PROCESSES FOR PREPARING JAK INHIBITORS AND RELATED INTERMEDIATE COMPOUNDS

• US 20100190981A1
• Filed: 01/14/2010
• Published: 07/29/2010
• Est. Priority Date: 01/15/2009
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Wang, Haisheng, Xia, Michael, Li, Mei, Zhou, Jiacheng, Lin, Qiyan, Liu, Pingli, Yue, Tai-Yuen, Meloni, David, Pan, Yongchun, Metcalf, Brian W., Rodgers, James D.
• Granted Patent: US 8,410,265 B2
• Time in Patent Office: Days
• US Class Current: 544/280
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 7/083 Syntheses without formation of a Si-C bond
• CPC Class Codes: C07F 7/10 containing nitrogen having a Si-N linkage
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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.

Claims

1. A process of preparing a composition comprising a compound of Formula I:

comprising 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 C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

R₂ is selected from —

C(═

O)—

NH₂, —

C(═

O)O—

R₃, and cyano;

R₃ is selected from C_1-4 alkyl or C_1-4 fluoroalkyl; and

P₁ is a protecting group.

2. A process according to claim 1, wherein said composition comprises an enantiomeric excess of a (R)- or (S)-enantiomer of the compound of Formula I;

and said hydrogenation catalyst is a ruthenium or rhodium catalyst having L₁;

wherein L₁ is a chiral phosphine ligand.

3. A process according to claim 2, wherein said enantiomeric excess is equal to or greater than about 90%.

4. A process according to claim 2, wherein said enantiomeric excess is equal to or greater than about 99%.

5. A process according to claim 2, wherein said chiral phosphine ligand is selected from one of the following:

6. A process according to claim 2, wherein said composition comprises an enantiomeric excess of the (S)-enantiomer of the compound of Formula I.

7. A process according to claim 6, wherein L₁ is selected from one of the following ligands:

8. A process according to claim 2, wherein said composition comprises an enantiomeric excess of the (R)-enantiomer of the compound of Formula I.

9. A process according to claim 8, wherein L₁ is selected from one of the following ligands:

10. A process according to claim 2, wherein said product is a compound of Formula Ia:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

11. A process according to claim 2, wherein R₂ is —

C(═

O)—

NH₂.

12. A process according to claim 11, further comprising reacting said compound of Formula I under dehydrating conditions to form a compound of Formula Ia:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

13. A process according to claim 12, wherein said dehydrating conditions comprises trichloroacetyl chloride in the presence of triethylamine.

14. A process according to claim 2, wherein R₂ is —

C(═

O)O—

R₃.

15. A process according to claim 2, wherein R₂ is —

C(═

O)OCH₃.

16. A process according to claim 14 or 15, further comprising reacting said compound of Formula I with a metal hydroxide to form a compound of Formula Ic:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

17. A process according to claim 16, wherein said metal hydroxide is an alkali metal hydroxide or an alkaline earth hydroxide.

18. A process according to claim 16, wherein said metal hydroxide is lithium hydroxide.

19. A process according to claim 16, further comprising reacting said compound of Formula Ic with ammonia or ammonium hydroxide in the presence of a coupling reagent to form a compound of Formula Ib:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

20. A process according to claim 19, wherein said coupling agent is N,N-carbonyldiimidazole.

21. A process according to claim 19, further comprising reacting said compound of Formula Ib under dehydrating conditions to form a compound of Formula Ia:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

22. A process according to claim 2, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

23. A process according to claim 2, wherein R₁ is cyclopentyl.

70. A process according to any one of claims 10, 12, 13, 35, 51, 54, and 61, further comprising reacting said compound of Formula Ia under deprotection conditions to form a compound of Formula III:

* is a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

71. A process according to claim 70, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

72. A process according to claim 70, wherein R₁ is cyclopentyl.

73. A process according to claim 70, 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.

74. A process according to claim 73, further comprising reacting the compound of Formula III with phosphoric acid to form a phosphate salt of said compound of Formula III.

