Purification of rapamycin derivatives using temperature induced phase separation

摘要

The present invention provides methods for obtaining purified rapamycin derivatives, including purified Biolimus A9. A crystalline form of Biolimus A9 is also described.

主权项

1. A method for obtaining a purified, solid compound having a structure according to Formula I: wherein R1 is selected from the group consisting of Ra—(O)d—Rb, wherein Ra is C1-5alkylene, Rb is C1-5alkyl or C1-5alkylene-OH, and the subscript d is an integer selected from 0-1; C1-5alkyl; C6-10arylC1-5alkylene; hydroxyC1-5alkylene; C1-5alkoxyC1-5alkylene; acyl; acylC1-5alkylene; aminoC1-5alkylene; C1-5alkylaminoC1-5alkylene; acylaminoC1-5alkylene; C1-5alkoxycarbonylaminoC1-5alkylene; and C6-10aryl; the method comprising: a) forming a mixture consisting essentially of a crude compound having a structure according to Formula I and a non-polar organic solvent under conditions sufficient to dissolve the compound, wherein the dielectric constant of the non-polar organic solvent is less than about 5, and wherein forming the mixture comprises heating the mixture; b) solidifying at least a portion of the compound having the structure according to Formula I, wherein the solidifying comprises cooling the mixture; and c) separating at least a portion of the solidified compound from the solvent in the mixture; thereby obtaining the purified, solid compound.