Electrochemical Method for the Production of Betulin Aldehyde

Abstract

The present invention provides a method for manufacturing betulin aldehyde from betulin. The method includes: (a) electrochemically forming a oxoammonium ion from a nitroxyl radical; and (b) contacting betulin with the oxoammonium ion, for a period of time effective to provide the betulin aldehyde. The betulin aldehyde can subsequently be converted to betulinic acid, employing, e.g., NaClO2 or KClO2. The betulinic acid can be purified from from any unreacted betulin by converting the betulinic acid into a corresponding salt (Na, K, Li, Na, Ca, Mg, Ba, or Al), and separating the salt from the unreacted betulin.

1 . A method for manufacturing betulin aldehyde from betulin, the method comprising:
 (a) electrochemically forming a oxoammonium ion from a nitroxyl radical; and   (b) contacting betulin with the oxoammonium ion, for a period of time effective to provide the betulin aldehyde.   
   
   
       2 . The method of  claim 1 , wherein the oxoammonium ion is electrochemically formed from a nitroxyl radical such that the level of voltage on cell is about 2.0 volts to about 4.0 volts and the current density is about 0.5 mA/cm 2  to about 20.0 mA/cm 2 . 
   
   
       3 - 5 . (canceled) 
   
   
       6 . The method of  claim 1 , wherein the electrolyte media comprises dimethylformamide, dimethylacetamide, γ-butyrolactone, acetone, glyme, 2-butyn-1-al diethyl acetal, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, acrolein diethyl acetal, cyclohexanone diethyl acetal, formaldehyde diethyl acetal, formaldehyde dimethyl acetal, glyoxal 1,1-dimethyl acetal, ketene diethyl acetal, ketene diethyl acetal, N,N-dimethylacetamide dimethyl acetal, N,N-dimethylformamide dibutyl acetal, N,N-dimethylformamide dicyclohexyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide dimethyl acetal, N,N-dimethylacetamide diethyl acetal, N,N-dimethylpropionamide, N,N-diethylacetamide, N,N-diethylformamide, 2-butanone, 2-pentanone, β-propiolactone, β-butyrolactone, water, or any combination thereof. 
   
   
       7 - 10 . (canceled) 
   
   
       11 . The method of  claim 1 , wherein the oxoammonium ion is a compound of formula (XXV): 
     
       
         
         
             
             
         
       
     
     wherein,
 each of R 1  and R 2  is independently hydrogen, alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y  or COOR x , wherein each R x  and R y  are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl; wherein any alkyl group is optionally substituted on carbon with keto (═O); wherein any alkyl group is optionally interrupted with one or more non-peroxide oxy (—O—), thio (—S—), imino (—N(H)—), methylene dioxy (—OCH 2 O—), carbonyl (—C(═O)—), carboxy (—C(═O)O—), carbonyldioxy (—OC(═O)O—), carboxylato (—OC(═O)—), imine (C═NH), sulfinyl (SO), sulfonyl (SO 2 ) or [SiO]x, wherein x is about 1-10,000; or R 1  and R 2  together are thioxo (═S) or keto (═O). 
 
   
   
       12 . The method of  claim 11 , wherein R 1  is hydrogen and R 2  is hydrogen, alkyl, alkoxy, haloalkyl, hydroxy, heterocycle, amino, alkylamino, cyano, carboxyl; wherein any alkyl group is optionally substituted on carbon with keto (═O); wherein any alkyl group is optionally interrupted with one or more imino (—N(H)—), carbonyl (—C(═O)—) or [SiO]x, wherein x is about 1-10,000; or R 1  and R 2  together are keto (═O). 
   
   
       13 . (canceled) 
   
   
       14 . The method of  claim 11 , wherein the oxoammonium ion (XXV) is electrochemically generated from the corresponding nitroxyl radical 
     
       
         
         
             
             
         
       
     
   
   
       15 . The method of  claim 1 , wherein TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) is the nitroxyl radical corresponding to the compound of formula (XXV). 
   
   
       16 . The method of  claim 1 , wherein the contacting is carried out in a solvent system selected from the group of dimethylformamide, dimethylacetamide, γ-butyrolactone, acetone, glyme, 2-butyn-1-al diethyl acetal, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, acrolein diethyl acetal, cyclohexanone diethyl acetal, formaldehyde diethyl acetal, formaldehyde dimethyl acetal, glyoxal 1,1-dimethyl acetal, ketene diethyl acetal, ketene diethyl acetal, N,N-dimethylacetamide dimethyl acetal, N,N-dimethylformamide dibutyl acetal, N,N-dimethylformamide dicyclohexyl acetal, N-dimethylformamide diethyl acetal, N,N-dimethylformamide dimethyl acetal, N,N-dimethylacetamide diethyl acetal, N,N-dimethylpropionamide, N,N-diethylacetamide, N,N-diethylformamide, 2-butanone, 2-pentanone, β-propiolactone, β-butyrolactone, water; or any combination thereof. 
   
   
       17 . The method of  claim 1 , wherein the contacting is carried out in the presence of an electrolyte selected from tetraalkyl- or tetraarylammonium salts and Li +  or Na +  or K +  or Cs +  salts of an acid. 
   
   
       18 - 19 . (canceled) 
   
   
       20 . The method of  claim 1 , wherein the contacting is carried out in the presence of tetraethylammonium p-toluene sulfonate, present in a concentration of up to about 0.1 Mol/L. 
   
   
       21 - 22 . (canceled) 
   
   
       23 . The method of  claim 1 , wherein the molar ratio of the oxoammonium ion to betulin is less than about 0.35. 
   
   
       24 . (canceled) 
   
   
       25 . The method of  claim 1 , wherein the effective period of time is about 2 hours to about 50 hours and the contacting occurs at a temperature of about 15° C. to about 130° C. 
   
