US2014275567A1PendingUtilityA1

Process for preparing alkyl esters of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1h-benzo[d]imidazol-2-yl)butyric acid

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Assignee: JOHNSON MATTHEY PLCPriority: Mar 15, 2013Filed: Mar 13, 2014Published: Sep 18, 2014
Est. expiryMar 15, 2033(~6.6 yrs left)· nominal 20-yr term from priority
Inventors:Xing FuSaroop Singh Matharu
C07D 235/16
58
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Claims

Abstract

An alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, such as ethyl 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate, is obtained by reacting an alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with 2-hydroxyacetaldehyde under reducing conditions.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of producing an alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, comprising a step of reacting an alkyl ester of 4-(5-amino-l-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with 2-hydroxyacetaldehyde. 
     
     
         2 . The method of  claim 1 , wherein the 2-hydroxyacetaldehyde is generated in situ from glycolaldehyde dimer. 
     
     
         3 . The method of  claim 1 , wherein the step of reacting the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with 2-hydroxyacetaldehyde is carried out under reducing conditions. 
     
     
         4 . The method of  claim 1 , wherein the step of reacting the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with 2-hydroxyacetaldehyde is carried out in the presence of a reducing agent. 
     
     
         5 . The method of  claim 4 , wherein the reducing agent is a borohydride reducing agent or combination of borohydride reducing agents. 
     
     
         6 . The method of  claim 5 , wherein the borohydride reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride. 
     
     
         7 . The method of  claim 1 , wherein the step of reacting the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with 2-hydroxyacetaldehyde is carried out under acidic conditions. 
     
     
         8 . The method of  claim 1 , wherein the step of reacting the alkyl ester of 4-(5-amino-l-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with 2-hydroxyacetaldehyde is carried out under acidic reducing conditions. 
     
     
         9 . The method of  claim 1 , wherein the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid is contacted with at least two equivalents of 2-hydroxyacetaldehyde per equivalent of the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid. 
     
     
         10 . The method of  claim 1 , wherein the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid is a C1 to C6 branched or straight chain alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid. 
     
     
         11 . The method of  claim 1 , wherein the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid is an ethyl or isopropyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid. 
     
     
         12 . A method of producing an alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1/-1-benzo[d]imidazol-2-yl)butyric acid, comprising a step of reacting an alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with glycolaldehyde dimer under acidic reducing conditions. 
     
     
         13 . A method of producing an alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, comprising a step of reacting an alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid with glycolaldehyde dimer in a reaction medium comprised of organic solvent, a glycolaldehyde dimer dissociation catalyst and a reducing agent. 
     
     
         14 . The method of  claim 13 , wherein the solvent is dichloromethane. 
     
     
         15 . The method of  claim 13 , wherein the glycolaldehyde dimer dissociation catalyst is an acid or combination of acids. 
     
     
         16 . The method of  claim 13 , wherein the glycolaldehyde dimer dissociation catalyst is a carboxylic acid or combination of carboxylic acids. 
     
     
         17 . The method of  claim 13 , wherein the reducing agent is a borohydride or combination of borohydrides. 
     
     
         18 . The method of  claim 13 , wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride. 
     
     
         19 . The method of  claim 13 , wherein the glycolaldehyde dimer is added incrementally to a mixture comprising the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, an organic solvent, a glycolaldehyde dimer dissociation catalyst and a reducing agent. 
     
     
         20 . The method of  claim 13 , wherein the glycolaldehyde dimer and the reducing agent are added incrementally to a mixture comprising the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, an organic solvent, and a glycolaldehyde dimer dissociation catalyst. 
     
     
         21 . The method of  claim 13 , wherein the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid is a C1 to C6 branched or straight chain alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid. 
     
     
         22 . The method of  claim 13 , wherein the alkyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid is an ethyl or isopropyl ester of 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid. 
     
     
         23 . An alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, substantially free of by-products containing oligooxyethylene groups. 
     
     
         24 . An alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, having a purity of at least 93% as measured by HPLC area % analysis. 
     
     
         25 . An alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, produced by the method of  claim 1 . 
     
     
         26 . An alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, produced by the method of  claim 12 . 
     
     
         27 . An alkyl ester of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, produced by the method of  claim 13 .

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