Methods for preparing JAK inhibitors and related intermediate compounds

Abstract

The invention relates to a method 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 can be used as inhibitors of the Janus kinase family (JAK) of protein tyrosine kinases, and are used for treating inflammatory diseases, myeloproliferative diseases and other diseases. # imgabs0 #

Description

[0001] This application is a divisional application of patent application No. 201810240146.1, filed on January 14, 2010, entitled "Method for preparing JAK inhibitors and related intermediate compounds". Application No. 201810240146.1 is a divisional application of patent application No. 201610105708.2, filed on January 14, 2010, entitled "Method for preparing JAK inhibitors and related intermediate compounds". Application No. 201610105708.2 is a divisional application of patent application No. 201080012029.1, filed on January 14, 2010, entitled "Method for preparing JAK inhibitors and related intermediate compounds". Technical Field

[0002] This invention relates to methods for preparing chiral substituted pyrazolylpyrrolo[2,3-d]pyrimidine and related synthetic intermediates. This chiral substituted pyrazolylpyrrolo[2,3-d]pyrimidine can be used as an inhibitor of the Janus kinase family (JAK) of protein tyrosine kinases for the treatment of inflammatory diseases, myeloproliferative disorders, and other diseases. Background Technology

[0003] Protein kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, particularly cell growth, survival and differentiation, organogenesis and morphogenesis, angiogenesis, tissue repair and regeneration. Protein kinases exert their physiological functions by catalyzing the phosphorylation of proteins (or substrates), thereby regulating the cellular activity of the substrates in various biological environments. In addition to their functions in normal tissues / organs, many protein kinases play more specific roles in many human diseases, including cancer. Dysregulation of a subgroup of protein kinases (also known as oncogenic protein kinases) can lead to tumor formation and growth, and further promote tumor maintenance and development (Blume-Jensen P et al., Nature 2001, 411(6835):355-365). To date, oncogenic protein kinases represent one of the largest and most compelling groups of protein targets for cancer intervention and drug development.

[0004] Protein kinases can be classified into receptor-type and non-receptor-type. Receptor tyrosine kinases (RTKs) have extracellular, transmembrane, and intracellular portions, while non-receptor tyrosine kinases are entirely intracellular. The Janus kinase family of protein tyrosine kinases (JAKs) belongs to the non-receptor tyrosine kinase family and includes the following members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3), and TYK2 (also known as protein tyrosine kinase 2).

[0005] The pathway involving JAKs and transcriptional signal transduction and activating proteins (STATs) is involved in the signaling activities of a wide range of cytokines. Cytokines are low molecular weight peptides or glycoproteins that stimulate biological responses in almost all cell types. Generally, cytokine receptors do not have intrinsic tyrosine kinase activity, thus requiring receptor-associated kinases to propagate the phosphorylation cascade. JAKs accomplish this function. Cytokines bind to their receptors, causing the receptors to dimerize, which allows JAKs to phosphorylate each other and specific tyrosine motifs within the cytokine receptors. STATs that recognize these phosphorylated tyrosine motifs are added to the receptors and are then activated by JAK-dependent tyrosine phosphorylation events. Upon activation, STATs dissociate from the receptors, dimerize, and translocate to the nucleus to bind to specific DNA sites and alter transcription (Scott, MJ, CJ, Godshall et al., (2002). "Jaks, STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6):1153-9").

[0006] The JAK family plays a role in cytokine-dependent proliferative regulation and cellular function involved in immune responses. The JAK / STAT pathway, particularly all four members of the JAK family, is believed to function in asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and other associated lower respiratory tract inflammatory diseases. Furthermore, various cytokines signaled by JAK kinases are associated with inflammatory diseases or symptoms of the upper respiratory tract (such as those affecting the nose and sinuses, e.g., rhinitis, sinusitis), regardless of whether they are typical allergic reactions. The JAK / STAT pathway is also involved in inflammatory diseases / symptoms of the eye (including but not limited to iritis, uveitis, scleritis, conjunctivitis, and chronic allergic reactions). Therefore, inhibition of JAK kinases may play a beneficial role in the treatment of these diseases.

[0007] Blocking signal transduction at the JAK kinase level holds promise for developing treatments for human cancers. Inhibition of JAK kinase is also expected to offer therapeutic benefits to patients with skin immune disorders such as psoriasis and allergic skin conditions. Therefore, inhibitors of Janus kinase or related kinases are widely sought, and compounds of effective classes have been reported in several patent publications. For example, certain JAK inhibitors, including (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, are reported in U.S. Patent Application Publication No. 2007 / 0135461, the disclosure of which is incorporated herein by reference.

[0008] Given the growing need for compounds to treat conditions associated with kinase inhibition (such as Janus kinase), there is a need for novel and more efficient pathways to obtain inhibitors, such as chiral substituted pyrazolylpyrrolo[2,3-d]pyrimidines and their associated intermediates. The methods and compounds described herein help to meet these and other needs. Summary of the Invention

[0009] In particular, this invention provides a method for preparing compositions comprising compound I:

[0010]

[0011] Including compounds of formula II:

[0012]

[0013] It reacts with hydrogen in the presence of a hydrogenation catalyst;

[0014] in:

[0015] * indicates chiral carbon;

[0016] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0017] R2 is selected from -C(=O)-NH2, -C(=O)O-R3 and cyano;

[0018] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0019] P1 is a protecting group.

[0020] The present invention further provides a method for preparing a composition comprising an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula I:

[0021]

[0022] Including compounds of formula II:

[0023]

[0024] It reacts with hydrogen in the presence of a ruthenium or rhodium catalyst with L1, where L1 is a chiral phosphine ligand;

[0025] in:

[0026] * indicates chiral carbon;

[0027] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0028] R2 is selected from -C(=O)-NH2, -C(=O)O-R3 and cyano;

[0029] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0030] P1 is a protecting group.

[0031] The present invention further provides a method for converting a compound of formula I into a compound of formula Ic, comprising converting the compound of formula I into:

[0032]

[0033] It reacts with metal hydroxides to form compounds of formula Ic:

[0034]

[0035] in:

[0036] * indicates chiral carbon;

[0037] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0038] R2 is -C(=O)O-R3; and

[0039] P1 is a protecting group.

[0040] This invention also provides a method for converting a compound of formula Ic into a compound of formula Ib, comprising making the compound of formula Ic:

[0041]

[0042] It reacts with ammonia or ammonium hydroxide in the presence of a coupling agent to form a compound of formula Ib:

[0043]

[0044]

[0045] in:

[0046] * indicates chiral carbon;

[0047] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0048] P1 is a protecting group.

[0049] This invention also provides a method for converting a compound of formula Ib into a compound of formula Ia, comprising making the compound of formula Ib:

[0050]

[0051] The reaction proceeds under dehydration conditions to form a compound of formula Ia:

[0052]

[0053] in:

[0054] * indicates chiral carbon;

[0055] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0056] P1 is a protecting group.

[0057] This invention provides a method for preparing compositions comprising an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula Id:

[0058]

[0059] Including compounds of formula IV:

[0060]

[0061] Compounds of formula V:

[0062]

[0063] The reaction is carried out in the presence of chiral amines and organic acids;

[0064] in:

[0065] * indicates chiral carbon;

[0066] R1 is selected from C3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0067] P1 is a protecting group.

[0068] The present invention further provides a method for preparing a composition containing an enantiomeric excess of (R)- or (S)-enantiomers of compound VI:

[0069]

[0070] Including compounds of formula V:

[0071]

[0072] Compounds of Formula VII:

[0073]

[0074] The reaction occurs in the presence of chiral amines and organic acids;

[0075] in:

[0076] * indicates chiral carbon;

[0077] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0078] X1 is a halogen.

[0079] The present invention further provides a method for converting a compound of formula VI into a compound of formula III, comprising: […].

[0080]

[0081] Treatment with ammonia or ammonium hydroxide and iodine to form a compound of formula VIII:

[0082]

[0083] in:

[0084] * indicates chiral carbon;

[0085] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0086] P1 is a protecting group; and

[0087] X1 is a halogen.

