synthesis.

1 . A process of synthesizing N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester comprising the steps of: 
 hydrolyzing a bisulfite adduct of 3,3-dimethylbutyraldehyde with a base in a solvent to produce 3,3-dimethylbutyraldehyde in situ; and    reacting the 3,3-dimethylbutyraldehyde produced in situ with L-α-aspartyl-L-phenylalanine 1-methyl ester in the presence of a catalyst and hydrogen for a time and at a temperature sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.    
   
   
       2 . The process according to  claim 1 , wherein the bisulfite adduct of 3,3-dimethylbutyraldehyde is used in an amount of about 0.90 to about 1.1 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine 1-methyl ester.  
   
   
       3 . The process according to  claim 2 , wherein the bisulfite adduct of 3,3-dimethylbutyraldehyde is used in an amount of about 0.98 to about 1.0 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine 1-methyl ester.  
   
   
       4 . The process according to  claim 1 , wherein the base is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, zinc oxide, zinc carbonate, magnesium oxide, calcium oxide, aluminum oxide, magnesium carbonate, calcium carbonate, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, ammonium phosphate, calcium phosphate, magnesium phosphate, ammonia, a tertiary amine, a secondary amine, a pyridine derivative, and combinations thereof.  
   
   
       5 . The process according to  claim 1 , wherein the base is present in an amount of about 1% to about 10% by weight of the bisulfite adduct.  
   
   
       6 . The process according to  claim 1 , wherein the catalyst is selected from the group consisting of platinum on activated carbon, palladium on activated carbon, platinum black, palladium black, nickel on silica, nickel on alumina, Raney nickel, ruthenium black, ruthenium on carbon, palladium hydroxide on carbon, palladium oxide, platinum oxide, rhodium black, rhodium on carbon and rhodium on alumina.  
   
   
       7 . The process according to  claim 1 , wherein the weight ratio of catalyst on a dry basis to L-α-aspartyl-L-phenylalanine 1-methyl ester is from about 0.01:1 to about 0.25:1.  
   
   
       8 . The process according to  claim 1 , wherein the solvent is selected from the group consisting of ethanol, ethyl acetate, acetonitrile, dioxane, isopropanol, methanol, isobutyl methyl ketone, tetrahydrofuran, cyclohexane, toluene, dimethylformamide, water and mixtures thereof.  
   
   
       9 . The process according to  claim 1 , wherein the temperature sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is from about 20° C. to about 60° C.  
   
   
       10 . The process according to  claim 1 , wherein the time sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is from about 1 hour to about 24 hours.  
   
   
       11 . The process according to  claim 1 , wherein the pressure of the hydrogen is from about 5 psi to about 100 psi.  
   
   
       12 . The process according to  claim 1  further comprising the step of neutralizing the solvent containing the 3,3-dimethylbutyraldehyde produced in situ to have a pH ranging from about 3 to about 7.  
   
   
       13 . A process of synthesizing N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester comprising the steps of: 
 regenerating 3,3-dimethylbutyraldehyde from a hydrazone, a semicarbazone or an oxime of 3,3-dimethylbutyraldehyde in a solvent to produce 3,3-dimethylbutyraldehyde in situ; and    reacting the 3,3-dimethylbutyraldehyde produced in situ with L-α-aspartyl-L-phenylalanine 1-methyl ester in the presence of a catalyst and hydrogen for a time and at a temperature sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.    
   
   
       14 . The process according to  claim 13 , wherein the regenerating step comprises hydrolyzing the hydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde with an acid.  
   
   
       15 . The process according to  claim 14  further comprising the step of neutralizing the solvent containing the 3,3-dimethylbutyraldehyde produced in situ to have a pH ranging from about 3 to about 7.  
   
   
       16 . The process according to  claim 14 , wherein the acid is selected from the group consisting of acetic acid, citric acid, nitrous acid and combinations thereof.  
   
   
       17 . The process according to  claim 14 , wherein the acid is present in an amount of about 1% to about 10% by weight of the hydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde.  
   
   
       18 . The process according to  claim 13 , wherein the regenerating step comprises oxidatively cleaving the hydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde with an oxidative agent.  
   
   
       19 . The process according to  claim 18 , wherein the oxidative agent is selected from the group consisting of m-chloroperbenzoic acid, ozone, sodium periodate, diacetoxyiodobenzene, iodosobenzene, and combinations thereof.  
   
