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, phosphorous 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, an inert support or ortho-phosphoric acid codiluent is advantageously included.

1 . A method of making a bisphosphonic acid comprising the steps of:
 a) combining, to form a reaction mixture, a carboxylic acid selected from the group consisting of (1-imidazoyl)ethanoic acid, and N-(n-pentyl)-N-methyl-3-aminopropanoic acid, with phosphorous acid and a halophosphorous compound selected from PCl 3 , PCl 5 , POCl 3 , PBr 3 , POBr 3 , and PBr 5  in the presence of a diluent, and optionally in the presence of a codiluent,   b) 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,   c) separating the aqueous phase,   d) combining the aqueous phase with ethanol, whereby a precipitate of the bisphosphonic acid is formed, and, optionally,   e) isolating the bisphosphonic acid;   
     wherein the diluent includes i) an aromatic hydrocarbon and ortho-phosphoric acid, or ii) a silicone fluid, with the proviso that when the diluent includes an aromatic hydrocarbon and ortho-phosphoric acid, the co-diluent, if present, is not a polyalkylene glycol. 
   
   
       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 comprises an aromatic hydrocarbon and 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 . (canceled) 
   
   
       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 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . A method of making zoledronic acid monohydrate comprising the steps of:
 a) combining, to form a reaction mixture, (1-imidazoyl)ethanoic acid or its hydrochloride, phosphorous acid, and a halophosphorous 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, and optionally in the presence of a codiluent,   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 monohydrate is formed, and, optionally,   e) isolating the zoledronic acid monohydrate from the suspension,   
     wherein the diluent includes i) an aromatic hydrocarbon and ortho-phosphoric acid, or ii) a silicone fluid, with the proviso that when the diluent includes an aromatic hydrocarbon and ortho-phosphoric acid, the co-diluent, if present, is not a polyalkylene glycol. 
   
   
       14 . (canceled) 
   
   
       15 . The method of  claim 13  wherein the diluent is an aromatic hydrocarbon and ortho-phosphoric acid 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, to form a reaction mixture, N-methyl-N-(n-pentyl)-3-aminopropanoic acid, phosphorous acid, and a halophosphorous 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, and optionally in the presence of a codiluent,   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, optionally,   e) isolating the ibandronic acid from the suspension,   
     wherein the diluent includes i) an aromatic hydrocarbon and ortho-phosphoric acid, or ii) a silicone fluid, with the proviso that when the diluent includes an aromatic hydrocarbon and ortho-phosphoric acid, the co-diluent, if present, is not a polyalkylene glycol. 
   
   
       17 . (canceled) 
   
   
       18 . The method of  claim 16  wherein the diluent is an aromatic hydrocarbon and ortho-phosphoric acid 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 - 24 . (canceled)