US 12,247,030 B2
Process for preparing compositions comprising an enantiomeric excess of a substituted pyrrolo[2,3-d]pyrimidine
Jiacheng Zhou, Newark, DE (US); David Meloni, Bear, DE (US); Yongchun Pan, Newark, DE (US); and Mei Li, Newark, DE (US)
Assigned to Incyte Holdings Corporation, Wilmington, DE (US); and Incyte Corporation, Wilmington, DE (US)
Filed by Incyte Holdings Corporation, Wilmington, DE (US); and Incyte Corporation, Wilmington, DE (US)
Filed on Feb. 16, 2021, as Appl. No. 17/176,914.
Application 17/176,914 is a division of application No. 16/436,195, filed on Jun. 10, 2019, granted, now 10,975,085.
Application 16/436,195 is a division of application No. 15/869,650, filed on Jan. 12, 2018, granted, now 10,364,248, issued on Jul. 30, 2019.
Application 15/869,650 is a division of application No. 15/016,918, filed on Feb. 5, 2016, granted, now 9,908,888, issued on Mar. 6, 2018.
Application 15/016,918 is a division of application No. 14/593,688, filed on Jan. 9, 2015, granted, now 9,290,506, issued on Mar. 22, 2016.
Application 14/593,688 is a division of application No. 13/761,830, filed on Feb. 7, 2013, granted, now 8,993,582, issued on Mar. 31, 2015.
Application 13/761,830 is a division of application No. 12/687,623, filed on Jan. 14, 2010, granted, now 8,410,265, issued on Apr. 2, 2013.
Claims priority of provisional application 61/144,991, filed on Jan. 15, 2009.
Prior Publication US 2021/0253584 A1, Aug. 19, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/519 (2006.01); C07D 487/04 (2006.01); C07F 5/02 (2006.01); C07F 7/08 (2006.01); C07F 7/10 (2006.01); C07F 7/18 (2006.01)
CPC C07D 487/04 (2013.01) [C07F 5/025 (2013.01); C07F 7/083 (2013.01); C07F 7/10 (2013.01); C07F 7/1892 (2013.01); Y02P 20/55 (2015.11)] 10 Claims
 
1. A process for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer or(S)-enantiomer of a compound of Formula Ia:

OG Complex Work Unit Chemistry
wherein:
R1 is C1-6 alkyl, C1-6 fluoroalkyl, or C3-7 cycloalkyl;
P1 is CH2OH, CH2OCH3, CH2OC(CH3)3, CH2OCH2-phenyl, CH2OCH2CH2Si(CH3)3, CH2OC(O)C(CH3)3, CH(OCH2CH3)2, CH2Si(CH3)2C(CH3)3, CH2-phenyl, CH2-(4-methoxyphenyl), CH2-(2-nitrophenyl), CH2-(4-nitrophenyl), CH(phenyl)2, C(phenyl)3, C(phenyl)2-pyrid-4-yl, CH(OCH2CH3)CH3, CH2CH2Cl, CH2CH2S(O)2-phenyl, CH═CH2, CH2CH═CH2, C(O)OC[CH(CH3)2]2, C(O)OCH2CCl3, C(O)OC(CH3)3, C(O)OC(CH3)2CCB, C(O)OCH2-phenyl, C(O)OCH2CH2Si(CH3)3, C(O)OCH2CH2S(O)2-(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH3)2, or tetrahydropyran-2-yl; and
* is a chiral carbon;
wherein the process comprises the following steps:
(a) reacting a composition comprising a racemate of a compound of Formula Ia:

OG Complex Work Unit Chemistry
wherein:
R1 is C1-6 alkyl, C1-6 fluoroalkyl, or C3-7 cycloalkyl;
P1 is CH2OH, CH2OCH3, CH2OC(CH3)3, CH2OCH2-phenyl, CH2OCH2CH2Si(CH3)3, CH2OC(O)C(CH3)3, CH(OCH2CH3)2, CH2Si(CH3)2C(CH3)3, CH2-phenyl, CH2-(4-methoxyphenyl), CH2-(2-nitrophenyl), CH2-(4-nitrophenyl), CH(phenyl)2, C(phenyl)3, C(phenyl)2-pyrid-4-yl, CH(OCH2CH3)CH3, CH2CH2Cl, CH2CH2S(O)2-phenyl, CH═CH2, CH2CH═CH2, C(O)OC[CH(CH3)2]2, C(O)OCH2CCB, C(O)OC(CH3)3, C(O)OC(CH3)2CCl, C(O)OCH2-phenyl, C(O)OCH2CH2Si(CH3)3, C(O)OCH2CH2S(O)2-(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH3)2, and tetrahydropyran-2-yl; and
* is a chiral carbon;
with a chiral acid selected from the group consisting of an optically active form of 2-acrylamide-7,7-dimethylbicyclo[2.2.1]heptan-1-methylenesulfonic acid, 2-amino-7,7-dimethylbicyclo[2.2.1]heptan-1-methylenesulfonic acid, camphorsulfonic acid, 3-bramocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, lactic acid, malic acid, mandelic acid, 2-chloromandelic acid, tartaric acid, dibenzoyltartaric acid, and di-p-taluoyltartaric acid;
in the presence of a solvent selected from the group consisting of acetone, acetonitrile, and tetrahydrofuran, or a combination thereof, to form a chiral acid addition salt of a compound of Formula Ia:

