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 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;
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl; and
P 1 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;
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl;
R 2 is cyano; and
P 1 is a protecting group.
2. The process according to claim 1 , wherein said composition comprises an enantiomeric excess of a (R)- or (S)-enantiomer of the compound of Formula Ia; and said hydrogenation catalyst is a ruthenium or rhodium catalyst having L 1 ; wherein L 1 is a chiral phosphine ligand.
3. The process according to claim 2 , wherein said enantiomeric excess is equal to or greater than about 90%.
4. The process according to claim 2 , wherein said enantiomeric excess is equal to or greater than about 99%.
5. The process according to claim 2 , wherein said chiral phosphine ligand is selected from one of the following:
6. The process according to claim 2 , wherein said composition comprises an enantiomeric excess of the (S)-enantiomer of the compound of Formula Ia.
7. The process according to claim 6 , wherein L 1 is selected from one of the following ligands:
8. The process according to claim 2 , wherein said composition comprises an enantiomeric excess of the (R)-enantiomer of the compound of Formula Ia.
9. The process according to claim 8 , wherein L 1 is selected from one of the following ligands:
10. 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;
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl; and
P 1 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;
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl;
R 2 is —C(═O)—NH 2 ; and
P 1 is a protecting group.
11. The process according to claim 10 , wherein said dehydrating conditions comprises trichloroacetyl chloride in the presence of triethylamine.
12. The process according to claims 1 or 10 , wherein P 1 is —CH 2 OC(═O)C(CH 3 ) 3 or —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 .
13. The process according to claims 1 or 10 , wherein R 1 is cyclopentyl.
14. 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;
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl; and
P 1 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;
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.
15. The process according to claim 14 , wherein said first base is cesium carbonate.
16. The process according to claim 14 , wherein said second base is 1,8-diazabicyclo undec-7-ene (DBU).
17. 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;
R 1 is selected from C 3-7 cycloalkyl, C 1-6 alkyl, and C 1-6 fluoroalkyl; and
P 1 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;
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.
18. The process according to claim 17 , wherein said base is potassium t-butoxide.
19. The process according to claims 14 or 17 wherein the mobile phase comprises isopropanol and hexanes, wherein said isopropanol is present in an amount of about 25% to about 10% by volume.
20. The process according to claims 14 or 17 wherein said chromatography unit is a stimulated moving bed (SMB) chromatography unit equipped with a set of eight columns or a chiral column unit, wherein each column is packed with a chiral stationary phase.
21. The process according to claims 14 or 17 , wherein P 1 is —CH 2 C(═O)C(CH 3 ) 3 or —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 .
22. The process according to claims 14 or 17 , wherein R 1 is cyclopentyl.
23. The process according to claims 1 , 10 , 14 or 17 , wherein said compound of Formula III is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.
24. The process according to claim 23 , further comprising reacting the compound of Formula III with phosphoric acid to form a phosphate salt of said compound of Formula III.
25. The process according to any of claims 1 , 10 , 14 , or 17 , wherein R 1 is n-butyl or n-pentyl.