24. A process of preparing a composition comprising an enantiomeric excess of a (R)- or (S)-enantiomer of a compound of Formula Id:

comprising reacting a compound of Formula IV;

with a compound of Formula V;

in the presence of a chiral amine and an organic acid;

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

26. A process according to claim 24 or 25, wherein said organic acid is p-toluenesulfonic acid.

27. A process according to claim 24 or 25, wherein said chiral amine is a (R)- or (S)-enantiomer of a compound of Formula A-1:

wherein;

X is CY₃Y₄ and Y is CY₅Y₆;

or

X is S or NY₇ and Y is CY₅Y₆;

or

X is CY₃Y₄ and Y is S;

Q₁ and Q2 are each independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, carboxy, C_1-6 alkylcarboxamide, C_1-6 alkoxycarbonyl, and phenyl;

wherein said C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkylcarboxamide, C_1-6 alkoxycarbonyl, and phenyl are each optionally substituted by 1, 2, or 3 groups independently selected from hydroxyl, carboxy, tri-C_1-6 alkylsilyl, tri-C_1-6 alkylsilyloxy, C_6-10 aryl, C_6-10 arylamino, C_1-9 heteroaryl, and C_1-9heteroarylamino;

wherein said C_6-10 aryl, C_6-10 arylamino, C_1-9 heteroaryl, and C_1-9heteroarylamino are each optionally substituted by 1, 2, 3, or 4 groups independently selected from halogen, C_1-6 alkyl, and C_1-6 haloalkyl; and

Y₁, Y₂, Y₃, Y₄, Y₅, Y₆ are each independently selected from H, hydroxyl, carboxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxycarbonyl, and phenyl;

or

Y₁ and Y₂ together form oxo;

or

Y₃ and Y₄ together form oxo;

or

Y₅ and Y₆ together form oxo;

or

Y₁ and Y₂, together with the carbon to which they are attached, form a 5- or 6-membered cycloalkyl ring;

or

Q₁ and Y5, together with the carbon atoms to which they are attached, form a 5- or 6-membered cycloalkyl ring.

28. A process of claim 24 or 25, wherein said chiral amine is a (R)- or (S)-enantiomer of a compound of Formula A-2:

wherein

* is a chiral carbon having a (R)- or (S)-configuration;

Ar₁ and Ar₂ are each independently C_6-10 aryl, which is optionally substituted by 1, 2, 3, or 4 groups independently selected from C_1-6 alkyl and C_1-6 haloalkyl;

each R_a are independently selected from C_1-6 alkyl; and

R_b is selected from H, C_1-6 alkyl, and C_1-6 haloalkyl.

29. A process according to claim 28, wherein:

Ar₁ and Ar₂ are each independently phenyl, which is optionally substituted by 1, 2, 3, or 4 groups independently selected from methyl and trifluoromethyl;

each R_a is independently selected from methyl, ethyl, or t-butyl;

R_b is H.

30. A process according to claim 24 or 25, wherein said chiral amine is a (R)- or (S)-enantiomer of a compound selected from proline, prolinamide, prolyl-L-leucine, prolyl-L-alanine, prolylglycine, prolyl-L-phenylalanine, diphenylpyrrolidine, dibenzylpyrrolidine, N-(1-methylethyl)-pyrrolidinecarboxamide, 2-(anilinomethyl)pyrrolidine, 2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, diphenyl(pyrrolidin-2-yl)methanol, prolinol, 4-thiazolidinecarboxylic acid, trans-3-hydroxyproline, trans-4-hydroxyproline, 4-benzyl-1-methyl-imidazolidine-2-carboxylic acid, 1-methyl-4-phenyl-imidazolidine-2-carboxylic acid, 4,5-octahydro-benzoimidazole-2-carboxylic acid, 4,5-diphenyl-imidazolidine-2-carboxylic acid, N1-methyl-3-phenylpropane-1,2-diamine, 1,2-diphenylethanediamine, 1-methyl-4-(1-methyl-1H-indol-3-ylmethyl)-imidazolidine-2-carboxylic acid, 4-benzyl-1-methyl-imidazolidine-2-carboxylic acid, 1,2-cyclohexanediamine, 2-phenyl-thiazolidine-4-carboxylic acid, tert-leucine methyl ester, 5-benzyl-2,2,3-trimethyl-imidazoline-4-one, methyl prolinate, 4,5-diphenylimidazolidine, 2-cyclohexyl-4,5-diphenylimidazolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-trimethylsilanyloxy-methyl}-pyrrolidine, 2-{bis-[3,5-dimethylphenyl]-trimethylsilanyloxy-methyl}-pyrrolidine, 2-{diphenyl-trimethylsilanyloxy-methyl}-pyrrolidine, 2-{bis[naphth-2-yl]-trimethylsilanyloxy-methyl}-pyrrolidine, 2-{tert-butyldimethylsilyloxy-diphenyl-methyl}-pyrrolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-triethylsilanyloxy-methyl}-pyrrolidine, and 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-ethyl-dimethylsilyloxy-methyl}-pyrrolidine;

wherein the (R)- or (S)-configuration is at the carbon adjacent to a NH group in said compound.