[0088] The present invention also provides a method for converting a compound of formula VIII into a compound of formula IX, comprising making the compound of formula VIII:

[0089]

[0090] Reaction with compound B-1:

[0091]

[0092] To form compounds of formula IX:

[0093]

[0094] in:

[0095] * indicates chiral carbon;

[0096] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0097] X1 is a halogen group; and

[0098] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[0099] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0100] This invention also provides a method for converting a compound of formula IX into a compound of formula Ia, comprising converting the compound of formula IX:

[0101]

[0102] Compound X:

[0103]

[0104] The reaction proceeds in the presence of a palladium catalyst and a base to form a compound of formula Ia:

[0105]

[0106] in:

[0107] * indicates chiral carbon;

[0108] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C1-6 fluoroalkyl;

[0109] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[0110] P1 is a protecting group; and

[0111] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[0112] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0113] In some embodiments, the present invention provides a composition comprising an enantiomerically excess of the (R)- or (S)-enantiomer of a compound of formula IX:

[0114]

[0115] in:

[0116] * indicates chiral carbon;

[0117] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0118] R c and R d Each independently for C 1-6 Alkyl; or

[0119] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0120] The present invention further provides a method for preparing a composition comprising an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula IX:

[0121]

[0122] The composition comprising passing a racemic mixture of a compound containing form IX through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of (R)- or (S)-enantiomers of the compound containing form IX;

[0123] in:

[0124] * indicates chiral carbon;

[0125] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0126] R c and R d Each independently for C 1-6 Alkyl; or

[0127] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0128] This invention provides a method for preparing compositions comprising racemic derivatives of compound Ia:

[0129]

[0130] include:

[0131] a) A composition comprising an enantiomer in excess of the (R)- or (S)-enantiomer of a compound of formula Ia as a compound of formula D-1:

[0132]

[0133] The treatment is carried out under conditions where the first base is present and sufficient to form a compound of formula IV:

[0134]

[0135] as well as

[0136] (b) Reacting compound IV with compound D-1 in the presence of a second base;

[0137] in:

[0138] * indicates chiral carbon;

[0139] P1 is a protecting group; and

[0140] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[0141] The present invention further provides a method for preparing compositions comprising racemic derivatives of compound Ia:

[0142]

[0143] This includes compositions containing an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula Ia as compounds of formula D-1:

[0144]

[0145] The treatment is carried out in the presence of a base sufficient to form a racemic compound of formula Ia;

[0146] in:

[0147] * indicates chiral carbon;

[0148] P1 is a protecting group; and

[0149] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[0150] The present invention further provides a method for preparing a composition comprising an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula Ia:

[0151]

[0152]

[0153] The composition comprising passing a racemic derivative of a compound containing form Ia through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of (R)- or (S)-enantiomers of the compound containing form Ia.

[0154] Where: * represents chiral carbon;

[0155] R1 is selected from C 3-7 Cycloalkyl, C1-6 alkyl and C 1-6 fluoroalkyl; and

[0156] P1 is a protecting group.

[0157] This invention provides a method for preparing compositions comprising an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula Ia:

[0158]

[0159] include:

[0160] (a) Reacting a composition containing a racemic derivative 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;

[0161] (b) Separating the composition, said composition comprising an enantiomerically excess of a chiral salt of the (R)- or (S)-enantiomer of the compound of formula Ia; and

[0162] (c) Treating a chiral salt with an alkali to form a composition containing an enantiomeric excess of (R)- or (S)-enantiomers of the compound of formula Ia;

[0163] in:

[0164] * indicates chiral carbon;

[0165] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0166] P1 is a protecting group.

[0167] The present invention further provides a method for converting a compound of formula Ia into a compound of formula III, comprising converting the compound of formula Ia:

[0168]

[0169] The reaction proceeds under deprotection conditions to form a compound of formula III:

[0170]

[0171] * indicates chiral carbon;

[0172] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0173] P1 is a protecting group.

[0174] This invention further provides a method for preparing compound XII:

[0175]

[0176]

[0177] Including compounds of formula X:

[0178]

[0179] Compounds of formula XIII:

[0180]

[0181] The reaction is carried out in the presence of a palladium catalyst, a base, and a solvent to form a compound of formula XII.

[0182] in:

[0183] * indicates chiral carbon;

[0184] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[0185] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0186] R c and R d Each independently is H or C 1-6 Alkyl; or

[0187] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles; and

[0188] P1 and P2 are each an independent protective base.

[0189] This invention further provides a method for preparing XVI compounds:

[0190]

[0191] include:

[0192] (a) Making compound XVIII

[0193]

[0194] With about 1 or more equivalent of C 1-6 Alkyl Grignard reagents or C 1-6 The reaction is carried out with an alkyllithium reagent, followed by treatment with about one or more equivalents of a compound of formula XVII:

[0195]

[0196] as well as

[0197] (b) Optionally, the product of step (a) is protected again to obtain compound XVI;

[0198] in:

[0199] P3 is a protecting group;

[0200] X3 is a halogen;

[0201] R4 is C 1-6 Alkyl; and

[0202] m is an integer selected from 1 and 2.

[0203] This invention also provides a method for preparing compounds of formula XIa:

[0204]

[0205] Including compounds of formula F-1:

[0206]

[0207] The mixture was treated with an acid under conditions sufficient to form a compound of formula XIa.

[0208] The present invention further provides a composition comprising an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula I:

[0209]

[0210] in:

[0211] * indicates chiral carbon;

[0212] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0213] R2 is selected from -C(=O)-NH2, -C(=O)O-R3, -C(=O)OH and -C(=O)H;

[0214] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0215] P1 is a protecting group.

[0216] This invention also provides compounds of formula II:

[0217]

[0218] in:

[0219] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl groups; R2 is selected from -C(=O)-NH2 and -C(=O)O-R3;

[0220] R3 is selected from C 1-4 Alkyl or C 1-4 Fluoroalkyl; and P1 is a protecting group.

[0221] This invention also relates to the following items.

[0222] 1. A method for preparing a composition containing a compound of formula I:

[0223]

[0224] Including compounds of formula II:

[0225]

[0226] It reacts with hydrogen in the presence of a hydrogenation catalyst;

[0227] in:

[0228] * indicates chiral carbon;

[0229] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0230] R2 is selected from -C(=O)-NH2, -C(=O)O-R3 and cyano;

[0231] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0232] P1 is a protecting group.

[0233] 2. The method according to Project 1, wherein the composition comprises an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of Formula I; and the hydrogenation catalyst is a ruthenium or rhodium catalyst having L1; wherein L1 is a chiral phosphine ligand.

[0234] 3. The method according to Project 2, wherein the excess of the enantiomer is equal to or greater than about 90%.

[0235] 4. The method according to Project 2, wherein the excess of the enantiomer is equal to or greater than about 99%.

[0236] 5. The method according to Project 2, wherein the chiral phosphine ligand is selected from one of the following:

[0237]

[0238] 6. The method according to item 2, wherein the composition comprises an enantiomer excess of the (S)-enantiomer of the compound of formula I.

[0239] 7. The method according to Item 6, wherein L1 is selected from one of the following ligands:

[0240]

[0241] 8. The method according to item 2, wherein the composition comprises an enantiomer excess of the (R)-enantiomer of the compound of formula I.

[0242] 9. The method according to Item 8, wherein L1 is selected from one of the following ligands:

[0243]

[0244] 10. The method according to any one of items 2 to 9, wherein the product is a compound of formula Ia:

[0245]

[0246] in:

[0247] * indicates chiral carbon;

[0248] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0249] P1 is a protecting group.

[0250] 11. The method according to any one of items 2 to 9, wherein R2 is -C(=O)-NH2.

[0251] 12. The method according to item 11 further comprises reacting the compound of formula I under dehydration conditions to form a compound of formula Ia:

[0252]

[0253] in:

[0254] * indicates chiral carbon;

[0255] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0256] P1 is a protecting group.

[0257] 13. The method according to item 12, wherein the dehydration conditions include trichloroacetyl chloride in the presence of triethylamine.

[0258] 14. The method according to any one of items 2 to 9, wherein R2 is -C(=O)O-R3.

[0259] 15. The method according to any one of items 2 to 9, wherein R2 is -C(=O)OCH3.

[0260] 16. The method according to item 14 or 15, further comprising reacting the compound of formula I with a metal hydroxide to form a compound of formula Ic:

[0261]

[0262] in:

[0263] * indicates chiral carbon;

[0264] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0265] P1 is a protecting group.

[0266] 17. The method according to item 16, wherein the metal hydroxide is an alkali metal hydroxide or an alkaline earth hydroxide.

[0267] 18. The method according to item 16, wherein the metal hydroxide is lithium hydroxide.

[0268] 19. The method according to any one of items 16 to 18, further comprising reacting the compound of formula Ic with ammonia or ammonium hydroxide in the presence of a coupling agent to form a compound of formula Ib:

[0269]

[0270] in:

[0271] * indicates chiral carbon;

[0272] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0273] P1 is a protecting group.

[0274] 20. The method according to item 19, wherein the coupling agent is N,N-carbonyldiimidazole.

[0275] 21. The method according to any one of items 19 to 20, further comprising reacting the compound of formula Ib under dehydration conditions to form the compound of formula Ia:

[0276]

[0277] in:

[0278] * indicates chiral carbon;

[0279] R1 is selected from C 3-7 cycloalkyl, C1-6 Alkyl and C 1-6 fluoroalkyl; and

[0280] P1 is a protecting group.

[0281] 22. The method according to any one of items 2 to 21, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0282] 23. The method according to any one of items 2 to 22, wherein R1 is cyclopentyl.

[0283] 24. A method for preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula Id:

[0284]

[0285] Including compounds of formula IV:

[0286]

[0287] Compounds of formula V:

[0288]

[0289] The reaction occurs in the presence of chiral amines and organic acids.

[0290] in:

[0291] * indicates chiral carbon;

[0292] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0293] P1 is a protecting group.

[0294] 25. A method for preparing a composition containing an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula VI:

[0295]

[0296] Including compounds of formula V:

[0297]

[0298] Compounds of Formula VII:

[0299]

[0300] The reaction occurs in the presence of chiral amines and organic acids.

[0301] Where: * indicates chiral carbon;

[0302] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0303] X1 is a halogen.

[0304] 26. The method according to item 24 or 25, wherein the organic acid is p-toluenesulfonic acid.

[0305] 27. The method according to any one of items 24 to 26, wherein the chiral amine is an (R)- or (S)-enantiomer of a compound of formula A-1:

[0306]

[0307] in:

[0308] X is CY3Y4 and Y is CY5Y6; or

[0309] X is S or NY7, and Y is CY5Y6; or

[0310] X is CY3Y4, and Y is S;

[0311] Q1 and Q2 are each independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated groups, carboxyl groups, C 1-6 Alkyl carboxamide, C 1-6 Alkoxycarbonyl and phenyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkyl carboxamide, C 1-6 Each of the alkoxycarbonyl and phenyl groups is optionally selected independently by one, two, or three groups from hydroxyl, carboxyl, tri-C 1-6 Alkyl silyl, tri-C 1-6 Alkylsilyloxy, C 6-10 Aryl, C 6-10 Aromatic amino, C 1-9 heteroaryl and C 1-9 Substitution of a heteroaryl amino group; wherein the C 6-10 Aryl, C 6-10 Aromatic amino, C 1-9 heteroaryl and C 1-9 Each of the heteroaryl amino groups is optionally selected independently from halogens, C, and D. 1-6 Alkyl and C 1-6 The alkyl halogroup is substituted; and each of Y1, Y2, Y3, Y4, Y5, and Y6 is independently selected from H, hydroxyl, carboxyl, C. 1-6 Alkyl, C1-6 Halogenated, C 1-6 Alkoxycarbonyl and phenyl; or

[0312] Y1 and Y2 combine to form an oxo group; or

[0313] Y3 and Y4 combine to form an oxo group; or

[0314] Y5 and Y6 combine to form an oxo group; or

[0315] Y1 and Y2, together with the carbon atoms they are attached to, form a 5- or 6-membered cycloalkyl ring; or

[0316] Q1 and Y5, together with the carbon atoms they are attached to, form 5- or 6-membered cycloalkyl rings.

[0317] 28. The method according to any one of items 24 to 26, wherein the chiral amine is an (R)- or (S)-enantiomer of compound A-2:

[0318]

[0319] in

[0320] * indicates a chiral carbon with an (R)- or (S)- configuration;

[0321] Ar1 and Ar2 are each independently selected from C by 1, 2, 3 or 4 independently. 1-6 Alkyl and C 1-6 C-substituted with alkyl halogen groups 6-10 Aryl;

[0322] Each R a Selected independently from C 1-6 Alkyl; and

[0323] R b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated groups.

[0324] 29. According to the method described in Item 28, wherein:

[0325] Ar1 and Ar2 are each independently a phenyl group optionally substituted with 1, 2, 3 or 4 groups independently selected from methyl and trifluoromethyl groups;

[0326] Each R a Independently selected from methyl, ethyl, or tert-butyl;

[0327] R b For H.

[0328] 30. The method according to any one of items 24 to 26, wherein the chiral amine is an (R)- or (S)-enantiomer selected from the group consisting of: proline, prolylamide, prolyl-L-leucine, prolyl-L-alanine, prolylglycine, prolyl-L-phenylalanine, diphenylpyrrolidine, dibenzylpyrrolidine, N-(1-methylethyl)pyrrolidine carboxamide, 2-(anilinemethyl)pyrrolidine, 2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, diphenyl(pyrrolidine-2-yl)pyrrolidine Methanol, proline, 4-thiazolidinylcarboxylic acid, trans-3-hydroxyproline, trans-4-hydroxyproline, 4-benzyl-1-methyl-imidazolium-2-carboxylic acid, 1-methyl-4-phenyl-imidazolium-2-carboxylic acid, 4,5-octahydro-benzimidazole-2-carboxylic acid, 4,5-diphenyl-imidazolium-2-carboxylic acid, N1-methyl-3-phenylpropane-1,2-diamine, 1,2-diphenylethylenediamine, 1-methyl-4-(1-methyl-1H-indol-3-ylmethyl)-imidazolium-2-carboxylic acid, 4-benzyl-1-methyl 2-Imidazolidine-2-carboxylic acid, 1,2-cyclohexanediamine, 2-phenyl-thiazolidin-4-carboxylic acid, tert-leucine methyl ester, 5-benzyl-2,2,3-trimethyl-imidazolin-4-one, proline methyl ester, 4,5-diphenylimidazolidin, 2-cyclohexyl-4,5-diphenylimidazolidin, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{bis-[3,5-dimethylphenyl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{diphenyl-trimethyl... Silalkoxy-methyl}-pyrrolidine, 2-{bis[naphthyl-2-yl]-trimethylsilalkoxy-methyl}-pyrrolidine, 2-{tert-butyldimethylsilalkoxy-diphenyl-methyl}-pyrrolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-triethylsilalkoxy-methyl}-pyrrolidine and 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-ethyl-dimethylsilalkoxy-methyl}-pyrrolidine; wherein the (R)- or (S)- configuration is on a carbon adjacent to the NH group in the compound.

[0329] 31. The method according to any one of items 27 to 30, wherein the chiral amine is an (R)-enantiomer.

[0330] 32. The method according to any one of items 24 to 26, wherein the chiral amine is selected from one of the following compounds:

[0331] 33. The method according to any one of items 24 to 32, wherein the excess of the enantiomer is equal to or greater than about 90%.

[0332] 34. The method according to any one of items 24 to 32, wherein the excess of said enantiomer is equal to or greater than about 99%.

[0333] 35. The method according to item 24 further comprises treating the compound of formula Id with ammonia or ammonium hydroxide and iodine to form the compound of formula Ia:

[0334]

[0335] in:

[0336] * indicates chiral carbon;

[0337] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0338] P1 is a protecting group.

[0339] 36. The method according to item 25 further comprises treating the compound of formula VI with ammonia or ammonium hydroxide and iodine to form the compound of formula VIII:

[0340]

[0341] in:

[0342] * indicates chiral carbon;

[0343] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0344] P1 is a protecting group; and

[0345] X1 is a halogen.

[0346] 37. The method according to item 36 further comprises reacting the compound of formula VIII with the compound of formula B-1:

[0347]

[0348] To form compounds of formula IX:

[0349]

[0350]

[0351] in:

[0352] * indicates chiral carbon;

[0353] R1 is selected from C 3-7 cycloalkyl, C1-6 Alkyl and C 1-6 fluoroalkyl;

[0354] X1 is a halogen group; and

[0355] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[0356] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0357] 38. The method according to item 37, wherein the compound of formula B-1 is 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bis[1,3,2-dioxoboronylcycloyl].

[0358] 39. The method according to item 37 or 38, further comprising reacting the compound of formula IX with the compound of formula X:

[0359]

[0360] The reaction proceeds in the presence of a palladium catalyst and a base to form a compound of formula Ia:

[0361]

[0362] in:

[0363] * indicates chiral carbon;

[0364] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0365] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[0366] P1 is a protecting group; and

[0367] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[0368] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0369] 40. The method according to any one of items 24, 26 to 35 and 24 to 39, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0370] 41. The method according to any one of items 24 to 40, wherein R1 is cyclopentyl.

[0371] 42. A composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula IX:

[0372]

[0373] in:

[0374] * indicates chiral carbon;

[0375] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0376] R c and R d Each independently for C 1-6 Alkyl; or

[0377] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0378] 43. The composition according to item 42, wherein R1 is cyclopentyl.

[0379] 44. A method for preparing a composition according to item 42 or 43, comprising passing a composition containing a racemic form of the IX compound through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of the (R)- or (S)-enantiomer of the IX compound.

[0380] 45. The method according to item 44, wherein the mobile phase comprises ethanol and hexane, wherein the ethanol is present in an amount of about 25 vol% to about 10 vol%.

[0381] 46. ​​The method according to item 42 or 45, wherein the chromatographic unit is a simulated moving bed (SMB) chromatographic unit comprising a set of eight columns or chiral column units, wherein each column is packed with a chiral stationary phase.

[0382] 47. The method according to item 46, wherein the chiral stationary phase is a cellulose-modified chiral stationary phase.

