Method for manufacture of ceftriaxone sodium

Abstract

An improved process for preparation of ceftriaxone sodium of formula (II), is disclosed.

1 . In a process for preparation of ceftriaxone sodium of formula (II),  
       
         
           
           
               
               
           
         
       
       comprising the steps of 
 i) reacting a silylated compound of formula (III),  
                     
 with a 4-halo-2-methoxyimino-3-oxo-butyric acid derivative of formula (IV),  
                     
 wherein X and Y represent a halogen atom to give a compound of formula (V),  
                     
 ii) desilylating the compound of formula (V), wherein X is as defined hereinabove to give the desilylated compound of formula (VI),  
                     
 iii) reacting the desilylated compound of formula (VI) with thiourea in a solvent system containing organic solvent and water, to obtain ceftriaxone of formula (I),  
                     
 iv) converting the compound of formula (I) to the sodium salt (II); wherefore the improvement comprises  
 i 1 ) reacting a silylated compound of formula (III),  
                     
 with a 4-halo-2-methoxyimino-3-oxo butyric acid derivative of formula (IV), having a purity of at least 95% and containing di- and poly-brominated compounds less than 0.50%,  
                     
 wherein X and Y represent a halogen atom in the presence of an inert water-immiscible organic solvent or mixtures thereof and in the presence of an acid scavenging agent at a temperature of between −10° C. to −0° C. to give a compound of formula (V),  
                     
 ii 1 ) adding the solution of compound of formula (V) in the inert water-immiscible organic solvent or mixtures thereof to a 1:1 mixture of water and a water-immiscible organic solvent and separation of the organic phase to provide a solution of compound of formula (VI) in the inert water-immiscible organic solvent or mixtures thereof,  
                     
 iii 1 ) reacting the solution of compound of formula (VI) in the inert water-immiscible organic solvent or mixtures thereof with a solution of thiourea in water in the presence of an alkali metal containing inorganic base at a temperature of between 0° C. to +10° C. at a pH ranging between 5.0 to 5.5 and separation of the organic layer to provide a solution of the alkali metal salt of ceftriaxone of formula (II 1 ) in water, wherein M is an alkali metal,  
                     
 iv 1 ) mixing the solution of the alkali metal salt of ceftriaxone (II′), wherein M is as defined hereinearlier in water with a water-immiscible organic solvent and a water-miscible solvent and treating the solution thus obtained with an acid to a pH of 3.6 to 4.0 and isolating the precipitated ceftriaxone of formula (I) by filtration,  
                     
 v 1 ) reacting a solution of ceftriaxone of formula (I) in water with an organic amine maintaining a pH of 5.4±0.2 to produce a solution of the amine salt of ceftriaxone in water of formula (VII),  
                     
 wherein Q represents the organic amine, and  
 vi 1 ) reaction of the amine salt of ceftriaxone of formula (VII) in a mixture of water and a water-miscible organic solvent with a sodium metal carrier to give ceftriaxone sodium of formula (II), substantially free of impurities and having low Color absorbance.  
                     
 
     
     
         2 . A process according to  claim 1 , in which in step i 1 ), the inert water-immiscible organic solvent is selected from chlorinated hydrocarbons, acetic acid (C 1-4 ) alkyl esters and ethers.  
     
     
         3 . A process according to  claim 1 , in which in step i 1 ), wherein the acid scavenging agent is selected from ethylene oxide, propylene oxide, butylene oxide, acetamide, epichlohydrin, calcium oxide, disodium hydrogen phosphate, calcium carbonate and quaternary ammonium phosphates.  
     
     
         4 . A process according to any one of claims  1  and  2 , wherein the preferred acid scavenging agent is acetamide.  
     
     
         5 . A process according to any one of claims  1 ,  2  and  3 , wherein the acid scavenging agent is employed in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (III).  
     
     
         6 . A process according to any one of claims  1 ,  2 ,  3  and  4 , wherein the acid scavenging agent is employed in molar proportions of 1.0 to 1.5 moles per mole of compound of formula (III).  
     
     
         7 . A process according to  claim 1 , in which in step ii 1 ), the water-miscible organic solvent is selected from tetrahydrofuran or acetonitrile.  
     
     
         8 . A process according to  claim 1 , in which in step iii 1 ), thiourea is employed in molar proportions of 1.0 to 3.0 moles per mole of compound of formula (III), preferably in molar proportions of 1.0 to 1.5 moles per mole of compound of formula (III).  
     
     
         9 . A process according to  claim 1 , in which in step iii 1 ), the alkali metal inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate.  
     
     
         10 . A process according to any one of claims  1  and  9 , wherein the alkali metal containing inorganic base is employed in molar proportions of 2.0 to 5.0 moles per mole of compound of formula (III), preferably in molar proportions of 2.0 to 3.0 moles per mole of compound of formula (III).  
     
