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US 9,000,161 B2Granted
Processes for preparing JAK inhibitors and related intermediate compounds
AssigneeIncyte Corporation
InventorsJiacheng Zhou, Pingli Liu, Qiyan Lin, David Meloni, Yongchun Pan, Michael Xia, Mei Li, Tai-Yuen Yue, Brian W. Metcalf
Life of this patent
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Abstract
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.
Claims25
A process of preparing a compound of Formula III:
- comprising reacting a composition comprising a compound of Formula Ia:
- under deprotection conditions to form a compound of Formula III;
- wherein:
- * is a chiral carbon;
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl;
- and
- P1 is a protecting group,
- wherein the composition comprising the compound of Formula Ia:
- is formed by reacting a compound of Formula II:
- with hydrogen gas in the presence of a hydrogenation catalyst;
- wherein:
- * indicates a chiral carbon;
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl;
- R2 is cyano;
- and
- P1 is a protecting group.
13 more elements
A process of preparing a compound of Formula III:
- comprising reacting a compound of Formula Ia:
- under deprotection conditions to form a compound of Formula III;
- wherein:
- * is a chiral carbon;
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl;
- and
- P1 is a protecting group,
- wherein the compound of Formula Ia:
- is formed by reacting a compound of Formula I under dehydrating conditions:
- wherein:
- * indicates a chiral carbon;
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl;
- R2 is —C(═O)—NH2;
- and
- P1 is a protecting group.
12 more elements
A process of preparing a compound of Formula III:
- comprising reacting an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia:
- under deprotection conditions to form a compound of Formula III;
- wherein:
- * is a chiral carbon;
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl;
- and
- P1 is a protecting group,
- wherein the enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia:
- is prepared by passing a composition comprising a racemate of a compound of Formula Ia through a chiral chromatography unit using a mobile phase and collecting the composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia;
- wherein:
- the process of preparing said composition comprising a racemate of a compound of Formula Ia:
- comprises:
- (a) treating a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia with a compound of Formula D-1:
- in the presence of a first base under conditions sufficient to form a compound of Formula IV:
- and
- (b) reacting a compound of Formula IV with a compound of Formula D-1 in the presence of a second base;
- and
- wherein:
- * is a chiral carbon;
- P1 is a protecting group;
- and
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl.
19 more elements
A process of preparing a compound of Formula III:
- comprising reacting an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia:
- under deprotection conditions to form a compound of Formula III;
- wherein:
- * is a chiral carbon;
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl;
- and
- P1 is a protecting group,
- wherein the enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia:
- is prepared by passing a composition comprising a racemate of a compound of Formula Ia through a chiral chromatography unit using a mobile phase and collecting a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia;
- wherein:
- the process of preparing said composition comprising a racemate of a compound of Formula Ia:
- comprises treating a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia with a compound of Formula D-1:
- in the presence of a base under conditions sufficient to form said racemate of said compound of Formula Ia;
- and
- wherein:
- * is a chiral carbon;
- P1 is a protecting group;
- and
- R1 is selected from C3-7 cycloalkyl, C1-6 alkyl, and C1-6 fluoroalkyl.
16 more elements
Dependencies are inferred from the claim text.