Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same

Abstract

The present invention relates to processes for preparing protected silylated clarithromycin oxime, preferably 6-O-methyl-2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (“S-MOP oxime”), and for converting protected silylated clarithromycin oxime, preferably S-MOP oxime, to clarithromycin. Processes for preparing protected silylated clarithromycin oxime according to the present invention, include reacting a silyl oxime derivative with methylating agent in the presence of at least one solvent and a base, where the solvent comprises methyl tertbutyl ether. Processes for converting protected silylated clarithromycin oxime to clarithromycin according to the present invention, include reacting protected silylated clarithromycin oxime with ethanol and water at an ethanol to water ratio of about 1:1, in the presence of an acid and a deoximating agent and cooling the reaction mixture prior to adding sodium hydroxide, where the process takes place without any additional water addition. Further processes for converting protected silylated clarithromycin oxime to clarithromycin, include heating a mixture of protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent to produce essentially oxime-free clarithromycin.

1 . A method of converting C-2′ and C-4″ silylated, protected clarithromycin oxime to clarithromycin comprising: 
 a) reacting the C-2′ and C-4″ silylated, protected clarithromycin oxime with an acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture;    b) cooling the reaction mixture to about 15° C. to about 25° C.; and    c) adding sodium hydroxide to the product of step b) having the ethanol to water ratio of about 1:1 in order to obtain the clarithromycin.    
   
   
       2 . The method of  claim 1 , wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.  
   
   
       3 . The method of  claim 1 , wherein the cooling is to about 20° C.  
   
   
       4 . The method of  claim 1 , wherein the acid is formic acid.  
   
   
       5 . The method of  claim 1 , wherein the deoximating agent is sodium metabisulfite.  
   
   
       6 . The method of  claim 1 , wherein no additional water is added in step c).  
   
   
       7 . The method of  claim 1 , further comprising isolating the clarithromycin after step c).  
   
   
       8 . Clarithromycin formed by a process comprising: 
 a) converting erythromycin A to 2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime;    b) reacting 2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with methylating agent while stirring in the presence of at least one solvent and a base, wherein the at least one solvent comprises methyl tertbutyl ether, to form 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime;    c) reacting the 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with an acid and a deoximating agent in the presence of aqueous ethanol at an ethanol to water ratio of about 1:1 to form a reaction mixture;    d) cooling the reaction mixture to about 15° C. to about 25° C.;    e) adding sodium hydroxide to the cooled reaction mixture of step d) having the ethanol to water ratio of about 1:1; and    f) obtaining crystalline clarithromycin from the product of step e).    
   
   
       9 . The clarithromycin of  claim 8 , wherein the methylating agent is selected from the group consisting of methyl iodide, methyl bromide, dimethylsulfate, methyl p-toluenesulfonate, and methanesulfonate.  
   
   
       10 . The clarithromycin of  claim 8 , wherein the base is selected from the group consisting of sodium hydride, potassium hydroxide, and sodium hydroxide.  
   
   
       11 . Clarithromycin as prepared by a process comprising: 
 a) converting erythromycin A to protected silylated clarithromycin oxime wherein the C-2′ and C-4″ hydroxy of the protected silylated clarithromycin oxime are silylated;    b) reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture;    c) cooling the reaction mixture to about 15° C. to about 25° C.;    d) adding sodium hydroxide solution to the reaction mixture of step c) having the ethanol to water ratio of about 1:1; and    e) obtaining crystalline clarithromycin from the product of step d).    
   
   
       12 . The clarithromycin of  claim 11 , wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.  
   
   
       13 . The clarithromycin of  claim 11 , wherein the cooling is to about 20° C.  
   
   
       14 . The clarithromycin of  claim 11 , wherein the acid is formic acid.  
   
   
       15 . The clarithromycin of  claim 11 , wherein the deoximating agent is sodium metabisulfite.  
   
   
       16 . A method of converting erythromycin A to clarithromycin comprising: 
 a) reacting C-2′ and C-4″ silylated, protected erythromycin A oxime with a methylating agent and a base while stirring in a solvent comprising methyl tertbutyl ether, to form C-2′ and C-4″ silylated clarithromycin oxime;    b) reacting the C-2′ and C-4″ silylated clarithromycin oxime with acid and a deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture;    c) cooling the reaction mixture to about 15° C. to about 25° C.;    d) adding sodium hydroxide to the product of step c) having the ethanol to water ratio of about 1:1; and    e) isolating the clarithromycin from the product of step d).    
   
   
       17 . A method of converting erythromycin A to clarithromycin comprising: 
 a) reacting C-2′ and C-4″ silylated erythromycin A oxime with a methylating agent and a base while stirring in a solvent comprising methyl tertbutyl ether, to form C-2′ and C-4″ silylated, protected clarithromycin oxime;    b) reacting the C-2′ and C-4″ silylated, clarithromycin oxime with an acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form the clarithromycin;    c) cooling the reaction mixture of step b) to about 20C; and    d) adding sodium hydroxide to the product of step c) having the ethanol to water ratio of about 1:1 in order to obtain the clarithromycin, wherein essentially no additional water is added to process the clarithromycin.    
   
   
       18 . The method of  claim 17 , wherein the protected silylated clarithromycin oxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxy prop-2-yl) oxime.