31. A process according to claim 27, wherein said chiral amine is the (R)-enantiomer.

32. A process according to claim 24 or 25, wherein said chiral amine is selected from one of the following compounds:

33. A process according to claim 24 or 25, wherein said enantiomeric excess is equal to or greater than about 90%.

34. A process according to claim 24 or 25, wherein said enantiomeric excess is equal to or greater than about 99%.

35. A process according to claim 24, further comprising treating said compound of Formula Id with ammonia or ammonium hydroxide and iodine to form said compound of Formula Ia:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

40. A process according to claim 24, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

41. A process according to claim 24 or 25, wherein R₁ is cyclopentyl.

25. A process of preparing a composition comprising an enantiomeric excess of a (R)- or (S)-enantiomer of a compound of Formula VI:

comprising reacting a compound of Formula V;

with a compound of Formula VII;

in the presence of a chiral amine and an organic acid;

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

X₁ is halogen.

36. A process according to claim 25, further comprising treating said compound of Formula VI with ammonia or ammonium hydroxide and iodine to form said compound of Formula VIII:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

P₁ is a protecting group; and

X₁ is halogen.

37. A process according to claim 36, further comprising reacting said compound of Formula VIII with a compound of Formula B-1:

to form a compound of Formula IX;

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

X₁ is halo; and

R_c and R_d are each independently selected from H and C_1-6 alkyl;

or

R_c and R_d, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C₁-₄ alkyl groups.

38. A process according to claim 37, wherein said compound of Formula B-1 is 4,4,5,5,4′

,4′

,5′

,5′

-octamethyl-[2,2′

]bis[1,3,2-dioxaborolanyl].

39. A process according to claim 37 or 38, further comprising reacting said compound of Formula IX with a compound of Formula X:

in the presence of a palladium catalyst and a base to form a compound of Formula Ia;

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

X₂ is a tosylate group, a triflate group, iodo, chloro, or bromo;

P₁ is a protecting group; and

R_c and R_d are each independently selected from H and C_1-6 alkyl;

or

R_c and R_d, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C_1-4 alkyl groups.

42. A composition comprising an enantiomeric excess of a (R)- or (S)-enantiomer of a compound of Formula IX:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

R_c and R_d are each independently C_1-6 alkyl;

or

R_c and R_d, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C_1-4 alkyl groups.

43. A composition according to claim 42, wherein R₁ is cyclopentyl.

44. A process of preparing a composition according to claim 42 or 43, comprising passing a composition comprising a racemate of a compound of Formula IX 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 IX.

45. A process according to claim 44, wherein the mobile phase comprises ethanol and hexanes, wherein said ethanol is present in an amount of about 25% to about 10% by volume.

46. A process according to claim 42, 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.

47. A process according to claim 46, wherein said chiral stationary phase is cellulose modified chiral stationary phase.

48. A process according to claim 44, wherein said compound of Formula IX has the formula:

49. A process according to claim 44, further comprising reacting the compound of Formula IX:

with a compound of Formula XI;

in the presence of a palladium catalyst, base, and a solvent to form a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula III;

wherein;

* is a chiral carbon;

X₂ is a tosylate group, a triflate group, iodo, chloro, or bromo;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6fluoroalkyl; and

R_c and R_d are each independently C_1-6 alkyl;

or

R_c and R_d, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C_1-4 alkyl groups.

50. A process according to claim 44, further comprising reacting the compound of Formula IX:

with a compound of Formula X;

in the presence of a palladium catalyst, base, and a solvent under conditions and for a time sufficient to form a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia;

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

R_c and R_d are each independently C_1-6 alkyl;

or

R_c and R_d, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C_1-4 alkyl groups;

X₂ is a tosylate group, a triflate group, iodo, chloro, or bromo; and

P₁ is a protecting group.

51. A process of preparing a composition comprising a racemate of a compound of Formula Ia:

comprising;

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;

wherein;

* is a chiral carbon;

P₁ is a protecting group; and

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6fluoroalkyl.

