Methods of synthesis for 9-substituted hypoxanthine derivatives

Abstract

An improved method of synthesis of a 9-substituted hypoxanthine derivative comprises the steps of: (1) reacting aminocyanacetamide with triethyl orthoformate to form an imidoester derivative of aminocyanacetamide; (2) forming a compound having a reactive amino group on a hydrocarbyl moiety, the hydrocarbyl moiety being linked through an amide group to a physiologically active moiety or an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group; (3) reacting the imidoester with the compound having the reactive amino group on the hydrocarbyl moiety to form a derivative of 5-aminoimidazole-4-carboxamide substituted at the 1-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; (4) forming the six-membered heterocyclic ring of the purine moiety of the hypoxanthine by reacting the derivative of 5-aminoimidazole-4-carboxamide formed in step (3) with triethyl orthoformate to form a 9-substituted hypoxanthine compound substituted at the 9-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; and (5) hydrolyzing the ester of the optionally esterified benzoyl group if present.

1 . A process of synthesizing a 9-substituted hypoxanthine derivative, the derivative comprising a hypoxanthine moiety substituted at the nitrogen-9 position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein a benzoyl group, the process comprising the steps of: 
 (a) reacting aminocyanacetamide with triethyl orthoformate to form an imidoester derivative of aminocyanacetamide;    (b) forming a compound having a reactive amino group on a hydrocarbyl moiety, the hydrocarbyl moiety being linked through an amide group to a physiologically active moiety or an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group;    (c) reacting the imidoester with the compound having the reactive amino group on the hydrocarbyl moiety to form a derivative of 5-aminoimidazole-4-carboxamide substituted at the 1-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group    (d) forming the six-membered heterocyclic ring of the purine moiety of the hypoxanthine by reacting the derivative of 5-aminoimidazole-4-carboxamide formed in step (c) with triethyl orthoformate to form a 9-substituted hypoxanthine compound substituted at the 9-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; and    (e) hydrolyzing the ester of the optionally esterified benzoyl group if present.    
     
     
         2 . The process of  claim 1  wherein the hydrocarbyl moiety has the structure (CH 2 ) n , wherein n is an integer from 1 to 6.  
     
     
         3 . The process of  claim 2  wherein n is 2.  
     
     
         4 . The process of  claim 1  wherein the physiologically active moiety is p-aminobenzoic acid.  
     
     
         5 . The process of  claim 1  wherein the hydrocarbyl moiety is linked through an amide group to an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group.  
     
     
         6 . The process of  claim 5  wherein the physiologically active moiety is p-aminobenzoic acid.  
     
     
         7 . The process of  claim 6  wherein the esterified benzoyl group is esterified with a linear or branched alkyl group of from 1 to 7 carbon atoms.  
     
     
         8 . The process of  claim 7  wherein the esterified benzoyl group is esterified with an alkyl group with the structure CH 3 —(CH 2 ) z , where z is an integer from 0 to 6.  
     
     
         9 . The process of  claim 8  wherein z is 1.  
     
     
         10 . The process of  claim 2  wherein the physiologically active moiety is p-aminobenzoic acid.  
     
     
         11 . The process of  claim 2  wherein the hydrocarbyl moiety is linked through an amide group to an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group.  
     
     
         12 . The process of  claim 11  wherein the physiologically active moiety is p-aminobenzoic acid.  
     
     
         13 . The process of  claim 12  wherein the esterified benzoyl group is esterified with a linear or branched alkyl group of from 1 to 7 carbon atoms.  
     
     
         14 . The process of  claim 12  wherein the esterified benzoyl group is esterified with a group with the structure CH 3 —(CH 2 ) z , where z is an integer from 0 to 6.  
     
     
         15 . The process of  claim 14  wherein z is 1.  
     
     
         16 . The process of  claim 3  wherein the physiologically active moiety is p-aminobenzoic acid.  
     
     
         17 . The process of  claim 3  wherein the hydrocarbyl moiety is linked through an amide group to an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group.  
     
     
         18 . The process of  claim 17  wherein the physiologically active moiety is p-aminobenzoic acid.  
     
     
         19 . The process of  claim 18  wherein the esterified benzoyl group is esterified with a linear or branched alkyl group of from 1 to 7 carbon atoms.  
     
     
         20 . The process of  claim 19  wherein the esterified benzoyl group is esterified with a group with the structure CH 3 —(CH 2 ) z , where z is an integer from 0 to 6.  
     
     
         21 . The process of  claim 20  wherein z is 1.  
     
     
         22 . The process of  claim 1  wherein the compound having the reactive amino group on the hydrocarbyl moiety is formed by a process comprising the steps of: 
 (i) activating a ω-aminocarboxylic acid with thionyl chloride; and    (ii) reacting the activated ω-aminocarboxylic acid with a p-aminobenzoic acid ester in the presence of a tertiary amine selected from the group consisting of triethylamine and ethyldiisopropylamine, wherein the p-aminobenzoic acid ester is esterified with an alkyl group of from 1 to 6 carbons.    
     
     
         23 . The process of  claim 22  wherein the alkyl group is ethyl.  
     
     
         24 . The process of  claim 22  wherein the ω-aminocarboxylic acid is 3-aminopropionic acid.  
     
     
         25 . The process of  claim 24  wherein the alkyl group is ethyl.  
     
     
         26 . The process of  claim 22  wherein the tertiary amine is triethylamine.  
     
     
         27 . A process of synthesizing the 9-substituted hypoxanthine derivative N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide comprising the steps of: 
 (a) forming ethyl 4-(β-alanyl) aminobenzoate by a process including the steps of: 
 (i) activating 3-aminopropionic acid with thionyl chloride; and  
 (ii) reacting the activated 3-aminopropionic acid with ethyl p-aminobenzoate in the presence of triethylamine in a solvent comprising toluene and chloroform;  
   (b) reacting aminocyanacetamide with triethyl orthoformate in the presence of acetonitrile to form an imidoester derivative of aminocyanacetamide;    (c) reacting the imidoester with ethyl 4-(β-alanyl) aminobenzoate in methanol;    (d) forming the six-membered ring of the purine moiety of the hypoxanthine by reacting the ester formed in step (c) with triethyl orthoformate in acetic acid; and    (e) hydrolyzing the ester group of the compound formed in step (d) to yield N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide.