IP Library › Granted Patent US 12,247,030
Granted Patent B2
US 12,247,030 · App. 17/176,914 · Granted Mar 11, 2025

Process for preparing compositions comprising an enantiomeric excess of a substituted pyrrolo[2,3-d]pyrimidine

Inventors: Jiacheng Zhou (Newark, DE); David Meloni (Bear, DE); Yongchun Pan (Newark, DE); Mei Li (Newark, DE)
Assignees: Incyte Holdings Corporation; Incyte Corporation
C07D487/04C07F5/025C07F7/083C07F7/10C07F7/1892Y02P20/55
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Quick Facts
Patent No.
US 12,247,030
App. No.
17/176,914
Granted
Mar 11, 2025
Kind
B2
Abstract

The present invention is related to processes for preparing a composition comprising an enantiomeric excess of a substituted pyrrolo[2,3-d]pyrimidine utilizing chiral acids.

Claims (38)

1. A process for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer or(S)-enantiomer of a compound of Formula Ia:

wherein:

R 1 is C 1-6 alkyl, C 1-6 fluoroalkyl, or C 3-7 cycloalkyl;

P 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 OCH 2 -phenyl, CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 OC(O)C(CH 3 ) 3 , CH(OCH 2 CH 3 ) 2 , CH 2 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 -phenyl, CH 2 -(4-methoxyphenyl), CH 2 -(2-nitrophenyl), CH 2 -(4-nitrophenyl), CH(phenyl) 2 , C(phenyl) 3 , C(phenyl) 2 -pyrid-4-yl, CH(OCH 2 CH 3 )CH 3 , CH 2 CH 2 Cl, CH 2 CH 2 S(O) 2 -phenyl, CH═CH 2 , CH 2 CH═CH 2 , C(O)OC[CH(CH 3 ) 2 ] 2 , C(O)OCH 2 CCl 3 , C(O)OC(CH 3 ) 3 , C(O)OC(CH 3 ) 2 CCB, C(O)OCH 2 -phenyl, C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH 3 ) 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:

wherein:

R 1 is C 1-6 alkyl, C 1-6 fluoroalkyl, or C 3-7 cycloalkyl;

P 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 OCH 2 -phenyl, CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 OC(O)C(CH 3 ) 3 , CH(OCH 2 CH 3 ) 2 , CH 2 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 -phenyl, CH 2 -(4-methoxyphenyl), CH 2 -(2-nitrophenyl), CH 2 -(4-nitrophenyl), CH(phenyl) 2 , C(phenyl) 3 , C(phenyl) 2 -pyrid-4-yl, CH(OCH 2 CH 3 )CH 3 , CH 2 CH 2 Cl, CH 2 CH 2 S(O) 2 -phenyl, CH═CH 2 , CH 2 CH═CH 2 , C(O)OC[CH(CH 3 ) 2 ] 2 , C(O)OCH 2 CCB, C(O)OC(CH 3 ) 3 , C(O)OC(CH 3 ) 2 CCl, C(O)OCH 2 -phenyl, C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH 3 ) 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:

wherein:

R 1 is C 1-6 alkyl, C 1-6 fluoroalkyl, or C 3-7 cycloalkyl;

P 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 OCH 2 -phenyl, CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 OC(O)C(CH 3 ) 3 , CH(OCH 2 CH 3 ) 2 , CH 2 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 -phenyl, CH 2 -(4-methoxyphenyl), CH 2 -(2-nitrophenyl), CH 2 -(4-nitrophenyl), CH(phenyl) 2 , C(phenyl) 3 , C(phenyl) 2 -pyrid-4-yl, CH(OCH 2 CH 3 )CH 3 , CH 2 CH 2 Cl, CH 2 CH 2 S(O) 2 -phenyl, CH═CH 2 , CH 2 CH═CH 2 , C(O)OC[CH(CH 3 ) 2 ] 2 , C(O)OCH 2 CCB, C(O)OC(CH 3 ) 3 , C(O)OC(CH 3 ) 2 CCl, C(O)OCH 2 -phenyl, C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH 3 ) 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:

wherein:

R 1 is C 1-6 alkyl, C 1-6 fluoroalkyl, or C 3-7 cycloalkyl;

