Process for preparing enantiomerically enriched substituted pyrrolo[2,3-d]pyrimidines
Improved processes for preparing enantiomerically enriched intermediates for the synthesis of ruxolitinib and deuterated forms of ruxolitinib and deuterated analogs of ruxolitinib of Formula I: wherein, Y 1 is hydrogen or deuterium; each Y 2 is the same and is hydrogen or deuterium; and each Y 3 is the same and is hydrogen or deuterium are disclosed. Certain aspects are also directed to deuterated intermediates useful in the synthesis of deuterated forms of ruxolitinib. Certain aspects are also directed to reaction mixtures for preparing enantiomerically enriched intermediates useful in the synthesis of ruxolitinib and deuterated forms of ruxolitinib.
1 . A process for preparing a compound of Formula I:
wherein:
Y 1 is H or D;
each Y 2 is H or D, wherein each Y 2 is identical;
each Y 3 is H or D, wherein each Y 2 is identical; and
(i) PG is H; or
(ii) PG is a protecting group selected from:
wherein the process comprises:
(a) reacting a compound of Formula II:
wherein each of Y 1 , Y 2 , Y 3 , and PG in Formula II is defined as in Formula I;
with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand, (L), according to Formula III:
wherein:
R 2a is independently H, CH 3 , CF 3 , or OCH 3 ;
R 2b is independently H, CH 3 , CF 3 , or OCH 3 ;
R 3a is independently H, CH 3 , CF 3 , or OCH 3 ;
R 3b is independently H, CH 3 , CF 3 , or OCH 3 ;
R 4 is independently H, CH 3 , CF 3 , or OCH 3 ; and
R 5 is independently alkyl or cycloalkyl, wherein alkyl is independently secondary or tertiary;
to provide the compound of Formula I above; or
(b) reacting a compound of Formula VII:
wherein each of Y 2 , Y 3 , and PG in Formula VII is defined as in Formula I;
with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand according to Formula VI:
wherein:
each of R 2a , R 2b , R 3a , R 3b , and R 4 in Formula VI is defined as in Formula III; and
each R 5a is phenyl;
to provide the compound of Formula I above; or
(c) reacting a compound of Formula VII:
wherein each of Y 2 , Y 3 , and PG in Formula VII is defined as in Formula I;
with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand according to Formula VIII:
wherein:
each of R 2a , R 2b , R 3a , R 3b , and R 4 in Formula VIII is defined as in Formula III; and
each R 5a is C(CH 3 ) 3 ;
to provide the compound of Formula I above.
2 . The process according to claim 1 , wherein:
(a) Y 1 is H;
each Y 2 is H; and
each Y 3 is H; or
(b) Y 1 is H;
each Y 2 is D; and
each Y 3 is D.
3 . The process according to claim 1 , wherein:
(i) PG is H; or
(ii) PG is
4 . The process according to claim 1 , wherein:
(a) R 2a is independently H;
R 2b is independently H;
R 3a is independently H;
R 3b is independently H; and
R 4 is independently H; or
(b) R 2a is independently H;
R 2b is independently H;
R 3a is independently CH 3 or CF 3 ;
R 3b is independently CH 3 or CF 3 ; and
R 4 is independently H; or
(c) R 2a is independently H;
R 2b is independently H;
R 3a is independently CH 3 ;
R 3b is independently CH 3 ; and
R 4 is independently OCH 3 ; or
(d) R 2a is independently H;
R 2b is independently H;
R 3a is independently H;
R 3b is independently H; and
R 4 is independently CH 3 , CF 3 , or OCH 3 ; or
(e) R 2a is independently H;
R 2b is independently CH 3 ;
R 3a is independently H;
R 3b is independently H; and
R 4 is independently H.
5 . The process according to claim 1 , wherein R 5 is independently C(CH 3 ) 3 , cyclopentyl, cyclohexyl, or norbornyl.
6 . The process according to claim 1 , wherein:
R 2a is independently H;
R 2b is independently H;
R 3a is independently H;
R 3b is independently H;
R 4 is independently H; and
R 5 is independently cyclohexyl or norbornyl.
