Purification process

Abstract

This invention a process for purifying a cyclosporin, e.g. cyclosporin A, or a macrolide, to a high degree of purity on a large scale. In another aspect this invention provides a bulk quantity of cyclosporin A with an impurity level of less than about 0.7%, e.g. about 0.5%, and composition thereof.

1 - 10 . (canceled)  
   
   
       11 . A process for purifying on a large scale a product from a feedstock containing one or more impurities having closely-related physical properties to the product, which process comprises: 
 feeding the feedstock into an extraction column under conditions adapted for separating more- or less-polar impurities from the feedstock, wherein a lighter phase flows counter to a heavier phase, thereby forming an output in one phase containing the product containing less more- or less-polar impurities so that the output contains the product in a substantially purified form, wherein the lighter phase comprises heptane and acetone or heptane and isopropanol, the heavier phase comprises water and acetone or water and isopropanol, and the product is a rapamycin or an ascomycin.    
   
   
       12 . A process of  claim 11 , wherein the lighter phase comprises about 25 wt-% n-heptane and about 75 wt-% acetone, or about 90 wt-% n-heptane and about 10 wt-% isopropanol.  
   
   
       13 . A process of  claim 11 , wherein the heavier phase comprises about 50 wt-% water and about 50 wt-% acetone, or about 68 wt-% water and about 32 wt-% isopropanol.  
   
   
       14 . A process for purifying on a large scale a product from a feedstock containing one or more impurities having closely-related physical properties to the product, which process comprises the steps of 
 a) feeding the feedstock into a first extraction column under conditions adapted for separating more- or less-polar impurities from the feedstock, wherein a lighter phase flows counter to a heavier phase, thereby forming a first output in one phase containing the product containing less more- or less-polar impurities, and    b) feeding the first output into a second extraction column under conditions adapted for separating less- or more-polar impurities respectively from the first output, wherein the lighter phase flows counter to the heavier phase, thereby forming in one phase a second output, so that the second output contains the product in a substantially purified form, wherein the lighter phase comprises heptane and acetone or heptane and isopropanol, the heavier phase comprises water and acetone or water and isopropanol, and the product is a cyclosporin.    
   
   
       15 . A process of  claim 14 , wherein the lighter phase comprises about 25 wt-% n-heptane and about 75 wt-% acetone, or about 90 wt-% n-heptane and about 10 wt-% isopropanol.  
   
   
       16 . A process of  claim 14 , wherein the heavier phase comprises about 50 wt-% water and about 50 wt-% acetone, or about 68 wt-% water and about 32 wt-% isopropanol.  
   
   
       17 . A process of  claim 11 , wherein the product is rapamycin, 40-O-(2-hydroxy)ethyl rapamycin, ascomycin, 33-epi-chloro-33-desoxyascomycin, or FK506.  
   
   
       18 . A countercurrent extraction column having between 100 and 200 compartments, and an overall efficiency of about 10 to 30%.  
   
   
       19 . A product which is a rapamycin or an ascomycin produced by a process of  claim 11 .  
   
   
       20 . A product of  claim 19  which is rapamycin, 40-O-(2-hydroxy)ethyl rapamycin, ascomycin, 33-epi-chloro-33-desoxyascomycin, or FK506.  
   
   
       21 . A product which is a rapamycin or an ascomycin produced by a process of  claim 14 .  
   
   
       22 . A product of  claim 21  which is rapamycin, 40-O-(2-hydroxy)ethyl rapamycin, ascomycin, 33-epi-chloro-33-desoxyascomycin, or F