[0383] 48. The method according to any one of items 44 to 47, wherein the compound of formula IX is as follows:

[0384]

[0385] 49. The method according to any one of items 44 to 48, further comprising making a compound of formula IX:

[0386]

[0387] Compounds of formula XI:

[0388]

[0389] The reaction is carried out in the presence of a palladium catalyst, a base, and a solvent to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of formula III:

[0390]

[0391] in:

[0392] * indicates chiral carbon;

[0393] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[0394] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0395] R c and R d Each independently for C 1-6 Alkyl; or

[0396] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0397] 50. The method according to any one of items 44 to 48, further comprising making a compound of formula IX:

[0398]

[0399] Compound X:

[0400]

[0401] Under certain conditions, in the presence of a palladium catalyst, a base, and a solvent, a reaction is carried out for a sufficient period of time to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of formula Ia:

[0402]

[0403] in:

[0404] * indicates chiral carbon;

[0405] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0406] R c and R d Each independently for C 1-6 Alkyl; or

[0407] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles;

[0408] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group; and

[0409] P1 is a protecting group.

[0410] 51. A method for preparing a composition containing a racemic compound of formula Ia:

[0411]

[0412] include:

[0413] a) A composition comprising an enantiomer in excess of the (R)- or (S)-enantiomer of a compound of formula Ia as a compound of formula D-1:

[0414]

[0415] The treatment is carried out in the presence of the first base, under conditions sufficient to form compound IV:

[0416]

[0417] as well as

[0418] (b) Reacting compound IV with compound D-1 in the presence of a second base;

[0419] in:

[0420] * indicates chiral carbon;

[0421] P1 is a protecting group; and

[0422] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[0423] 52. The method according to item 51, wherein the first base is cesium carbonate.

[0424] 53. The method according to item 51 or 52, wherein the second base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0425] 54. A method for preparing a composition containing a racemic compound of formula Ia:

[0426]

[0427] This includes compositions containing an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula Ia as compounds of formula D-1:

[0428]

[0429] The treatment is carried out in the presence of a base, under conditions sufficient to form the racemic compound of formula Ia;

[0430] in:

[0431] * indicates chiral carbon;

[0432] P1 is a protecting group; and

[0433] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[0434] 55. The method according to item 54, wherein the base is potassium tert-butoxide.

[0435] 56. The method according to any one of items 51 to 55, further comprising preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia:

[0436]

[0437] The composition comprising passing a racemic derivative of a compound containing form Ia through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of (R)- or (S)-enantiomers of the compound containing form Ia.

[0438] in:

[0439] * indicates chiral carbon;

[0440] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0441] P1 is a protecting group.

[0442] 57. The method according to item 56, wherein the mobile phase comprises isopropanol and hexane, wherein the isopropanol is present in an amount of about 25 vol% to about 10 vol%.

[0443] 58. The method according to any one of items 56 to 57, wherein the chromatographic unit is a simulated moving bed (SMB) chromatographic unit having a set of eight columns or chiral column units, wherein each column is filled with a chiral stationary phase.

[0444] 59. The method according to any one of items 51 to 58, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0445] 60. The method according to any one of items 51 to 60, wherein R1 is cyclopentyl.

[0446] 61. A method for preparing a composition comprising an enantiomeric excess of a (R)- or (S)-enantiomer of a compound of formula Ia:

[0447]

[0448] include:

[0449] (a) Reacting a composition containing a racemic derivative 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;

[0450] (b) Separating the composition, said composition comprising an enantiomerically excess of a chiral salt of the (R)- or (S)-enantiomer of the compound of formula Ia; and

[0451] (c) Treat the chiral salt with an alkali to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia;

[0452] in:

[0453] * indicates chiral carbon;

[0454] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C1-6 fluoroalkyl; and

[0455] P1 is a protecting group.

[0456] 62. The method according to item 61, wherein the chiral acid is selected from optically active forms of mandelic acid, 2-chloromandelic acid, camphor sulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphor sulfonic acid, dibenzoyl tartaric acid, di-p-toluyl tartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]hept-1-methylenesulfonic acid and 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methylenesulfonic acid.

[0457] 63. The method according to item 61, wherein the chiral acid is (+)-dibenzoyl-D-tartaric acid.

[0458] 64. The method according to any one of items 61 to 63, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0459] 65. The method according to any one of items 61 to 64, wherein R1 is cyclopentyl.

[0460] 66. A method for preparing compound XII:

[0461]

[0462] Including compounds of formula X:

[0463]

[0464] Compounds of formula XIII:

[0465]

[0466] The reaction is carried out in the presence of a palladium catalyst, a base, and a solvent to form a compound of formula XII; wherein:

[0467] * indicates chiral carbon;

[0468] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[0469] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0470] R c and R d Each independently is H or C 1-6 Alkyl; or

[0471] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles; and

[0472] P1 and P2 are each an independent protective base.

[0473] 67. The method according to item 66, wherein the compound of formula XIII is as follows:

[0474]

[0475] 68. The method according to any one of items 66 to 67, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0476] 69. The method according to any one of items 66 to 68, wherein P2 is 1-(ethoxy)ethyl.

[0477] 70. The method according to any one of items 10, 12, 13, 21, 35, 39, 50 and 56 to 63, further comprising reacting the compound of formula Ia under deprotection conditions to form the compound of formula III:

[0478]

[0479] * indicates chiral carbon;

[0480] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0481] P1 is a protecting group.

[0482] 71. The method according to item 70, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0483] 72. The method according to item 70 or 71, wherein R1 is cyclopentyl.

[0484] 73. The method according to item 70 or 71, wherein the compound of formula III is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile.

[0485] 74. The method according to any one of items 70 to 73 further comprises reacting the compound of formula III with phosphoric acid to form a phosphate of said compound of formula III.

[0486] 75. A method for preparing compound XVI:

[0487]

[0488] include:

[0489] (a) Making compound XVIII

[0490]

[0491] With about 1 or more equivalent of C 1-6 Alkyl Grignard reagents or C 1-6 The reaction is carried out with an alkyllithium reagent, followed by treatment with about one or more equivalents of a compound of formula XVII:

[0492]

[0493] as well as,

[0494] (b) Optionally, the product of step (a) is protected again to obtain compound XVI;

[0495] in:

[0496] P3 is a protecting group;

[0497] X3 is a halogen;

[0498] R4 is C 1-6 Alkyl; and

[0499] m is an integer selected from 1 and 2.

[0500] 76. The method according to item 75, wherein X3 is an iodine group or a bromine group.

[0501] 77. The method according to item 75 or 76, wherein P3 is 1-(ethoxy)ethyl.

[0502] 78. The method according to any one of items 75 to 77, wherein the compound of formula XVI is as follows:

[0503]

[0504] 79. The method according to any one of items 75 to 78, further comprising a method for preparing a compound of formula XVIII, including a protected compound of formula XIX:

[0505]

[0506] in:

[0507] P3 is a protecting group;

[0508] X3 is a halogen;

[0509] And m is an integer selected from 1 and 2.

[0510] 80. The method according to any one of items 75 to 79, further comprising preparing the compound of formula XIX by a method comprising reacting 1H-pyrazole with a halogenating agent, wherein:

[0511] X3 is a halogen; and

[0512] m is an integer selected from 1 and 2.

[0513] 81. The method according to any one of items 75 to 80, wherein the halogenating agent is selected from N-bromosuccinimide or N-iodosuccinimide.

[0514] 82. A method for preparing compounds of formula XIa:

[0515]

[0516] Including compounds of formula F-1:

[0517]

[0518] The mixture was treated with an acid under conditions sufficient to form a compound of formula XIa.

[0519] 83. The method according to item 82, wherein the acid is a concentrated hydrochloric acid aqueous solution.

[0520] 84. The method according to any one of items 82 to 83, further comprising preparing the compound of formula F-1 by a method comprising causing the compound of formula F-2:

[0521]

[0522] It reacts with about 1 or more equivalents of a Wittig-type reagent having the formula -CH2OCH3 ylide in the presence of a base.

[0523] 85. The method according to any one of items 82 to 84, further comprising preparing the compound of formula F-1 by a method comprising causing the compound of formula F-3:

[0524]

[0525] It reacts with about 2 or more equivalents of ammonia in a solvent.

[0526] 86. The method according to any one of items 82 to 85, further comprising preparing the compound of formula F-1 by a method comprising causing the compound of formula F-4:

[0527]

[0528] It reacts with chlorinating agents.

[0529] 87. A composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula I:

[0530]

[0531] in:

[0532] * indicates chiral carbon;

[0533] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0534] R2 is selected from -C(=O)-NH2, -C(=O)O-R3, -C(=O)OH and -C(=O)H;

[0535] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0536] P1 is a protecting group.

[0537] 88. The composition according to item 87, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0538] 89. The composition according to item 87 or 88, wherein R1 is cyclopentyl.

[0539] 90. A compound of formula II:

[0540]

[0541] in:

[0542] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0543] R2 is selected from -C(=O)-NH2 and -C(=O)O-R3;

[0544] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0545] P1 is a protecting group.

[0546] 91. According to the compound in item 90, P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[0547] 92. Compounds according to item 90 or 91, wherein R1 is cyclopentyl.