   
       26 - 29 . (canceled) 
   
   
       30 . The method of  claim 1 , further comprising converting betulin aldehyde into betulinic acid employing NaClO 2 , KClO 2 , or a combination thereof. 
   
   
       31 - 32 . (canceled) 
   
   
       33 . A method for manufacturing betulinic acid from betulin, the method comprising
 (a) electrochemically forming a oxoammonium ion from a nitroxyl radical;   (b) contacting betulin with the oxoammonium ion, for a period of time effective to provide the betulin aldehyde; and   (c) contacting the betulin aldehyde with NaClO 2 , KClO 2 , or a combination thereof, for a period of time effective to provide the betulinic acid.   
   
   
       34 . The method of  claim 33 , wherein the oxoammonium ion is electrochemically formed from a nitroxyl radical such that the level of voltage on cell is about 2.0 volts to about 4.0 volts and the current density is about 0.5 mA/cm 2  to about 20.0 mA/cm 2 . 
   
   
       35 - 37 . (canceled) 
   
   
       38 . The method of  claim 33 , wherein the electrolyte media comprises dimethylformamide, dimethylacetamide, γ-butyrolactone, acetone, glyme, 2-butyn-1-al diethyl acetal, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, acrolein diethyl acetal, cyclohexanone diethyl acetal, formaldehyde diethyl acetal, formaldehyde dimethyl acetal, glyoxal 1,1-dimethyl acetal, ketene diethyl acetal, ketene diethyl acetal, N,N-dimethylacetamide dimethyl acetal, N,N-dimethylformamide dibutyl acetal, N,N-dimethylformamide dicyclohexyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide dimethyl acetal, N,N-dimethylacetamide diethyl acetal, N,N-dimethylpropionamide, N,N-diethylacetamide, N,N-diethylformamide, 2-butanone, 2-pentanone, β-propiolactone, β-butyrolactone, water, or any combination thereof. 
   
   
       39 - 42 . (canceled) 
   
   
       43 . The method of  claim 33 , wherein the oxoammonium ion is a compound of formula (XXV): 
     
       
         
         
             
             
         
       
     
     wherein,
 each of R 1  and R 2  is independently hydrogen, alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR x R y  or COOR x , wherein each R x  and R y  are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxyl; wherein any alkyl group is optionally substituted on carbon with keto (═O); wherein any alkyl group is optionally interrupted with one or more non-peroxide oxy (—O—), thio (—S—), imino (—N(H)—), methylene dioxy (—OCH 2 O—), carbonyl (—C(═O)—), carboxy (—C(═O)O—), carbonyldioxy (—OC(═O)O—), carboxylato (—OC(═O)—), imine (C═NH), sulfinyl (SO), sulfonyl (SO 2 ) or [SiO]x, wherein x is about 1-10,000; or R 1  and R 2  together are thioxo (═S) or keto (═O). 
 
   
   
       44 . The method of  claim 43 , wherein R 1  is hydrogen and R 2  is hydrogen, alkyl, alkoxy, haloalkyl, hydroxy, heterocycle, amino, alkylamino, cyano, carboxyl; wherein any alkyl group is optionally substituted on carbon with keto (═O); wherein any alkyl group is optionally interrupted with one or more imino (—N(H)—), carbonyl (—C(═O)—) or [SiO]x, wherein x is about 1-10,000; or R 1  and R 2  together are keto (═O). 
   
   
       45 . (canceled) 
   
   
       46 . The method of  claim 43 , wherein the oxoammonium ion (XXV) is electrochemically generated from the corresponding nitroxyl radical 
     
       
         
         
             
             
         
       
     
   
   
       47 . The method of  claim 43 , wherein TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) is the nitroxyl radical corresponding to the compound of formula (XXV). 
   
   
       48 . The method of  claim 33 , wherein the contacting is carried out in a solvent system selected from the group of dimethylformamide, dimethylacetamide, γ-butyrolactone, acetone, glyme, 2-butyn-1-al diethyl acetal, acetaldehyde diethyl acetal, acetaldehyde dimethyl acetal, acrolein diethyl acetal, cyclohexanone diethyl acetal, formaldehyde diethyl acetal, formaldehyde dimethyl acetal, glyoxal 1,1-dimethyl acetal, ketene diethyl acetal, ketene diethyl acetal, N,N-dimethylacetamide dimethyl acetal, N,N-dimethylformamide dibutyl acetal, N,N-dimethylformamide dicyclohexyl acetal, N-dimethylformamide diethyl acetal, N,N-dimethylformamide dimethyl acetal, N,N-dimethylacetamide diethyl acetal, N,N-dimethylpropionamide, N,N-diethylacetamide, N,N-diethylformamide, 2-butanone, 2-pentanone, β-propiolactone, β-butyrolactone, water; or any combination thereof. 
   
   
       49 . The method of  claim 33 , wherein the contacting is carried out in the presence of an electrolyte selected from tetraalkyl- or tetraarylammonium salts and Li +  or Na +  or K +  or Cs +  salts of an acid. 
   
   
       50 - 51 . (canceled) 
   
   
       52 . The method of  claim 33 , wherein the contacting is carried out in the presence of tetraethylammonium p-toluene sulfonate, present in a concentration of up to about 0.1 Mol/L. 
   
   
       53 - 54 . (canceled) 
   
   
       55 . The method of  claim 33 , wherein the molar ratio of the oxoammonium ion to betulin is less than about 0.35. 
   
   
       56 . (canceled) 
   
   
       57 . The method of  claim 33 , wherein the effective period of time is about 2 hours to about 50 hours and the contacting occurs at a temperature of about 15° C. to about 130° C. 
   
   
       58 - 60 . (canceled)