Novel process for making bisphosphonic acids using diluents other than halogenated hydrocarbons

Abstract

Provided is a novel method of making bisphosphonic acids, e.g. risedronic acid, including the step of combining a carboxylic acid, phoshorous acid, and a halophosphorous compound in the presence of a diluent that is an aromatic hydrocarbon or a silicone fluid. When the diluent is an aromatic hydrocarbon, a inert support or ortho-phosphoric acid codiluent is advantageously included.

1 . A method of making a bisphosphonic acid comprising the steps of: 
 of combining, to form a reaction mixture, a carboxylic acid selected from the group consisting of 4-aminobutanoic acid, (1-imidazoyl)ethanoic acid, N-(n-pentyl)-N-methyl-3-aminopropanoic acid, 2-(imidazo[1,2-a]pyridin-3-yl_ethanoic acid, and 6-aminohexanoic acid; with phosphorous acid and a halophosporous compound selected from PCl 3 , PCl 5 , POCl 3 , PBr 3 , POBr 3 , and PBr 5  in the presence of a diluent that is either an aromatic hydrocarbon in combination with a codiluent that is ortho-phosphoric acid, or a silicone fluid,-wherein, when the diluent includes an aromatic hydrocarbon, a polyalkylene glycol is not present as a codiluent in the reaction mixture.    combining the reaction mixture with water or a water solution of a non-oxidizing acid, whereby at least aqueous and non-aqueous phases are formed,    separating the aqueous phase,    combining the aqueous phase with ethanol, whereby a precipitate is formed, and    isolating the bisphosphonic acid.    
   
   
       2 . The method of  claim 1  wherein the phosphorous acid and the halophosphorous compound are each combined together in at least a first portion and a second portion.  
   
   
       3 . The method of  claim 1  wherein the diluent is an aromatic hydrocarbon in combination with a codiluent that is ortho-phosphoric acid and the reaction is conducted in the presence of a heterogeneous solid support.  
   
   
       4 . The method of  claim 3  wherein the heterogeneous solid support is diatomite silica.  
   
   
       5 . The method of  claim 3  wherein the aromatic hydrocarbon is toluene.  
   
   
       6 . The method of  claim 1  wherein the silicone fluid is a poly(dimethysiloxane).  
   
   
       7 . The method of  claim 1  wherein the halophosphorous compound is POCl 3 .  
   
   
       8 . The method of  claim 1  wherein the carboxylic acid is 4-aminobutanoic acid or its hydrochloride and the isolated bisphosphonic acid is alendronic acid monohydrate.  
   
   
       9 . The method of  claim 1  wherein the carboxylic acid is (1-imidazoyl)ethanoic acid or its hydrochloride and the isolated bisphosphonic acid is zoledronic acid monohydrate.  
   
   
       10 . The method of  claim 1  wherein the carboxylic acid is N-(n-pentyl)-N-methyl-3-aminopropanoic acid or its hydrochloride and the isolated bisphosphonic acid is ibandronic acid.  
   
   
       11 . The method of  claim 1  wherein the carboxylic acid is 2-(imidazo[1,2-a]pyridin-3-yl)ethanoic acid and the isolated bishosphonic acid is minodronic acid hemihydrate.  
   
   
       12 . The method of  claim 1  wherein the carboxylic acid is 6-aminohexanoic acid and the isolated bisphosphonic acid is neridronic acid.  
   
   
       13 . A method of making zoledronic acid monohydrate comprising the steps of: 
 a) combining (1-imidazoyl)ethanoic acid or its hydrochloride, phosphorous acid, and a halophosporous compound selected from PCl 3 , PCl 5 , POCl 3 , PBr 3 , POBr 3 , and PBr 5  at a temperature of about 80° C. to about 100° C. in the presence of a diluent that is an aromatic hydrocarbon or a silicone fluid to form a reaction mixture, with the proviso that, when the diluent is an aromatic hydrocarbon, a polyalkylene glycol is not present as a codiluent in the reaction mixture,    b) combining the reaction mixture with water, whereby an aqueous and a non-aqueous phase are formed,    c) separating the aqueous phase,    d) combining the aqueous phase with ethanol whereby a suspension comprising zoledronic acid is formed, and    e) isolating zoledronic acid monohydrate from the suspension.    
   