[0548] 93. A method for preparing a composition comprising a compound of formula III' in an enantiomeric excess of 90% or more (R)-enantiomers:

[0549]

[0550] include:

[0551] (a) Compound of formula XI':

[0552]

[0553] Treatment with sodium hydride and N-pentanoyloxymethyl chloride to form compound X':

[0554]

[0555] (b) The compound of formula X' is converted into compound of formula XIII':

[0556]

[0557] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII':

[0558]

[0559] (c) Reacting the compound of formula XII' under deprotection conditions to obtain the compound of formula IV':

[0560]

[0561] (d) Mixing the compound of formula IV" with the compound of formula XIV':

[0562]

[0563] The reaction was carried out in the presence of 1,8-diaza-bicyclo[5.4.0]undec-7-ene to give compound II':

[0564]

[0565] (e) Reacting the compound of formula II' with hydrogen in the presence of [Rh(COD)2]CF3SO3 and a chiral phosphine ligand selected from the following:

[0566]

[0567] To form compounds of formula I':

[0568] as well as

[0569] (f) Reacting the compound of formula I' under deprotection conditions to form the compound of formula III';

[0570] * indicates chiral carbon.

[0571] 94. The method according to item 93 further includes preparing the compound of formula XI':

[0572]

[0573] include:

[0574] (i) To make F-4 compound:

[0575]

[0576] It reacts with 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:

[0577]

[0578] (ii) Reacting the F-3 compound with about two equivalents of ammonia in methanol to form a compound of formula F-2:

[0579]

[0580] (iii) Mixing the compound of formula F-2 with about 1 to about 1.5 equivalents of formula [Ph3P] + The Wittig-type reagent of (CH2OCH3)]Cl- reacts in the presence of about 1 to about 1.5 equivalents of potassium tert-butoxide, wherein Ph is a phenyl group, to form a compound of formula F-1:

[0581] as well as

[0582] (iv) The compound of formula F-1 is refluxed in tetrahydrofuran with concentrated hydrochloric acid aqueous solution to form compound of formula XI'.

[0583] 95. The method according to item 93 further comprises preparing the compound of formula XIII':

[0584]

[0585] include:

[0586] (i) React 1H-pyrazole with N-bromosuccinimide to form a compound of formula XIX';

[0587]

[0588] (ii) Protect the compound of formula XIX to form compound of formula XVIII':

[0589] as well as

[0590] (iii) Reacting the compound of formula XVIII' with about one or more equivalents of isopropyl magnesium chloride, followed by treatment with about one or more equivalents of the compound of formula XVII':

[0591]

[0592] To form compound XIII'.

[0593] 96. The method according to item 93 further comprises preparing the compound of formula XIII':

[0594]

[0595]

[0596] include:

[0597] (i) Protect 4-iodo-1H-pyrazole to form a compound of formula XVIII":

[0598] as well as

[0599] (ii) Reacting the compound of formula XVIII" with about one or more equivalents of isopropyl magnesium chloride in tetrahydrofuran, followed by treatment with about one or more equivalents of the compound of formula XVII':

[0600]

[0601] To form compound XIII'.

[0602] 97. The method according to item 93, wherein in step (e):

[0603] The solvent is 2,2,2-trifluoroethanol (TFE);

[0604] The hydrogenation catalyst is loaded in an amount of about 0.005 to about 0.01 mol%.

[0605] The ratio of the compound of formula II to the hydrogenation catalyst is from about 20,000 / 1 to about 10,000 / 1;

[0606] The hydrogen pressure is approximately 7 to approximately 60 bar;

[0607] The reaction was carried out at a temperature of approximately room temperature to approximately 75°C;

[0608] The reaction is run until the conversion of compound II to compound III is approximately equal to or greater than 99.5%; and

[0609] The reaction takes approximately 10 to 25 hours.

[0610] 98. A method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[0611]

[0612] include:

[0613] (a) Compound of formula XI':

[0614]

[0615] Treatment with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form compound X":

[0616]

[0617] (b) The compound of formula X" is converted into compound of formula XIII':

[0618]

[0619] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII":

[0620]

[0621] (c) Reacting the compound of formula XII" under deprotection conditions to form the compound of formula IV":

[0622]

[0623] (d) Mixing the compound of formula IV" with the compound of formula D-1':

[0624]

[0625] The reaction is carried out under conditions sufficient to form a racemic compound containing formula I":

[0626]

[0627] (e) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[0628] (f) React the compound of formula I" with lithium tetrafluoroborate, and then with an aqueous solution of ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[0629] * represents chiral carbon.

[0630] 99. A method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[0631]

[0632] include:

[0633] (a) A composition containing an enantiomer excess of the (S)-enantiomer of a compound of formula I":

[0634]

[0635] Compound of formula D-1':

[0636]

[0637] The mixture is treated in acetonitrile in the presence of cesium carbonate under conditions sufficient to form a racemic product of formula I".

[0638] (b) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[0639] (c) React the compound of formula I" with lithium tetrafluoroborate, and then with an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[0640] * represents chiral carbon.

[0641] 100. A method for preparing a composition comprising an enantiomeric excess of (R)-enantiomer of a compound of formula III':

[0642]

[0643] include:

[0644] (a) Compound of formula XI':

[0645]

[0646] Treatment with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form compound X":

[0647]

[0648] (b) The compound of formula X" is converted into compound of formula XIII':

[0649]

[0650] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII":

[0651]

[0652] (c) Reacting the compound of formula XII" under deprotection conditions to form the compound of formula IV":

[0653]

[0654]

[0655] (d) Mixing the compound of formula IV" with the compound of formula D-1':

[0656]

[0657] The reaction is carried out under conditions sufficient to form a racemic compound containing formula I":

[0658]

[0659] (e) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[0660] (f) React the compound of formula I" with boron trifluoride diethyl ether, and then with an aqueous solution of ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[0661] * represents chiral carbon.

[0662] 101. A method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[0663]

[0664] include:

[0665] (a) A composition containing an enantiomer excess of the (S)-enantiomer of a compound of formula I":

[0666]

[0667] Compound of formula D-1':

[0668]

[0669] The mixture is treated in acetonitrile in the presence of cesium carbonate under conditions sufficient to form a racemic product of formula I".

[0670] (b) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[0671] (c) React the compound of formula I" with boron trifluoride diethyl ether, followed by an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[0672] * represents chiral carbon.

[0673] 102. A method for preparing a composition comprising an enantiomeric excess of (R)-enantiomer of a compound of formula III':

[0674]

[0675] Includes: compounds of formula I:

[0676]

[0677] The compound is reacted with boron trifluoride ether, followed by an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III'; wherein * is a chiral carbon.

[0678] 103. A method for preparing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate, 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.

[0679] 104. A method for purifying (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate, comprising recrystallizing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate from a solvent mixture comprising methanol, 2-propanol and n-heptane.

[0680] 105. The method according to item 104, wherein the 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 in methanol. Detailed Implementation Plan

[0681] Substituents of the compounds of the present invention are disclosed in different locations throughout this patent specification, in the manner of groups or ranges. Specifically, this is intended to indicate that the invention includes each individual sub-combination of members of such groups and ranges. For example, the term "C" 1-6 The term "alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0682] To further understand, for clarity, certain features of the invention are described with respect to individual embodiments, but combinations of individual embodiments may also be provided. Conversely, for simplicity, various features of the invention are described with respect to individual embodiments, but may also be provided individually or in any suitable sub-combinations.

[0683] The term "n-membered" (where n is an integer) typically describes the number of atoms forming a ring in a portion, where the number of atoms forming the ring is n. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, while 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring.

[0684] For compounds of the invention where a variable appears more than once, each variable may be a different portion of the group that defines that variable, selected independently. For example, in describing a structure having two R groups simultaneously present on the same compound, the two R groups may represent different portions selected independently of the group defined with respect to R. In another example, when multiple substituents are optionally indicated in the following form:

[0685]

[0686] It should be understood that the substituent R can appear p times on the ring, and each appearance of R can be a different part. It should also be understood that each R group can substitute for any hydrogen atom attached to a ring atom, including (CH2). nOne or two hydrogen atoms. Additionally, in the examples above, if the variable Q includes hydrogen, such as when Q is CH2, NH, etc., any non-fixed substituent (such as R in the examples above) can replace the hydrogen in the variable Q as well as hydrogen in any other non-variable part of the ring.

[0687] For compounds of the present invention where a variable appears more than once, each variable can be a different part of the group that independently defines the variable. For example, in describing a structure having two R groups present simultaneously on the same compound, the two R groups can represent different parts independently selected from the group defined with respect to R.

[0688] The term “optionally substituted” as used herein means either unsubstituted or substituted. The term “substituted” as used herein means that a hydrogen atom has been removed and replaced by a substituent. The term “substituted with an oxo group” as used herein means that two hydrogen atoms have been removed from a carbon atom and replaced by an oxygen atom bonded to the carbon atom via a double bond. It should be understood that substitution on a given atom is limited by the valence of the atom.

