Process for the production of clavulanic acid salts

Abstract

Use of the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid as an intermediate in the production of pharmaceutically acceptable salts of clavulanic acid.

1. A process for the production of a pharmaceutically acceptable salt of clavulanic acid, which comprises forming the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid and converting this salt into a pharmaceutically acceptable salt of clavulanic acid. 
     
     
       2. A process for the production of a pharmaceutically acceptable salt of clavulanic acid, which comprises the steps of:
 a) treating a solution of clavulanic acid in an organic solvent with 2-amino-2,4,4-trimethylpentane;  
 b) isolating the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid; and  
 c) converting the obtained 2-amino-2,4,4-trimethylpentane salt of clavulanic acid into a pharmaceutically acceptable salt of clavulanic acid.  
 
     
     
       3. A process for the production of a pharmaceutically acceptable salt of clavulanic acid, comprising converting the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid into a pharmaceutically acceptable salt of clavulanic acid. 
     
     
       4. A process of  claim 1 , wherein the pharmaceutically acceptable salt of clavulanic acid is an alkali or alkaline earth metal salt of clavulanic acid. 
     
     
       5. A process of  claim 4 , wherein the salt is an alkali salt. 
     
     
       6. A process of  claim 4 , wherein the salt is the potassium salt. 
     
     
       7. A process of  claim 2 , wherein the organic solvent is a ketone, an alcohol, or an ester which is immiscible or only partly miscible in water. 
     
     
       8. A process of  claim 7 , wherein the organic solvent is diethyl ketone, cyclohexanone, methyl isobutyl ketone, cyclohexanol, n-butanol, ethyl acetate, or n-butyl acetate. 
     
     
       9. A process of  claim 2 , wherein, in step a), the solution of clavulanic acid is obtained by extracting a fermentation broth, or a filtrate thereof, with an organic solvent. 
     
     
       10. A process of  claim 9 , wherein the organic solvent is diethyl ketone, cyclohexanone, methyl isobutyl ketone, cyclohexanol, n-butanol, ethyl acetate, or n-butyl acetate. 
     
     
       11. A process for the production of a pharmaceutically acceptable salt of clavulanic acid, which comprises the steps of:
 a) treating a solution of clavulanic acid in an organic solvent with 2-amino-2,4,4-trimethylpentane;  
 b) isolating the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid;  
 c) recrystallizing the product of step b); and  
 d) converting the product of step c) into a pharmaceutically acceptable salt of clavulanic acid.  
 
     
     
       12. A process of  claim 11 , wherein the product of step b) is recrystallized by dissolving said product in alcohol, water, or a mixture of water and a water-miscible organic solvent. 
     
     
       13. A process of  claim 12 , wherein the alcohol is methanol, ethanol, or isopropanol. 
     
     
       14. A process of  claim 12 , wherein the water-miscible organic solvent is isopropanol, tetrahydrofuran, or acetone. 
     
     
       15. A process of  claim 12 , wherein recrystallization is effected by the addition of tetrahydrofuran, acetone, diethyl ketone, methyl isobutyl ketone, methyl t-butyl ether, or n-butyl acetate to said dissolved 2-amino-2,4,4-trimethylpentane salt of clavulanic acid. 
     
     
       16. A process of  claim 2 , wherein the product of step b) is a crystalline solid. 
     
     
       17. A method which comprises using the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid as an intermediate in the production of a pharmaceutically acceptable salt of clavulanic acid. 
     
     
       18. A process of  claim 2 , wherein said converting is in a non-aqueous medium. 
     
     
       19. In a process of  claim 2 , the steps which comprise:
 a) mixing a dried methyl isobutyl ketone solution which contains clavulanic acid with 2-amino-2,4,4-trimethylpentane;  
 b) stirring said mixture at room temperature for 30 minutes; and  
 c) cooling said stirred mixture to 5° C. and stirring for 2 hours at 5° C. to isolate the crystalline 2-amino-2,4,4-trimethylpentane salt of clavulanic acid.  
 
     
     
       20. In a process of  claim 2 , the steps which comprise:
 a) mixing a dried ethyl acetate solution which contains clavulanic acid with 2-amino-2,4,4- trimethylpentane in ethyl acetate;  
 b) stirring said mixture at room temperature for 30 minutes; and  
 c) cooling said stirred mixture to 15° C. and stirring for 3 hours at 15° C. to isolate the crystalline 2-amino-2,4,4-trimethylpentane salt of clavulanic acid.  
 
     
     
       21. In a process of  claim 2 , the steps which comprise:
 a) adding 2-amino-2,4,4-trimethylpentane to a dried ethyl acetate solution of clavulanic acid, which has been obtained by extraction of a fermentation broth with ethyl acetate and concentrating the organic layer by vacuum distillation;  
 b) stirring said mixture at room temperature for 2 hours; and  
 c) cooling said stirred mixture to 5° C. and stirring overnight at 5° C. to isolate the crystalline 2-amino-2,4,4-trimethylpentane salt of clavulanic acid.  
 
     
     
       22. In a process of  claim 2 , the steps which comprise:
 a) dissolving the 2-amino-2,4,4-trimethylpentane salt of clavulanic acid in isopropanol at 20° C.;  
 b) adding a solution of potassium-2-ethylhexanoate in isopropanol;  
 c) stirring said mixture for 30 minutes at 20° C.; and  
 d) cooling said stirring mixture for 2 hours to 0-5° C. to produce crystalline potassium clavulanate.