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 - 105 . (canceled)
106 . A compound of Formula Ia:
or a pharmaceutically acceptable salt thereof;
wherein:
* is a chiral carbon;
P 1 is a protecting group; and
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl.
107 . The compound of claim 106 , wherein P 1 is —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 .
108 . The compound of claim 106 , wherein R 1 is C 3-7 cycloalkyl.
109 . The compound of claim 106 , wherein R 1 is cyclopentyl.
110 . The compound of claim 106 , wherein the compound of Formula Ia is a compound of Formula I″:
or a pharmaceutically acceptable salt thereof.
111 . 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 tosylate, triflate, iodo, chloro, or bromo;
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 1-4 alkyl groups; and
P 1 is —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 ; and
P 2 is 1-(ethoxy)ethyl.
112 . The process according to claim 111 , wherein 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 1-4 alkyl groups.
113 . The process according to claim 111 , wherein said compound of Formula XIII has the formula:
114 . The process according to claim 111 , wherein the process further comprises preparing a compound of Formula IV:
comprising reacting the compound of Formula XII:
with an acid to produce the compound of Formula IV;
wherein:
P 1 is —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 ; and
P 2 is 1-(ethoxy)ethyl.
115 . The process according to claim 114 , wherein the acid is hydrochloric acid.
116 . The process according to claim 114 , wherein the process further comprises preparing a compound of Formula Ia:
comprising:
reacting the compound of Formula IV with a compound of Formula D-1:
in the presence of a base to form a compound of Formula Ia;
wherein:
* is a chiral carbon;
P 1 is —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 ; and
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl.
117 . The process according to claim 116 , wherein said base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
118 . The process according to claim 116 , further comprising reacting said compound of Formula Ia under deprotection conditions to form a compound of Formula III:
wherein
* is a chiral carbon; and
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl.
119 . The process according to claim 116 , wherein R 1 is cyclopentyl.
120 . The process according to claim 118 , wherein R 1 is cyclopentyl.