Processes for preparing JAK inhibitors and related intermediate compounds
The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
1. A process of preparing a compound of Formula XII:
comprising reacting a compound of Formula X:
with a compound of Formula XIII:
in the presence of a palladium catalyst, base, and a solvent, to form a compound of Formula XII;
wherein:
X 2 is a tosylate group, a triflate group, iodo, chloro, or bromo; and
R c and R d are each independently H or C 1-6 alkyl; or
R c and R d , together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C 14 alkyl groups;
P 1 is independently a protecting group; and
P 2 is a protecting group selected from the group consisting of 1-(ethoxy)ethyl, p-methoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, methoxymethyl, and t-butyldimethylsilylmethyl.
2. A process according to claim 1 , wherein said compound of Formula XIII has formula:
3. A process according to claim 1 to 2 , wherein P 1 is —CH 2 OC(═O)C(CH 3 ) 3 or —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 .
4. A process according to any one of claims 1 to 3 , wherein P 2 is 1 -(ethoxy)ethyl.