52. A process according to claim 51, wherein said first base is cesium carbonate.

53. A process according to claim 51 or 52, wherein said second base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

56. A process according to claim 51 or 54, further comprising preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of Formula Ia:

comprising 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;

* is a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

57. A process according to claim 56, wherein the mobile phase comprises isopropanol and hexanes, wherein said isopropanol is present in an amount of about 25% to about 10% by volume.

58. A process according to claim 56, 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.

59. A process according to claim 51 or 54, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

60. A process according to any one of claim 51 or 54, wherein R₁ is cyclopentyl.

54. A process of preparing a composition comprising a racemate of a compound of Formula Ia:

comprising 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;

wherein;

* is a chiral carbon;

P₁ is a protecting group; and

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl.

55. A process according to claim 54, wherein said base is potassium t-butoxide.

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

comprising;

(a) reacting a composition comprising a racemate of a compound of Formula Ia with a chiral acid in the presence of a solvent to form a salt of a compound of Formula Ia;

(b) separating a composition comprising an enantiomer excess of a chiral salt of the (R)- or (S)-enantiomer of the compound of Formula Ia; and

(c) treating said chiral salt with a base to form a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of Formula Ia;

wherein;

* is a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

P₁ is a protecting group.

62. A process according to claim 61, wherein said chiral acid is selected from optically active forms of mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyl tartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclop[2,2,1]heptan-1-methylene sulfonic acid, and 2-acrylamide-7,7-dimethylbicyclo[2,2,1]heptan-1-methylene sulfonic acid.

63. A process according to claim 61, wherein said chiral acid is (+)-dibenzoyl-D-tartaric acid.

64. A process according to claim 61, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

65. A process according to claim 61, wherein R₁ is cyclopentyl.

66. A process of preparing a compound of Formula XII:

comprising reacting a compound of Formula X;

with a compound of Formula XIII;

in the presence of a palladium catalyst, base, and a solvent, to form a compound of Formula XII.

wherein;

* is a chiral carbon;

X₂ is a tosylate group, a triflate group, iodo, chloro, or bromo;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl; and

R_c and R_d are each independently H or C_1-6 alkyl;

or

R_c and R_d, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3, or 4 C_1-4 alkyl groups; and

P₁ and P₂ are each independently a protecting group.

67. A process according to claim 66, wherein said compound of Formula XIII has formula:

68. A process according to claim 66, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

69. A process according to claim 66, wherein P₂ is 1-(ethoxy)ethyl.

75. A process for preparing a compound of Formula XVI:

comprising;

(a) reacting a compound of Formula XVIII

with about 1 or more equivalents of an C_1-6 alkyl Grignard reagent or C_1-6 alkyl lithium reagent followed by treating with about 1 or more equivalents of a compound of Formula XVII;

and

(b) optionally, reprotecting the product of step (a) to give a compound of Formula XVI;

wherein;

P₃ is a protecting group;

X₃ is halogen;

R₄ is C_1-6 alkyl; and

m is an integer selected from 1 and 2.

76. A process according to claim 75, wherein X₃ is iodo or bromo.

77. A process according to claim 75, wherein P₃ is 1-(ethoxy)ethyl.

78. A process according to any one of claims 75 to 77, wherein said compound of Formula XVI has formula:

79. A process according to any one of claims 75 to 77, further comprising a method for preparing a compound of Formula XVIII, comprising protecting a compound of Formula XIX:

wherein;

P₃ is a protecting group;

X₃ is halogen; and

m is an integer selected from 1 and 2.

80. A process according to any one of claims 75 to 77, further comprising preparing said compound of Formula XIX by a process comprising reacting 1H-pyrazole with a halogenating agent, wherein:

X₃ is halogen; and

m is an integer selected from 1 and 2.

81. A process according to any one of claims 75 to 77, wherein said halogenating agent is selected from N-bromosuccinimide or N-iodosuccinimide.

82. A process for preparing a compound of Formula XIa:

comprising treating a compound of Formula F-1;

with acid under conditions sufficient to form a compound of Formula XIa.

83. A process according to claim 82, wherein said acid is aqueous concentrated hydrochloric acid.

84. The process according to claim 82, further comprising preparing said compound of Formula F-1 by a process comprising reacting a compound of Formula F-2:

with about 1 or more equivalents of a Wittig-type reagent having a glide of formula —

CH₂OCH₃ in the presence of a base.