OG Complex Work Unit Chemistry
wherein:
R1 is C1-6 alkyl, C1-6 fluoroalkyl, or C3-7 cycloalkyl;
P1 is CH2OH, CH2OCH3, CH2OC(CH3)3, CH2OCH2-phenyl, CH2OCH2CH2Si(CH3)3, CH2OC(O)C(CH3)3, CH(OCH2CH3)2, CH2Si(CH3)2C(CH3)3, CH2-phenyl, CH2-(4-methoxyphenyl), CH2-(2-nitrophenyl), CH2-(4-nitrophenyl), CH(phenyl)2, C(phenyl)3, C(phenyl)2-pyrid-4-yl, CH(OCH2CH3)CH3, CH2CH2Cl, CH2CH2S(O)2-phenyl, CH═CH2, CH2CH═CH2, C(O)OC[CH(CH3)2]2, C(O)OCH2CCB, C(O)OC(CH3)3, C(O)OC(CH3)2CCl, C(O)OCH2-phenyl, C(O)OCH2CH2Si(CH3)3, C(O)OCH2CH2S(O)2-(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH3)2, and tetrahydropyran-2-yl; and
* is a chiral carbon;
(b) separating the composition comprising the chiral acid addition salt of the compound of Formula Ia formed in step (a) above into:
(i) a composition comprising an enantiomeric excess of the chiral acid addition salt of the (R)-enantiomer of the compound of Formula Ia:

OG Complex Work Unit Chemistry
wherein:
R1 is C1-6 alkyl, C1-6 fluoroalkyl, or C3-7 cycloalkyl;
P1 is CH2OH, CH2OCH3, CH2OC(CH3)3, CH2OCH2-phenyl, CH2OCH2CH2Si(CH3)3, CH2OC(O)C(CH3)3, CH(OCH2CH3)2, CH2Si(CH3)2C(CH3)3, CH2-phenyl, CH2-(4-methoxyphenyl), CH2-(2-nitrophenyl), CH2-(4-nitrophenyl), CH(phenyl)2, C(phenyl)3, C(phenyl)2-pyrid-4-yl, CH(OCH2CH3)CH3, CH2CH2Cl, CH2CH2S(O)2-phenyl, CH═CH2, CH2CH═CH2, C(O)OC[CH(CH3)2]2, C(O)OCH2CCl3, C(O)OC(CH3)3, C(O)OC(CH3)2CCB, C(O)OCH2-phenyl, C(O)OCH2CH2Si(CH3)3, C(O)OCH2CH2S(O)2-(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH3)2, and tetrahydropyran-2-yl; and
* is a chiral carbon; or
(ii) a composition comprising an enantiomeric excess of the chiral acid addition salt of the(S)-enantiomer of the compound of Formula Ia:

OG Complex Work Unit Chemistry
wherein:
R1 is C1-6 alkyl, C1-6 fluoroalkyl, or C3-7 cycloalkyl;
P1 is CH2OH, CH2OCH3, CH2OC(CH3)3, CH2OCH2-phenyl, CH2OCH2CH2Si(CH3)3, CH2OC(O)C(CH3)3, CH(OCH2CH3)2, CH2Si(CH3)2C(CH3)3, CH2-phenyl, CH2-(4-methoxyphenyl), CH2-(2-nitrophenyl), CH2-(4-nitrophenyl), CH(phenyl)2, C(phenyl)3, C(phenyl)2-pyrid-4-yl, CH(OCH2CH3)CH3, CH2CH2Cl, CH2CH2S(O)2-phenyl, CH═CH2, CH2CH═CH2, C(O)OC[CH(CH3)2]2, C(O)OCH2CCl3, C(O)OC(CH3)3, C(O)OC(CH3)2CCB, C(O)OCH2-phenyl, C(O)OCH2CH2Si(CH3)3, C(O)OCH2CH2S(O)2-(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH3)2, and tetrahydropyran-2-yl; and
* is a chiral carbon; and
(c) treating the composition comprising an enantiomeric excess of the chiral acid addition salt of Formula (R)-Ia or the composition comprising an enantiomeric excess of the chiral acid addition salt of Formula(S)-Ia formed in step (b) above with a base selected from the group consisting of an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal hydroxide, and an alkaline earth metal hydroxide, to form the composition comprising an enantiomeric excess of the (R)-enantiomer or(S)-enantiomer of the compound of Formula Ia above.