[0689] The term "alkyl" as used alone or in combination with other terms herein refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, or 1 to 6 carbon atoms. Examples of alkyl moiety include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher carbon homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, n-octyl, etc. In some embodiments, the alkyl moiety is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or 2,4,4-trimethylpentyl. In some embodiments, the alkyl moiety is methyl.

[0690] As used herein, the terms "alkylcarboxamide" or "alkylaminocarbonyl" refer to a group of the formula -C(O)-NH(alkyl). In some embodiments, each alkyl group has 1 to 6 carbon atoms.

[0691] As used alone or in conjunction with other terms herein, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 10 or 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0692] As used alone or in conjunction with other terms herein, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 10 or 2 to 6 carbon atoms.

[0693] The term "alkoxy" as used alone or in combination with other terms herein refers to a group of the formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. In some embodiments, each alkyl group has 1 to 6 carbons.

[0694] As used herein, the term "alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl. In some embodiments, each alkyl group has 1 to 6 carbons.

[0695] The term "tri-C" as used in this article n-m "alkylsilyl" refers to a group of the formula -Si(alkyl)3, wherein each alkyl group has n to m carbon atoms. In some embodiments, each alkyl group has 1 to 6 carbon atoms.

[0696] The term "tri-C" as used in this article n-m "alkylsilyloxy" refers to a group of the formula -OSi(alkyl)3, wherein each alkyl group has n to m carbon atoms. In some embodiments, each alkyl group has 1 to 6 carbon atoms.

[0697] The term "aryl," used alone or in combination with other terms herein, refers to a monocyclic or polycyclic aromatic hydrocarbon moiety (e.g., having 2, 3, or 4 fused rings), such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracene, phenanthrene, etc. In some embodiments, the aryl moiety may be further fused to a cycloalkyl ring. In some embodiments, the aryl group has 6 to 20 carbon atoms, about 6 to 10 carbon atoms, or about 6 to 8 carbon atoms.

[0698] The term "aromatic amino" as used in this document refers to a group of the formula -NH (aryl).

[0699] The term "carboxyl group" as used in this document refers to the group of formula -C(O)OH.

[0700] The term "cycloalkyl" as used alone or in combination with other terms herein refers to a non-aromatic cyclic hydrocarbon moiety that optionally contains one or more alkenyl or alynyl groups as part of a ring structure. A cycloalkyl group may comprise a mono- or polycyclic (e.g., having 2, 3, or 4 fused or covalently linked rings) ring system. One or more cyclic carbon atoms of a cycloalkyl group may be oxidized to form a carbonyl bond. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, etc. In some embodiments, the cycloalkyl group is cyclopentyl.

[0701] The term “haloalkyl” as used alone or in combination with other terms herein refers to an alkyl group having one to 2n+1 halogen atoms, which may be the same or different, where “n” is the number of carbon atoms in the alkyl group.

[0702] The term "fluorinated alkyl" as used alone or in combination with other terms herein refers to an alkyl group having one to 2n+1 fluorine atoms, which may be the same or different, where "n" is the number of carbon atoms in the alkyl group. In some embodiments, the fluorinated alkyl group is trifluoromethyl.

[0703] The terms “halogen” and “halogen” as used alone or in combination with other terms in this document refer to fluorine, chlorine, bromine, and iodine groups.

[0704] The terms “heteroaryl,” “heteroaryl ring,” or “heteroaryl group,” used alone or in combination with other terms herein, refer to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon moiety having one or more heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl ring or group has 1, 2, 3, or 4 heteroatoms selected from N, O, or S. In some embodiments, the heteroaryl ring or group has 1 or 2 rings. When a heteroaryl contains more than one heteroatom ring member, the heteroatoms can be the same or different. In some embodiments, the heteroaryl moiety may be further fused to a cycloalkyl or heterocycloalkyl ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purine, carbazoleyl, benzimidazolyl, indololinyl, etc. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms, and in further embodiments, has about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. The linking heteroaryl group is referred to herein as a "hybrid aryl".

[0705] The term “heteroarylamine” as used herein refers to a group of the formula -NH (heteroaryl).

[0706] As used herein, “heterocyclic alkyl” refers to a non-aromatic heterocycle, including cyclic alkyl, alkenyl, and alkynyl groups, wherein one or more cyclic carbon atoms are substituted with heteroatoms (such as O, N, or S atoms). Heterocyclic alkyl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems, as well as spirocyclic groups. Examples of “heterocyclic alkyl groups” include morpholino, thiomorpholino, piperazine, tetrahydrofuranyl, tetrahydrothiophene, 2,3-dihydrobenzofuranyl, 1,3-benzodioxotropine, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, etc. The cyclic carbon atoms and heteroatoms of a heterocyclic alkyl group may optionally be substituted with oxo or thio groups. Also included in the definition of heterocyclic alkyl is a portion of an aromatic ring having one or more fused to a non-aromatic heterocycle (i.e., having chemical bonds shared with the non-aromatic heterocycle), such as a phthalimide group, a naphthalimide group, and a benzo[a] derivative of the heterocycle. Heterocyclic alkyl groups may be linked via cyclic carbon atoms or cyclic heteroatoms. Heterocyclic alkyl groups containing fused aromatic rings may be linked via any cyclic atom (including cyclic atoms of fused aromatic rings). In some embodiments, the heterocyclic alkyl group has 1 to about 20 carbon atoms, and in further embodiments, about 3 to about 20 carbon atoms. In some embodiments, the heterocyclic alkyl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double or triple bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double or triple bonds. The linking heterocyclic alkyl group is referred to herein as a "heterocyclic alkyl subgroup".

[0707] The term "oxo" as used in this article refers to the =O group.

[0708] The term “trifluoromethanesulfonate group” as used in this document refers to trifluoromethanesulfonyloxy.

[0709] The term "toluenesulfonate group" as used herein refers to p-toluenesulfonyloxy.

[0710] The processes described herein can be monitored using any suitable method known in the art. For example, the formation of products can be monitored using spectroscopic devices, such as nuclear magnetic resonance spectroscopy (e.g., nuclear magnetic resonance spectroscopy). 1 H or 13 C) Infrared spectroscopy or spectrophotometry (e.g., UV-Vis light); or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) or other related techniques.

[0711] The term "reaction" as used herein is known in the art and generally refers to the combination of chemical reagents in such a way that they interact at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reaction involves two reagents, wherein one or more equivalents of a second reagent are used relative to the first reagent. The reaction steps of the methods described herein may be carried out for a period of time and under conditions suitable for the preparation of the determined product.

[0712] As used herein, the terms “chiral chromatography”, “chiral column”, or “chiral column” refer to a chromatographic apparatus or method for separating mixtures of enantiomers or diastereomers dissolved in a mobile phase. When the term “preparative” is used in conjunction with any of the foregoing terms, it indicates that the apparatus or method is large enough to separate the desired number of enantiomers or diastereomers. Exemplary separation methods suitable for chiral chromatography include batch and continuous HPLC (high performance liquid chromatography), SFC (supercritical fluid chromatography), such as SMB (simulated moving bed), and related techniques. The method of the present invention can utilize any chromatographic method for separating racemic compounds to produce optically pure desired enantiomers. This method includes, but is not limited to, conventional single-column batch chromatography, continuous chromatography, or steady-state sequential injection methods (as described, for example, in U.S. Patent 5,630,943 and PCT Publication WO 98 / 51391). Continuous chromatography methods include, but are not limited to, multi-column continuous chromatography methods, including countercurrent chromatography methods such as SMB (as described, for example, in U.S. Patents 2,985,589, 4,402,832, and 4,498,991), or those referred to as "Varicol". TM "The non-steady-state continuous chromatography method (as described, for example, in U.S. Patents 6,136,198; 6,375,839; 6,413,419; and 6,712,973).

[0713] In enantiomer separation, these methods involve the use of a chiral stationary phase. Chiral stationary phases can be used to separate diastereomers. The term "stationary phase" refers to a suitable inert support material on which the interacting agent is coated or fixed.