85. The process according to claim 82, further comprising preparing said compound of Formula F-1 by a process comprising reacting a compound of F-3:

with about 2 or more equivalents of ammonia in a solvent.

86. The process according to claim 82, further comprising preparing said compound of Formula F-1 by a process comprising reacting a compound of F-4:

with a chlorinating agent.

87. A composition comprising an enantiomeric excess of a (R)- or (S)-enantiomer of a compound of Formula I:

wherein;

* indicates a chiral carbon;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

R₂ is selected from —

C(═

O)—

NH₂, —

C(═

O)O—

R₃, —

C(═

O)OH, and —

C(═

O)H;

R₃ is selected from C_1-4 alkyl or C_1-4 fluoroalkyl; and

P₁ is a protecting group.

88. A composition according to claim 87, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

89. A composition according to claim 87 or 88, wherein R₁ is cyclopentyl.

90. A compound of Formula II:

wherein;

R₁ is selected from C_3-7 cycloalkyl, C_1-6 alkyl, and C_1-6 fluoroalkyl;

R₂ is selected from —

C(═

O)—

NH₂ and —

C(═

O)O—

R₃;

R₃ is selected from C_1-4 alkyl or C_1-4 fluoroalkyl; and

P₁ is a protecting group.

91. A compound according to claim 90, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

92. A compound according to claim 90 or 91, wherein R₁ is cyclopentyl.

93. A process of preparing a composition comprising an enantiomeric excess of equal to or greater than 90% of the (R)-enantiomer of a compound of formula III′

;

comprising;

(a) treating a compound of Formula XI′

;

with sodium hydride and N-pivaloyloxymethyl chloride to form a compound of Formula X′

;

(b) treating said compound of Formula X′

with a compound of Formula XIII′

;

in the presence of Pd(triphenylphosphine)₄, potassium carbonate, and a solvent, to form a compound of Formula XII′

;

(c) reacting said compound of Formula XII′

under deprotection conditions to give a compound of Formula IV′

;

(d) reacting said compound of Formula IV″

with a compound of Formula XIV′

;

in the presence of 1,8-diaza-bicyclo[5.4.0]undec-7-ene to give a compound of Formula II′

;

(c) reacting said compound of Formula II′

with hydrogen gas in the presence of [Rh(COD)₂]SF₃SO₃ and a chiral phosphine ligand selected from;

to form a compound of Formula I′

;

(f) reacting said compound of Formula I′

under deprotection conditions to form said compound of Formula III′

;

wherein * indicates a chiral carbon.

94. The process of claim 93, further comprising preparing said compound of Formula XI′

;

comprising;

(i) reacting a compound of F-4;

with from about three to about five equivalents of POCl₃ in the presence of about one to about two equivalents of dimethylformamide to form a compound of Formula F-3;

(ii) reacting said compound of F-3 with about two equivalents of ammonia in methanol to form a compound of Formula F-2;

(iii) reacting said compound of Formula F-2 with from about 1 to about 1.5 equivalents of a Wittig-type reagent of formula [Ph₃P⁺(CH₂OCH₃)]Cl—

, wherein Ph is phenyl, in the presence of from about 1 to about 1.5 equivalents of potassium tert-butoxide to form a compound of Formula F-1;

and

(iv) treating said compound of Formula F-1 with aqueous concentrated hydrochloric acid in tetrahydrofuran at reflux to form compound of Formula XI′

.

95. The process of claim 93, further comprising preparing said compound of Formula XIII′

;

comprising;

(i) reacting 1H-pyrazole with N-bromosuccinimide to form a compound of Formula XIX′

;

(ii) protecting said compound of Formula XIX to form a compound of Formula XVIII′

;

and

(iii) reacting said compound of Formula XVIII′

with about one or more equivalents of a isopropylmagnesium chloride followed by treating with about one or more equivalents of compound of Formula XVII′

;

to form a compound of Formula XIII′

.

96. The process of claim 93, further comprising preparing said compound of Formula XIII′

;

comprising;

(i) protecting 4-iodo-1H-pyrazole to form a compound of Formula XVIII″

;

and

(ii) reacting a compound of Formula XVIII″

with about one or more equivalents of a isopropylmagnesium chloride in tetrahydrofuran followed by treating with about one or more equivalents of compound of Formula XVII′

;

to form a compound of Formula XIII′

.