   
       20 . The process according to  claim 18 , wherein the oxidative agent is present in an amount of about 0.5 to about 3.0 on an equivalent molar ratio basis with the hydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde.  
   
   
       21 . The process according to  claim 13 , wherein the hydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde is used in an amount of about 0.90 to about 1.1 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine 1-methyl ester.  
   
   
       22 . The process according to  claim 21 , wherein the hydrazone, the semicarbazone or the oxime of 3,3-dimethylbutyraldehyde is used in an amount of about 0.98 to about 1.0 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine 1-methyl ester.  
   
   
       23 . The process according to  claim 13 , wherein the catalyst is selected from the group consisting of platinum on activated carbon, palladium on activated carbon, platinum black, palladium black, nickel on silica, nickel on alumina, Raney nickel, ruthenium black, ruthenium on carbon, palladium hydroxide on carbon, palladium oxide, platinum oxide, rhodium black, rhodium on carbon and rhodium on alumina.  
   
   
       24 . The process according to  claim 13 , wherein the weight ratio of catalyst on a dry basis to L-α-aspartyl-L-phenylalanine 1-methyl ester is from about 0.01:1 to about 0.25:1.  
   
   
       25 . The process according to  claim 13 , wherein the solvent is selected from the group consisting of ethanol, ethyl acetate, acetonitrile, dioxane, isopropanol, methanol, isobutyl methyl ketone, tetrahydrofuran, cyclohexane, toluene, dimethylformamide, water and mixtures thereof.  
   
   
       26 . The process according to  claim 13 , wherein the temperature sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is from about 20° C. to about 60° C.  
   
   
       27 . The process according to  claim 13 , wherein the time sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is from about 1 hour to about 24 hours.  
   
   
       28 . The process according to  claim 13 , wherein the pressure of the hydrogen is from about 5 psi to about 100 psi.  
   
   
       29 . A process of synthesizing N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester comprising the steps of: 
 hydrolyzing a trimer of 3,3-dimethylbutyraldehyde with an acid in a solvent to produce 3,3-dimethylbutyraldehyde in situ; and    reacting the 3,3-dimethylbutyraldehyde produced in situ with L-α-aspartyl-L-phenylalanine 1-methyl ester in the presence of a catalyst and hydrogen for a time and at a temperature sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.    
   
   
       30 . The process according to  claim 29 , wherein the trimer of 3,3-dimethylbutyraldehyde is used in an amount of about 0.3 to about 1.1 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine 1-methyl ester.  
   
   
       31 . The process according to  claim 30 , wherein the trimer of 3,3-dimethylbutyraldehyde is used in an amount of about 0.33 to about 0.35 on an equivalent molar ratio basis with L-α-aspartyl-L-phenylalanine 1-methyl ester.  
   
   
       32 . The process according to  claim 29 , wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, sulfuric acid and combinations thereof.  
   
   
       33 . The process according to  claim 29 , wherein the acid is present in an amount of about 1% to about 20% by weight of the trimer.  
   
   
       34 . The process according to  claim 29 , wherein the catalyst is selected from the group consisting of platinum on activated carbon, palladium on activated carbon, platinum black, palladium black, nickel on silica, nickel on alumina, Raney nickel, ruthenium black, ruthenium on carbon, palladium hydroxide on carbon, palladium oxide, platinum oxide, rhodium black, rhodium on carbon and rhodium on alumina.  
   
   
       35 . The process according to  claim 29 , wherein the weight ratio of catalyst on a dry basis to L-α-aspartyl-L-phenylalanine 1-methyl ester is from about 0.01:1 to about 0.25:1.  
   
   
       36 . The process according to  claim 29 , wherein the solvent is selected from the group consisting of ethanol, ethyl acetate, acetonitrile, dioxane, isopropanol, methanol, isobutyl methyl ketone, tetrahydrofuran, cyclohexane, toluene, dimethylformamide, water and mixtures thereof.  
   
   
       37 . The process according to  claim 29 , wherein the temperature sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is from about 20° C. to about 60° C.  
   
   
       38 . The process according to  claim 29 , wherein the time sufficient to produce N—[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is from about 1 hour to about 24 hours.  
   
   
       39 . The process according to  claim 29 , wherein the pressure of the hydrogen is from about 5 psi to about 100 psi.  
   
   
       40 . The process according to  claim 29  further comprising the step of neutralizing the solvent containing the 3,3-dimethylbutyraldehyde produced in situ to have a pH ranging from about 3 to about 7.