P 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 OCH 2 -phenyl, CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 OC(O)C(CH 3 ) 3 , CH(OCH 2 CH 3 ) 2 , CH 2 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 -phenyl, CH 2 -(4-methoxyphenyl), CH 2 -(2-nitrophenyl), CH 2 -(4-nitrophenyl), CH(phenyl) 2 , C(phenyl) 3 , C(phenyl) 2 -pyrid-4-yl, CH(OCH 2 CH 3 )CH 3 , CH 2 CH 2 Cl, CH 2 CH 2 S(O) 2 -phenyl, CH═CH 2 , CH 2 CH═CH 2 , C(O)OC[CH(CH 3 ) 2 ] 2 , C(O)OCH 2 CCl 3 , C(O)OC(CH 3 ) 3 , C(O)OC(CH 3 ) 2 CCB, C(O)OCH 2 -phenyl, C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH 3 ) 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:

wherein:

R 1 is C 1-6 alkyl, C 1-6 fluoroalkyl, or C 3-7 cycloalkyl;

P 1 is CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 OCH 2 -phenyl, CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 OC(O)C(CH 3 ) 3 , CH(OCH 2 CH 3 ) 2 , CH 2 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 -phenyl, CH 2 -(4-methoxyphenyl), CH 2 -(2-nitrophenyl), CH 2 -(4-nitrophenyl), CH(phenyl) 2 , C(phenyl) 3 , C(phenyl) 2 -pyrid-4-yl, CH(OCH 2 CH 3 )CH 3 , CH 2 CH 2 Cl, CH 2 CH 2 S(O) 2 -phenyl, CH═CH 2 , CH 2 CH═CH 2 , C(O)OC[CH(CH 3 ) 2 ] 2 , C(O)OCH 2 CCl 3 , C(O)OC(CH 3 ) 3 , C(O)OC(CH 3 ) 2 CCB, C(O)OCH 2 -phenyl, C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, NHN(CH 3 ) 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.

2. The process according to claim 1 , wherein R 1 is cyclopentyl.

3. The process according to claim 1 , wherein P 1 is CH 2 OH, CH 2 OC(CH 3 ) 3 , CH 2 OCH 2 -phenyl, CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 OC(O)C(CH 3 ) 3 , CH(OCH 2 CH 3 ) 2 , CH 2 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 -(4-methoxyphenyl), CH(phenyl) 2 , C(phenyl) 3 , CH(OCH 2 CH 3 )CH 3 , CH 2 CH 2 Cl, CH 2 CH 2 S(O) 2 -phenyl, CH═CH 2 , C(O)OC[CH(CH 3 ) 2 ] 2 , C(O)OCH 2 CCl 3 , C(O)OC(CH 3 ) 3 , C(O)OC(CH 3 ) 2 CCl 3 , C(O)OCH 2 -phenyl, C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH 2 S(O) 2 -(4-trifluoromethylphenyl), C(O)Ocyclohexyl, C(O)O-adamant-1-yl, C(O)O-adamant-2-yl, or tetrahydropyran-2-yl.

4. The process according to claim 1 , wherein P 1 is CH 2 OCH 2 CH 2 Si(CH 3 ) 3 or CHOC(O)C(CH 3 ) 3 .

5. The process according to claim 1 , wherein the chiral acid is an optically active form of dibenzoyltartaric acid.

6. The process according to claim 1 , wherein the chiral acid is (+)-dibenzoyl-D-tartaric acid.

7. The process according to claim 1 , wherein the solvent is a combination of acetone, acetonitrile, and tetrahydrofuran.

8. The process according to claim 1 , wherein the solvent is a 90:15:15 ratio by volume of acetonitrile, tetrahydrofuran, and acetone.

9. The process according to claim 1 , wherein the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

10. The process according to claim 1 , wherein the base is sodium hydroxide.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 14, 2021
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION
Reel/Frame 056537/0501 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 7, 2021
From: ZHOU, JIACHENG; LIU, PINGLI; LIN, QIYAN; METCALF, BRIAN W.; MELONI, DAVID; PAN, YONGCHUN; XIA, MICHAEL; LI, MEI; YUE, TAI-YUEN; RODGERS, JAMES D.; WANG, HAISHENG
To: INCYTE CORPORATION
Reel/Frame 056453/0921 →
Continuity (8)
Division 16436195 · Jun 10, 2019
Division 15869650 · Jan 12, 2018
Division 15016918 · Feb 5, 2016
Division 14593688 · Jan 9, 2015
Division 13761830 · Feb 7, 2013
Division 12687623 · Jan 14, 2010
Provisional Application 61144991 · Jan 15, 2009
Related Publication 20210253584A1 · Aug 19, 2021
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