[0714] As used herein, the term "chiral stationary phase" refers to a stationary phase in which the interacting agent is an enantiomerically enriched resolving agent, which is immobilized on an inert support material, for example by coating, chemical bonding, or by reducing solubility via cross-linking. Suitable inert support materials are preferably macroporous, such as cross-linked polystyrene, polyacrylamide, polyacrylate, alumina, diatomite, quartz, kaolin, magnesium oxide, or titanium dioxide. In some embodiments, the inert support material comprises silica gel. The average particle size of the packing material varies depending on the volumetric flow rate of the solvent flowing in the chromatographic system. In some embodiments, it is 1 to 300 micrometers, 2 to 100 micrometers, 5 to 75 micrometers, or 10 to 30 micrometers. Appropriate selection of the average particle size of the packing material helps to regulate the pressure drop during chromatography and the efficiency of the packing material. Examples of stationary phases containing enantiomerically enriched resolving agents include, for example, phases based on synthetic or naturally occurring chiral polymers, macrocyclic phases, ligand-exchange phases, and pirkle-type phases. Such chiral stationary phases are known and commercially available. In some embodiments, the chiral stationary phase is derived from at least one sugar derivative, particularly a polysaccharide derived from polysaccharides selected from amylose, cellulose, chitosan, xylan, gelatin, dextran, and isoflavones. In some embodiments, the chiral stationary phase is a member of amylose or cellulose polysaccharides. Esters and carbamates of these substances are particularly suitable. In other embodiments, the chiral stationary phase is selected from cellulose phenyl carbamate derivatives, such as cellulose tris(3,5-dimethylphenyl)carbamate (which can be "…"). OD or " "IB" is derived from Daicel Chemical Industries, Ltd. (Daicel), where carbamate derivatives are bonded to the cellulose backbone; cellulose tribenzoate derivatives, such as cellulose tri-4-methylbenzoate (which can " "OJ" is derived from Daicel; cellulose tricinnamate (can be " "OK" is derived from Daicel; amylase phenyl and benzyl carbamate derivatives, such as amylose tri[(S)-benzyl carbamate α-methyl ester] (can " "AS" is derived from Daicel; amylose tris(3,5-dimethylphenyl)carbamate (can be " AD" or " "IA" is derived from Daicel, wherein a carbamate derivative is bonded to the amylose backbone; 3,4-substituted phenyl carbamate or 4-substituted phenyl carbamate of amylose; and amylose tricinnamate. In some embodiments, the chiral phase is a member of the Pirkle phase family; (S,S) 1 and (R,R) 1 (available from Regis Technologies Inc.) is preferred.

[0715] As used herein, the term "mobile phase" refers to a solvent or solvent mixture in which the enantiomer mixture to be separated is dissolved. Suitable solvents for the preparative chromatographic method according to the invention are solvents known for use in analytical chromatography. In liquid chromatography, nonpolar, polar proton or aprotic solvents or mixtures thereof are typically used. In supercritical chromatography, a mixture of carbon dioxide and a polar proton solvent is preferred. Suitable nonpolar solvents are, for example, hydrocarbons such as n-pentane, n-hexane, hexane, n-heptane, heptane, cyclohexane, and methylcyclohexane. Suitable proton or aprotic solvents are, for example, alcohols, particularly methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol; ethers, such as methyl tert-butyl ether; esters, such as ethyl acetate; halogenated hydrocarbons; and acetonitrile. Adding, for example, less than 1% (v / v) of water, an acid (e.g., formic acid, acetic acid, trifluoroacetic acid), or a base (e.g., an organic base such as triethylamine) to the solvent can have an advantageous effect.

[0716] In liquid chromatography, C1-C3 alcohols or mixtures of these alcohols with hydrocarbons (e.g., n-hexane or n-heptane) can be used. In supercritical chromatography, mixtures of carbon dioxide with polar protic solvents (e.g., methanol) can be used. Optimal solvents (combinations) can be screened using methods known in the art. Different optimal solvents (combinations) may exist when using a different stationary phase.

[0717] The compounds of this invention also include pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by adding a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the term "pharmaceutically acceptable" means a substance that is acceptable from a toxicological point of view for pharmaceutical use and does not adversely interact with the active ingredient. Pharmaceutically acceptable salts (including mono- and di-salts) include, but are not limited to, salts derived from organic and inorganic acids, such as, but not limited to, acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, and similar known acceptable acids. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0718] The preparation of compounds may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine whether protection and deprotection are necessary and to select appropriate protecting groups. The chemical properties of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th Edition, Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. The regulation of protecting groups and the formation and cleavage methods described herein can be adapted to various substituent combinations.

[0719] Reactions described herein can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. At the temperature at which the reaction takes place, for example within the range of the solvent's freezing point to its boiling point, a suitable solvent can be substantially non-reactive to the starting material (reactant), intermediate, or product. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a solvent suitable for that particular reaction step can be selected. In some embodiments, the reaction can be carried out in the absence of a solvent (e.g., when at least one reagent is a liquid or gas).

[0720] Suitable solvents may include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, and mixtures thereof.

[0721] Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, and mixtures thereof.

[0722] Suitable proton solvents may include (as examples and not limitations) water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol or 3-pentanol, neopentanol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol or glycerol.

[0723] Suitable aprotic solvents may include (as examples and not limitations) tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolium ketone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0724] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-xylene, o-xylene or p-xylene, octane, indane, nonane or naphthalene.

[0725] Supercritical carbon dioxide and ionic liquids can also be used as solvents.

[0726] The reactions described herein can be carried out at a suitable temperature, which can be readily determined by those skilled in the art. The reaction temperature will depend on, for example, the melting and boiling points of the reagents and solvents (if present), the thermodynamics of the reaction (e.g., a violently exothermic reaction may require a low temperature), and the kinetics of the reaction (e.g., a high activation barrier may require a high temperature). “High temperature” means a temperature above room temperature (approximately 22°C).

[0727] The reactions described herein can be carried out in air or under an inert atmosphere. Typically, air-sensitive synthesis techniques well known to those skilled in the art can be used to carry out reactions involving reagents or products that are substantially reactive with air.

[0728] In some embodiments, the preparation of a compound may involve the addition of an acid or base to achieve, for example, catalysis of a desired reaction or the formation of a salt form such as an acid addition salt.

[0729] Examples of acids can be inorganic or organic. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propynic acid, butyric acid, 2-butynic acid, vinylacetic acid, valeric acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0730] Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amines, metal hydrides, metal dialkylamines, and arylamines, wherein: alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and tert-butyl oxides; metal amines include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamines include sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl, and cyclohexyl-substituted amines.

[0731] This invention also includes salt forms of the compounds described herein. Examples of salts (or salt forms) include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); etc. Generally, salt forms can be prepared by reacting a free base or acid with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid or base in a suitable solvent or a combination of various solvents. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418, the entire disclosure of which is incorporated herein by reference.

[0732] After the compounds are prepared according to the methods described herein, the desired products can be separated by common separation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, and chromatography.

[0733] In some embodiments, the compounds of the present invention and their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions enriching the compounds of the present invention. Substantially isolated may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of the present invention or their salts. Methods for separating the compounds and their salts are conventional methods in the art.

[0734] Methods and intermediates

[0735] This invention particularly provides a method for synthesizing III-type nitrile compounds and intermediates thereof, said compounds and intermediates being usable as JAK inhibitors. In one aspect, the method is a hydrogenation method. In some embodiments, the method is an asymmetric hydrogenation method, which produces an enantiomeric excess of (R)- or (S)-enantiomers of the JAK inhibitor or its intermediates. In another aspect, the method is an asymmetric aza-Michael addition method, which produces an enantiomeric excess of (R)- or (S)-enantiomers of the JAK inhibitor or its intermediates.

[0736]

[0737] In a further aspect, the present invention provides a method for enriching an enantiomeric excess of a Formula III compound by chiral separation techniques or chiral salt resolution. In some embodiments, these methods involve chiral separation (e.g., chiral preparative chromatography) or chiral salt resolution of an intermediate compound, followed by a subsequent reaction to form a Formula III compound. In some embodiments, the present invention further provides a method for racemicizing a non-desired enantiomer of an intermediate compound to produce a Formula III compound, which can then be resolved by the aforementioned techniques to obtain an enantiomeric excess of the desired enantiomer.

[0738] In a further aspect, the present invention provides a method for preparing an intermediate compound that can be used to generate a compound of formula III. In another aspect, the present invention provides an intermediate compound of any intermediate described herein. In yet another aspect, the present invention provides an enantiomeric enrichment composition of any intermediate described herein, provided that the intermediate has at least one chiral center.

[0739] The methods described herein include methods for preparing compounds, intermediates thereof, and compositions thereof, wherein R1 is selected from cyclopentyl, methyl, and trifluoromethyl. In some embodiments, R1 is cyclopentyl or cyclopropyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is methyl. In some embodiments, R1 is trifluoromethyl. In any method, these examples may be applied as appropriate to any intermediate or compound described herein.

[0740] In some embodiments, the method can be used to form a compound of formula III, which is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile or a pharmaceutically acceptable salt thereof. In some embodiments, the method can be used to form a compound of formula III, which is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile or a pharmaceutically acceptable salt thereof. It should be understood that the methods described herein include methods for preparing these compounds, especially (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile.

[0741] Methods for preparing some intermediates can be found in U.S. Patent Publication No. 20070135461 (filed December 12, 2006, application serial number 11 / 637,545), published June 14, 2007; and U.S. Patent Application No. 12 / 138,082, filed June 12, 2008, each of which is incorporated herein by reference in its entirety.

[0742] I. Catalytic hydrogenation methods (including asymmetric hydrogenation methods)

[0743] Compound III can be formed by catalytic hydrogenation of compound II to form compound I, followed by conversion of compound I to compound III via functional group transformation and / or deprotection steps. In some embodiments, these methods form compound I as a racemic compound, while in more preferred embodiments, these methods produce an enantiomeric excess of (S)- or (R)-enantiomers of compound I. One step of the method involves the hydrogenation of the α,β-unsaturated compound of formula II as shown below.