97. The process of claim 93, wherein, in step (e):

the solvent is 2,2,2-trifluoroethanol (TFE);

the hydrogenation catalyst loading is about 0.005 to about 0.01 mol %;

the ratio of said compound of Formula II to said hydrogenation catalyst is from about 20000/1 to about 10000/1;

the hydrogen pressure is from about 7 to about 60 bar;

the reacting is run at a temperature from about room temperature to about 75°

C.;

the reacting is run until the conversion of said compound of Formula II to said compound of Formula is about equal to or greater than 99.5%; and

the reacting is from about 10 to about 25 hours.

98. A process of preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of Formula III′

;

comprising;

(a) treating a compound of Formula XI′

;

with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form a compound of Formula X″

;

(b) treating said compound of Formula X″

with a compound of Formula XIII′

;

in the presence of Pd(triphenylphosphine)₄, potassium carbonate, and a solvent, to form a compound of Formula XII″

;

(c) reacting said compound of Formula XII″

under deprotection conditions to form a compound of Formula IV″

;

(d) reacting said compound of Formula IV″

with a compound of Formula D-1′

;

under conditions sufficient to form a composition comprising a racemate of a compound of Formula I″

;

(e) passing said composition comprising said racemate of said compound of Formula I″

through a chiral chromatography unit using a mobile phase and collecting a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula I″

; and

(f) reacting said compound of Formula I″

with lithium tetrafluoroborate, followed by aqueous ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula III′

;

wherein * is a chiral carbon.

99. A process of preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of Formula III′

;

comprising;

(a) treating a composition comprising an enantiomeric excess of the (S)-enantiomer of a compound of Formula I″

;

with a compound of Formula D-1′

;

in the presence of cesium carbonate in acetonitrile under conditions sufficient to form the racemate of the compound of Formula I″

;

(b) passing said composition comprising said racemate of said compound of Formula I″

through a chiral chromatography unit using a mobile phase and collecting a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula I″

; and

(c) reacting said compound of Formula I″

with lithium tetrafluoroborate, followed by aqueous ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula III′

;

wherein * is a chiral carbon.

100. A process of preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of Formula III′

;

comprising;

(a) treating a compound of Formula XI′

;

with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form a compound of Formula X″

;

(b) treating said compound of Formula X″

with a compound of Formula XIII′

;

in the presence of Pd(triphenylphosphine)₄, potassium carbonate, and a solvent, to form a compound of Formula XII″

;

(c) reacting said compound of Formula XII″

under deprotection conditions to form a compound of Formula IV″

;

(d) reacting said compound of Formula IV″

with a compound of Formula D-1′

;

under conditions sufficient to form a composition comprising a racemate of a compound of Formula I″

;

(e) passing said composition comprising said racemate of said compound of Formula I″

through a chiral chromatography unit using a mobile phase and collecting a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula I″

; and

(f) reacting said compound of Formula I″

with boron trifluoride diethyl etherate, followed by aqueous ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula III′

;

wherein * is a chiral carbon.

101. A process of preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of Formula III′

;

comprising;

(a) treating a composition comprising an enantiomeric excess of the (S)-enantiomer of a compound of Formula I″

;

with a compound of Formula D-1′

;

in the presence of cesium carbonate in acetonitrile under conditions sufficient to form the racemate of the compound of Formula I″

;

(b) passing said composition comprising said racemate of said compound of Formula I″

through a chiral chromatography unit using a mobile phase and collecting a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula I″

; and

(c) reacting said compound of Formula I″

with boron trifluoride diethyl etherate, followed by aqueous ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula III′

;

wherein * is a chiral carbon.

102. A process of preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of Formula III′

;

comprising;

reacting said compound of Formula I″

;

with boron trifluoride diethyl etherate, followed by aqueous ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of said compound of Formula III′

;

wherein * is a chiral carbon.

103. A process for preparing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt comprising reacting (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile with phosphoric acid in the presence of 2-propanol and dichloromethane.

104. A method of purifying (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt comprising recrystallizing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt from a solvent mixture comprising methanol, 2-propanol, and n-heptane.

105. The method of claim 104 wherein said 2-propanol and n-heptane are added to a mixture of (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt in methanol.