Process for preparation of mycophenolic acid and ester derivatives thereof

Abstract

Provided are processes for preparation of mycophenolic acid.

1 . A process for isolating mycophenolic acid comprising the steps of:
 a) providing a concentrated alkaline mixture containing mycophenolic acid;   b) admixing the mixture with a first water-immiscible solvent to form an aqueous phase and a first water-immiscible phase;   c) separating the aqueous phase;   d) admixing the aqueous phase with a second water-immiscible solvent at a pH of less than about 7 to form an aqueous phase and a second water-immiscible phase;   e) separating the second water-immiscible phase;   f) concentrating the second water-immiscible phase; and   g) crystallizing mycophenolic acid.   
   
   
       2 . The process of  claim 1 , wherein the admixing of step (b) is at a pH of about 8 to about 11. 
   
   
       3 . The process of  claim 1 , wherein the pH is adjusted with ammonium hydroxide or sodium hydroxide. 
   
   
       4 . The process of  claim 1 , wherein at least one of the first or second water-immiscible solvents is a C 4  to C 7  ester, C 4  to C 7  ketone, or mixtures thereof. 
   
   
       5 . The process of  claim 1 , wherein at least one of the first or second water-immiscible solvents is ethylacetate, isobutylacetate, n-butylacetate, or mixtures thereof. 
   
   
       6 . The process of  claim 1 , wherein the first or second water-immiscible solvent is ethylacetate. 
   
   
       7 . The process of  claim 1  wherein the aqueous phase in step (c) is further extracted at least once by repeating step (b). 
   
   
       8 . The process of  claim 1 , wherein the pH of step (d) is about 5 to about 6.5. 
   
   
       9 . The process of  claim 1 , wherein the pH of step (d) is adjusted with at least one of sulfuric acid, phosphoric acid, or hydrochloric acid. 
   
   
       10 . The process of  claim 1 , wherein the aqueous phase in step (d) is further extracted at least once by repeating step (d). 
   
   
       11 . The process of  claim 1 , wherein the concentrating in step (f) is carried out by distillation. 
   
   
       12 . The process of  claim 1 , wherein the concentrating in step (f) is carried out by filtration. 
   
   
       13 . The process of  claim 12 , wherein the filtration is carried out by membrane filtration. 
   
   
       14 . The process of  claim 13 , wherein the filtration membrane is a plastic filtration membrane. 
   
   
       15 . The process of  claim 1 , wherein the crystallization is carried out by cooling the concentrate. 
   
   
       16 . The process of  claim 1 , wherein the obtained mycophenolic acid has a purity of at least about 99.5% as measured by HPLC area percentage. 
   
   
       17 . The process of  claim 1 , wherein the concentrated alkaline mixture containing mycophenolic acid is prepared by whole broth extraction. 
   
   
       18 . The process of  claim 1 , wherein the concentrated alkaline mixture containing mycophenolic acid is obtained by a process comprising the steps of:
 a) basifying a fermentation broth containing mycophenolic acid and removing mycelia to obtain a basic mixture;   b) acidifying the basic mixture to obtain an acidic mixture; and   c) filtering and basifying the acidic mixture to obtain the concentrated alkaline mixture.