     
         11 . A process according to  claim 1 , in which in step iv 1 ), the water-immiscible organic solvent is selected from chlorinated hydrocarbons, acetic acid (C 1-4 ) alkyl esters and ethers.  
     
     
         12 . A process according to  claim 1 , in which in step iv 1 ), the water-miscible organic solvent is selected from tetrahydrofuran, acetonitrile or a C 1-4  lower alcohol.  
     
     
         13 . A process according to  claim 1 , in which in step v 1 ), the organic amine is selected from diethylamine, triethylamine, diisopropylamine, cyclohexylamine, pyridine, 2,4-dimethylamino pyridine and N-methyl morpholine.  
     
     
         14 . A process according to  claim 1 , in which in step vi 1 ), the water-miscible organic solvent is selected from tetrahydrofuran, acetonitrile, a C 1-4  lower alcohol and a ketonic solvent.  
     
     
         15 . A process according to  claim 1 , in which in step vi 1 ), the sodium metal carrier carrier is selected from sodium acetate, 2-ethyl sodium hexanoate and 2-ethyl sodium octanoate.  
     
     
         16 . A process according to  claim 1 , wherein the ceftriaxone sodium of formula (II) has a Color absorbance of 0.04 to 0.05 AU at 450 nrn.  
     
     
         17 . A process according to  claim 1 , wherein the level of total impurities in ceftriaxone sodium (II) obtained is the range of between 0.05 to 0.20%.  
     
     
         18 . A process for the production of a compound of formula  
       
         
           
           
               
               
           
         
       
       wherein X and R 1  are substituents useful in cephalosporin chemistry and R E  is hydrogen, a negative charge or together with the COO— group to which R E  is attached is an ester; comprising 
 i) reacting a compound of formula  
                     
 wherein R is hydrogen or silyl, R′ E  is silyl or together with the COO— group to which R E  is attached is an ester; and X is as defined above, with a compound of formula  
                     
 wherein Y is halogen, Y′ is a group which forms a basis that a compound of formula III is in a reactive form; and R 1  is as defined above, to obtain a compound of formula  
                     
 wherein Y, X, R′ E  and R 1  are as defined above;  
 ii) desilylating a compound of formula II wherein Y, X, R′ E  and R 1  are as defined above, and reacting a desilylated compound of formula II with thiourea in a solvent system containing organic solvent and water; to obtain a compound of formula I.  
 
     
     
         19 . A process for preparation of ceftriaxone sodium of formula II,  
       
         
           
           
               
               
           
         
       
       comprising the steps of 
 i) reacting a silylated compound of formula III,  
                     
 with a 4-halo-2-methoxyimino-3-oxo butyric acid derivative of formula IV, having a purity of at least 95% and containing di- and poly-brominated compounds less than 0.50%,  
                     
 wherein X and Y represent a halogen atom in the presence of an inert water-immiscible organic solvent or mixtures thereof and in the presence of an acid scavenging agent at a temperature of between −10° C. to −0° C. to give a compound of formula V,  
                     
 ii) adding the solution of compound of formula V in the inert water-immiscible organic solvent or mixtures thereof to a 1:1 mixture of water and a water-immiscible organic solvent and separation of the organic phase to provide a solution of compound of formula VI in the inert water-immiscible organic solvent or mixtures thereof,  
                     
 iii) reacting the solution of compound of formula VI in the inert water-immiscible organic solvent or mixtures thereof with a solution of thiourea in water in the presence of an alkali metal containing inorganic base at a temperature of between 0° C. to +10° C. at a pH ranging between 5.0 to 5.5 and separation of the organic layer to provide a solution of the alkali metal salt of ceftriaxone of formula II in water, wherein M is an alkali metal,  
                     
 
     
     
         20 . The process according to  claim 19 , further comprising the step of mixing the solution of the alkali metal salt of ceftriaxone of the formula II, wherein M is as defined hereinearlier in water with a water-immiscible organic solvent and a water-miscible solvent and treating the solution thus obtained with an acid to a pH of 3.6 to 4.0 and isolating the precipitated ceftriaxone of formula I  
       
         
           
           
               
               
           
         
       
       by filtration.  
     
     
         21 . The process according to  claim 20 , further comprising the step of reacting a solution of ceftriaxone of formula I in water with an organic amine maintaining a pH of 5.4±0.2 to produce a solution of the amine salt of ceftriaxone in water of formula VII,  
       
         
           
           
               
               
           
         
       
       wherein Q represents the organic amine.  
     
     
         22 . The process according to  claim 21 , further comprising the step of reacting an amine salt of ceftriaxone of formula VII in a mixture of water and a water-miscible organic solvent with a sodium metal carrier to give ceftriaxone sodium of formula II  
       
         
           
           
               
               
           
         
       
       substantially free of impurities and having low color absorbance.