Process for manufacture of fosinopril sodium

Abstract

The present invention discloses a process for the synthesis of fosinopril as a single desired isomer of high purity in two steps comprising of (a) preparation of fosinopril as a mixture of four diastereomers and (b) separation of the desired isomer from the mixture through formation of alkali metal salts followed by crystallisation.

1 - 22 . (canceled)  
   
   
       23 . The process of claim  1  wherein any cesium salts of diastereomers: (II B), (II C) and (II D) contained in the waste stream obtained obtained in Step (b), (v) are converted into said compound of formula (II A) by 
 d) ix) hydrolysing the mixture of diastereomers (IIB), (II C) and (II D) contained in the waste stream of Step (b), (v) to give compound of formula (VIII)                          X) selective esterifying the carboxylic acid group in compound (VIII) in presence of a base or an acid and in presence of a solvent to give compound of formula (VI)                          wherein R 7  is hydrogen and R 8  is a group removable easily by hydrogenolysis as defined above.    xi) reacting compound (VI) with a compound of formula (VII)                          in the presence of a base and a solvent to give compound of formula (II a )                          xii) deprotecting the group R 8  in compound of formula (II a ) by reacting it with hydrogen in presence of palladium on carbon as catalyst in presence of a solvent to give fosinopril as a mixture of four diastereomers (II A), (II B), (II C) and (II D)    xiii) mixing together fosinopril mixture of four diastereomers (II A), (II B), (II C) and (II D) with a cesium metal carrier in the presence of a solvent and crystallisation of the mixture of cesium salts thus formed from the same solvent or a mixture of solvents containing 1-10 moles of water with respect to compound (II A)/(II B)/(II C)/(II D) to give compound of formula (III A)                          xiv) reacting compound of formula (III A) with an acid in the presence of a solvent and water to give the fosinopril diastereomer (II A)                          and e) converting said compound (II A) to fosinopril sodium polymorphic Form-A comprising    xv) mixing together compound (II A) with a sodium metal carrier in presence of a solvent or a mixture of solvents to fosinopril sodium of formula (I) and    xvi) crystallisation of the fosinopril sodium of formula (I) thus formed in the same solvent or mixture of solvents containing water content <0.20% to give fosinopril sodium polymorphic Form-A    
   
   
       24 . The process of  claim 23  wherein in said step (d) (ix) the hydrolysis is effected by employing a base or an acid or a mixture of trichloromethyl silane and sodium iodide, with base preferred.  
   
   
       25 . The process of  claim 23 , wherein in said step (d) (x), the base during esterification is selected from triethylamine, potassium carbonate, sodium carbonate and N-methyl morpholine.  
   
   
       26 . The process of  claim 25 , wherein said esterification in presence of base is carried out in a solvent selected from acetone and acetonitrile.  
   
   
       27 . The process of  claim 23 , wherein in said step (d) (x), the acid during esterification is selected from sulphuric acid and p-toluene sulfonic acid.  
   
   
       28 . The process of  claim 27 , wherein the esterification in presence of acid is carried out in presence of a solvent selected from benzene, cyclohexane and toluene, with cyclohexane preferred.  
   
   
       29 . The process of  claim 23 , wherein the solvent in step (d) (xi) is selected from acetonitrile, dichloroethane, dichloroethane, ethyl acetate, N,N-dimethyl acetamide, N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene, with ethyl acetate, toluene and xylene preferred.  
   
   
       30 . The process of  claim 23 , wherein in said step (d) (xi), compound (VI), wherein R 7  is hydrogen is employed in a molar ratio to compound (VII) of within the range of about 1:4, preferably from about 1:1.5 to about 1:2.  
   
   
       31 . The process of  claim 23 , wherein in said step (d)(xi), the base is selected from triethylamine, pyridine, tripropylamine, diazabicycloundecene and N-methylmorpholine.  
   
   
       32 . The process of  claim 31 , wherein the base is employed in a molar ratio to compound (VI), wherein R 7  is hydrogen of within the range of about 1:4, preferably from about 1:1.5 to about 1:2.  
   
   
       33 . The process of  claim 23 , wherein in said step (d) (xii), the solvent is selected from the group consisting of one or more of acetonitrile, ethanol, ethyl acetate, methanol, N,N-dimethyl acetamide, N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene, with dichloromethane, ethyl acetate, toluene and xylene preferred.  
   
   
       34 . The process of  claim 23 , wherein in said step (d) (xiii), the cesium metal carrier is selected from cesium carbonate, cesium bicarbonate and cesium ethyl hexanoate.  
   
   
       35 . The process of  claim 34 , wherein the cesium metal carrier is employed in a molar ratio to compound (II A)/(II B)/(II C)/(II D) of within the range of about 1:3, preferably from about 1:1.5.  
   
   
       36 . The process of  claim 23 , wherein in said step (d) (xiii), the solvent is selected from one or more of acetone, acetonitrile, dichloromethane, dichloroethane, diethyl ether, diisopropyl ether, dioxane, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethyl acetamide, N,N-dimethyl formamide, tertiary butyl methyl ether, tetrahydrofuran, toluene and xylene or mixtures thereof.  
   
   
       37 . The process of  claim 23 , wherein in said step (d) (xiii), the water content in the solvent during crystallisation of compound (III A) is in a molar ratio of 1:10 to compound (II A)/(II B)/(II C)/(II D), preferably of within the range of about 1:5.  
   
   
       38 . The process of  claim 23 , wherein in said step (d) (xiv), the acid is selected from hydrochloric acid, nitric acid, sulphuric acid and potassium hydrogen sulfate, with potassium hydrogen sulfate preferred.  
   
   
       39 . The process of  claim 23 , wherein in said step (d) (xiv), the solvent is selected from dichloromethane, dichloroethane, diethyl ether, diisopropyl ether, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethyl acetamide, N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene.  
   
   
       40 . The process of  claim 23 , wherein in said step (e) (xv), the sodium metal carrier is selected from sodium acetate, sodium carbonate, sodium bicarbonate and sodium ethyl hexanoate.  
   
   
       41 . The process of  claim 23 , wherein in said step (e) (xv), the solvent is selected from one or more of acetonitrile, dichloromethane, dichloroethane, diethyl ether, diisopropyl ether, dioxane, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethyl acetamide, N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene, with dichloromethane and ethyl acetate preferred.  
   
   
       42 . The process of  claim 23 , wherein in said step (e) (xvi), the water content of the total solvents is within the range from about 0.03 to 0.05%.  
   
   
       43 - 53 . (canceled)