Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate
AssigneeWyeth
InventorsChunhao Zhang, Clifford William Coughlin, Anthony Pilcher, Adam P. Michaud, James S. Farina, Ayman Sahli
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Abstract
A scalable process for the preparation of a rapamycin 42-ester by reacting a rapamycin 42-ester boronate with a diol and purifying crude rapamycin 42-ester by recrystallization and treatment with a diol is provided. Also provided is a method for isolating and purifying a rapamycin 42-ester boronate from mother liquors comprising acetone and rapamycin contaminants.
Claims30
A process for preparing a rapamycin 42-ester, the process comprising:
- (a) reacting a rapamycin 42-ester boronate with a first diol in diethyl ether/heptanes at about 30° C. to about 40° C.;
- (b) isolating the solid from step (a);
- (c) recrystallizing the solid of (b);
- and
- (d) treating the product of step (c) with a second diol.
A method of purifying crude rapamycin 42-ester boronate from a mixture comprising the rapamycin 42-ester boronate, rapamycin, and at least one solvent, the method comprising:
- (a) heating a mixture comprising the crude rapamycin 42-ester boronate and a solvent for at least about 1 hour;
- (b) cooling the mixture of step (a);
- (c) stirring the mixture of step (b) for at least about 6 hours
- (d) concentrating the mixture of step (c) to form a concentrated slurry;
- (e) treating the mixture of step (d) with an ether;
- (f) isolating the precipitate from step (e);
- (g) purifying the product of step (f);
- (h) optionally repeating steps (a)-(g).
A method of purifying rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) boronate, the method comprising:
- (a) heating to reflux a mixture comprising crude CCI-779 and a solvent comprising acetone;
- (b) cooling the mixture of step (a) to room temperature;
- (c) stirring the mixture of step (b) for at least about 6 hours;
- (e) removing at least about half of the solvent to form a concentrated CCI-779 boronate slurry;
- (e) treating the concentrated slurry of step (e) with diethyl ether;
- (f) recovering the solid product of step (e);
- and
- (g) repeating steps (a)-(f) at least once.
A process for preparing a rapamycin 42-ester, the process comprising:
- (a) reacting a rapamycin 42-ester boronate with a first diol in diethyl ether/heptanes at about 30° C. to about 40° C.;
- (b) isolating the solid from step (a);
- (c) treating the product of step (b) with a second diol;
- and
- (d) recrystallizing the product of step (c).
Dependencies are inferred from the claim text.