   
       14 . The method of  claim 13  wherein, when the diluent is an aromatic hydrocarbon, ortho-phosphoric acid codiluent is combined in the reaction mixture.  
   
   
       15 . The method of  claim 13  wherein the diluent is an aromatic hydrocarbon and a heterogeneous solid support is combined in the reaction mixture and wherein the method further comprises the step of filtering the aqueous and non-aqueous phases before the aqueous phase is separated.  
   
   
       16 . A method of making ibandronic acid comprising the steps of: 
 a) combining N-methyl-N-(n-pentyl)-3-aminopropanoic acid, phosphorous acid, and a halophosporous compound selected from PCl 3 , PCl 5 , POCl 3 , PBr 3 , POBr 3 , and PBr 5  at a temperature of about 80° C. to about 100° C. in the presence of a diluent that is an aromatic hydrocarbon or a silicone fluid to form a reaction mixture, with the proviso that, when the diluent is an aromatic hydrocarbon, a polyalkylene glycol is not present as a codiluent in the reaction mixture,    b) combining the reaction mixture with water, whereby an aqueous and a non-aqueous phase are formed,    c) separating the aqueous phase,    d) combining the aqueous phase with ethanol whereby a suspension comprising ibandronic acid is formed, and    e) isolating ibandronic acid from the suspension.    
   
   
       17 . The method of  claim 16  wherein, when the diluent is an aromatic hydrocarbon, ortho-phosphoric acid codiluent is combined in the reaction mixture.  
   
   
       18 . The method of  claim 16  wherein the diluent is an aromatic hydrocarbon and a heterogeneous solid support is combined in the reaction mixture and wherein the method further comprises the step of filtering the aqueous and non-aqueous phases before the aqueous phase is separated.  
   
   
       19 . A method of making minodronic acid hemihydrate comprising the steps of: 
 a) combining 2-(imidazo[1,2-a]pyridin-3-yl)ethanoic acid, phosphorous acid, and a halophosporous compound selected from PCl 3 , PCl 5 , POCl 3 , PBr 3 , POBr 3 , and PBr 5  at a temperature of about 80° C. to about 100° C. in the presence of a diluent that is an aromatic hydrocarbon or a silicone fluid to form a reaction mixture, with the proviso that, when the diluent is an aromatic hydrocarbon, a polyalkylene glycol is not present as a codiluent in the reaction mixture,    b) combining the reaction mixture with water, whereby an aqueous and a non-aqueous phase are formed,    c) separating the aqueous phase,    d) combining the aqueous phase with ethanol whereby a suspension comprising minodronic acid is formed, and    e) isolating minodronic acid hemihydrate from the suspension.    
   
   
       20 . The method of  claim 19  wherein, when the diluent is an aromatic hydrocarbon, ortho-phosphoric acid codiluent is combined in the reaction mixture.  
   
   
       21 . The method of  claim 19  wherein the diluent is an aromatic hydrocarbon and a heterogeneous solid support is combined in the reaction mixture and wherein the method further comprises the step of filtering the aqueous and non-aqueous phases before the aqueous phase is separated.  
   
   
       22 . A method of making neridronic acid comprising the steps of: 
 a) combining 6-aminohexanoic acid, phosphorous acid, and a halophosporous compound selected from PCl 3 , PCl 5 , POCl 3 , PBr 3 , POBr 3 , and PBr 5  at a temperature of about 80° C. to about 100° C. in the presence of a diluent that is an aromatic hydrocarbon or a silicone fluid to form a reaction mixture, with the proviso that, when the diluent is an aromatic hydrocarbon, a polyalkylene glycol is not present as a codiluent in the reaction mixture,    b) combining the reaction mixture with water, whereby an aqueous and a non-aqueous phase are formed,    c) separating the aqueous phase,    d) combining the aqueous phase with ethanol whereby a suspension comprising neridronic acid is formed, and    e) isolating minodronic acid from the suspension.    
   
   
       23 . The method of  claim 22  wherein, when the diluent is an aromatic hydrocarbon, ortho-phosphoric acid codiluent is combined in the reaction mixture.  
   
   
       24 . The method of  claim 22  wherein the diluent is an aromatic hydrocarbon and a heterogeneous solid support is combined in the reaction mixture and wherein the method further comprises the step of filtering the aqueous and non-aqueous phases before the aqueous phase is separated.