7 . The process according to claim 1 , wherein the process comprises:
(a) reacting a compound of Formula II:
wherein each of Y 1 , Y 2 , Y 3 , and PG in Formula II is defined as in Formula I;
with hydrogen gas in the presence of a hydrogenation catalyst comprising rhodium and a chiral phosphine ligand, (L), according to Formula III:
wherein:
R 2a is independently H, CH 3 , CF 3 , or OCH 3 ;
R 2b is independently H, CH 3 , CF 3 , or OCH 3 ;
R 3a is independently H, CH 3 , CF 3 , or OCH 3 ;
R 3b is independently H, CH 3 , CF 3 , or OCH 3 ;
R 4 is independently H, CH 3 , CF 3 , or OCH 3 ; and
R 5 is independently alkyl or cycloalkyl, wherein alkyl is independently secondary or tertiary;
wherein the hydrogenation catalyst comprising rhodium and the chiral phosphine ligand, (L), according to Formula III is formed by mixing the chiral phosphine ligand, (L), according to Formula III above with a rhodium pre-catalyst of the following formula:
[Rh(L 1 )(L 2 )] + NC − ,
wherein:
(i) L 1 is a pair of monodentate ligands, wherein the pair of monodentate ligands is a pair of identical alkene ligands or a pair of identical solvent ligands; or L 1 is a bidentate ligand, wherein the bidentate ligand is a diene ligand;
(ii) L 2 is a pair of monodentate ligands, wherein the pair of monodentate ligands is a pair of identical alkene ligands or a pair of identical solvent ligands; or
L 2 is a bidentate ligand, wherein the bidentate ligand is a diene ligand; and
NC − is a non-coordinating counterion selected from the group consisting of BF 4 − , OS(O) 2 CF 3 , PF 6 − , SbF 6 − , and ClO 4 − .
8 . The process according to claim 7 , wherein:
(1) the step of reacting is optionally performed in a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, trifluoroethanol, isopropanol, ethyl acetate, and isopropyl acetate, or a mixture thereof; or
(2) the hydrogen gas is present at a pressure of 20 bar or less; or
(3) L 1 is a pair of identical alkene ligands selected from the group consisting of ethylene, cyclooctene, and norbornene; or
L 1 is a pair of identical solvent ligands selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, trifluoroethanol, and isopropanol; or
L 1 is a bidentate ligand selected from the group consisting of 1,5-cyclooctadiene (COD), 1,5-hexadiene, and norbornadiene; and
L 2 is a pair of identical alkene ligands selected from the group consisting of ethylene, cyclooctene, and norbornene; or
L 2 is a pair of identical solvent ligands selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, trifluoroethanol, and isopropanol; or
L 2 is a bidentate ligand selected from the group consisting of 1,5-cyclooctadiene (COD), 1,5-hexadiene, and norbornadiene; or
(4) the hydrogenation catalyst comprises [Rh(L 1 )(L 2 )] + BF 4 − wherein:
(a) L 1 is a pair of monodentate ligands, wherein the pair of monodentate ligands is a pair of identical alkene ligands or a pair of identical solvent ligands; or
L 1 is a bidentate ligand, wherein the bidentate ligand is a diene ligand; and
(b) L 2 is or
(5) the hydrogenation catalyst comprises [Rh(L 1 )(L 2 )] + BF 4 − wherein:
(a) L is a pair of monodentate ligands, wherein the pair of monodentate ligands is a pair of identical alkene ligands or a pair of identical solvent ligands; or
L 1 is a bidentate ligand, wherein the bidentate ligand is a diene ligand; and
(b) L 2 is or
(6) the rhodium pre-catalyst is [Rh(COD) 2 ] + BF 4 − ; or
(7) the compound of Formula I has an enantiomeric excess of the (R)-enantiomer of at least 90%; or
(8) the compound of Formula I has an enantiomeric excess of the (R)-enantiomer of at least 95%; or
(9) the compound of Formula I has an enantiomeric excess of the (R)-enantiomer of at least 97%.
9 . The process according to claim 8 , wherein the step of reacting is performed in a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, trifluoroethanol, isopropanol, ethyl acetate, and isopropyl acetate, or a mixture thereof.
10 . The process according to claim 8 , wherein the hydrogen gas is present at a pressure of 10 bar or less.