[0744] Therefore, in one aspect, the present invention provides a method for preparing a composition comprising a compound of formula I:

[0745]

[0746] Including compounds of formula II:

[0747]

[0748]

[0749] It reacts with hydrogen in the presence of a hydrogenation catalyst;

[0750] in:

[0751] * indicates chiral carbon;

[0752] R1 is selected from C 3-7cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0753] R2 is selected from -C(=O)-NH2, -C(=O)O-R3 and cyano;

[0754] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0755] P1 is a protecting group.

[0756] In some embodiments, R1 is selected from cyclopentyl, methyl, and trifluoromethyl. In some embodiments, R1 is cyclopentyl or cyclopropyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is methyl. In some embodiments, R1 is trifluoromethyl.

[0757] In some embodiments, R2 is -C(=O)O-R3. In some embodiments, R2 is -C(=O)OCH3. In some embodiments, R2 is a cyano group.

[0758] In some embodiments, R3 is selected from C. 1-4 Alkyl group. In some embodiments, R3 is selected from methyl group.

[0759] The bent symbol of the bond attached to R2 indicates that the compound may be in an (E)- or (Z)- conformation. In some embodiments, when R2 is cyano or -C(=O)-NH2, the compound of formula II is a (Z)- isomer, while when R2 is -C(=O)O-R3, the compound of formula II is an (E)- isomer. In some embodiments, the compound of formula II is a (Z)- isomer. In some embodiments, the compound of formula II is an (E)- isomer. In some embodiments, P1 is -CH2OC(=O)C(CH3)3. In some embodiments, P1 is selected from -CH2OCH2CH2Si(CH3)3. Suitable P1 protecting groups include, but are not limited to, protecting groups for amines described by Wuts and Greene in “Protective Groups in Organic Synthesis” (4th edition, John Wiley & Sons: New Jersey, pp. 696-887 (especially pp. 872-887), 2007), the full text of which is incorporated herein by reference. In some embodiments, the protecting group of the P1 group is a protecting group that is stable to the conditions for removing the P2 protecting group in the other processing steps described below. In some embodiments, P1 is a group resistant to acidic conditions at room temperature. In some embodiments, P1 is a group that is not removed from about 1 to about 5 N hydrochloric acid at room temperature, about 10°C to about 40°C, about 15°C to about 40°C, or about 15°C to about 30°C. In some embodiments, P1 is benzyloxycarbonyl, which is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazyl, methoxymethyl, tert-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP). In some embodiments, P1 is three (C 1-4 Alkyl)silyl (e.g., tri(isopropyl)silyl). In some embodiments, P1 is 1,1-diethoxymethyl. In some embodiments, P1 is 2-(trimethylsilyl)ethoxymethyl (SEM). In some embodiments, P1 is N-tervapotranoxymethyl (POM).

[0760] In some embodiments, the method produces a composition comprising a racemic compound of formula II. Any hydrogenation catalyst known in the art may be used if a racemic compound is desired. In some embodiments, the hydrogenation catalyst is a carbon-supported palladium.

[0761] In other embodiments, the method produces a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula I. Generally, an asymmetric hydrogenation catalyst is utilized when an enantiomeric excess of the compound of formula I is desired. In some embodiments, the hydrogenation catalyst is a ruthenium or rhodium catalyst having L1; wherein L1 is a chiral ligand. Many suitable catalysts are known in the art. In some embodiments, a chiral phosphine ligand is used. An active catalyst system (metal, ligand, and additives) can be generated in situ during the reaction or prior to the reaction.

[0762] In some embodiments, catalysts may be screened first by conducting catalytic asymmetric hydrogenation experiments using relatively high catalyst loadings. Once a catalyst system is selected, experimental conditions, including catalyst loading, hydrogen pressure, reaction solvent or solvent system, reaction temperature, and reaction time, can be further optimized to improve chemical conversion and enantioselectivity. In some embodiments, the catalyst loading is about 0.005 to about 0.1 mol% based on the compound of Formula II.

[0763] In some embodiments, it is known which enantiomer of Formula I compound will be produced by a specific chiral ligand. In some embodiments, chiral ligands in an asymmetric hydrogenation catalyst may be screened to determine which enantiomer of Formula I compound will be produced by the method. The desired chiral ligand may then be selected to provide the desired enantiomer of Formula I compound. For example, in some embodiments, the method further includes the following steps prior to the reaction:

[0764] (i) Reacting the compound of formula II with hydrogen in the presence of a ruthenium or rhodium catalyst having L2; and analyzing the resulting composition to determine whether the (R)- or (S)-enantiomer is in excess; wherein L2 is a chiral ligand;

[0765] (ii) Reacting a compound of formula II with hydrogen in the presence of a ruthenium or rhodium catalyst having L3; and analyzing the resulting composition to determine whether the (R)- or (S)-enantiomer is in excess; wherein L3 and L2 are the same chiral ligands but have opposite stereochemistry; and

[0766] (iii) Select L2 or L3 as L1 based on the desired stereochemistry of the composition with enantiomeric excess.

[0767] In some embodiments, the hydrogenation catalyst is selected from [Ru(p-methylisopropylbenzene)(L1)Cl]Cl, Rh(COD)(L1)(BF4), Rh(COD)2(L1)(CF3SO3), and Ru(L1)(CF3CO2)2. In some embodiments, the hydrogenation catalyst is selected from [Ru(L4)(L1)Cl]Cl, Rh(L4)(L1)(BF4), Rh(L4)2(L1)(CF3SO3), and Ru(L1)(CF3CO2)2. In some embodiments, L4 is isopropylbenzene or COD. In some embodiments, X' is a halogen. In some embodiments, X' is a chlorine group. In some embodiments, the hydrogenation catalyst is a mixture of [Rh(COD)2]CF3SO3 and a chiral phosphine ligand. In some embodiments, the solvent is 2,2,2-trifluoroethanol (TFE). In some embodiments, the hydrogenation catalyst is loaded at a rate of about 0.005 to about 0.01 mol%; and the ratio of compound II to hydrogenation catalyst is about 20,000 / 1 to about 10,000 / 1. In some embodiments, the reaction concentration is about 5 to about 6 mL TFE / g, the hydrogen pressure is about 7 to about 60 bar, and the reaction is carried out at a temperature of about room temperature to about 75°C. In some embodiments, the reaction is carried out until the conversion of compound II to compound II is about equal to or greater than 99.5%. In some embodiments, the reaction is carried out for about 10 to about 25 hours. In some embodiments, the enantiomer excess is equal to or greater than about 94%.

[0768] In some embodiments:

[0769] The hydrogenation catalyst is a mixture of [Rh(COD)2]CF3SO3 and chiral phosphine ligands selected from the following:

[0770]

[0771] The solvent is 2,2,2-trifluoroethanol (TFE);

[0772] The hydrogenation catalyst loading is from about 0.005 to about 0.01 mol%.

[0773] The ratio of the compound of formula II to the hydrogenation catalyst is approximately 20,000 / 1 to approximately 10,000 / 1;

[0774] The hydrogen pressure is approximately 7 to approximately 60 bar;

[0775] The reaction was carried out at a temperature of approximately room temperature to approximately 75°C;

[0776] The reaction proceeds to the point where the conversion rate of compound II to compound I is approximately equal to or greater than 99.5%;

[0777] The reaction takes approximately 10 to 25 hours; and

[0778] The excess of enantiomeric enzymes is equal to or greater than about 94%.

[0779] In some embodiments, the chiral ligand is a chiral phosphine ligand. In some embodiments, the chiral ligand is selected from one of the following:

[0780]

[0781] In a further embodiment, the composition comprises an enantiomeric excess of the (S)-enantiomer of the compound of formula I. In some embodiments, L1 is selected from one of the following ligands:

[0782]

[0783] In other embodiments, the composition comprises an enantiomeric excess of the (R)-enantiomer of the compound of formula I. In some embodiments, L1 is selected from one of the following ligands:

[0784]

[0785] In some embodiments, the chiral catalyst is selected from the hydrogenation catalysts described in Sigma Aldrich, “Asymmetric Catalysis: Privileged Ligands and Complexes”, ChemFiles, Vol. 8, No. 2, pp. 1-88, the full text of which is incorporated herein by reference. In some embodiments, the enantiomeric excess is equal to or greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.

[0786] In a further embodiment, the method further includes reacting the compound of formula Ic under deprotection conditions to form the compound of formula III:

[0787]

[0788] in:

[0789] * indicates chiral carbon;

[0790] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0791] P1 is a protecting group.

[0792] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[0793] The P1 group can be removed from compound Ic by methods known in the art for removing specific protecting groups from amines, as described in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, pp. 696-887 (particularly pp. 872-887) (2007), the entire text of which is incorporated herein by reference. For example, in some embodiments, the P1 group is removed by treatment with fluoride ions (e.g., with tetrabutylammonium fluoride), hydrochloric acid, pyridinium p-toluenesulfonate (PPTS), or Lewis acids (e.g., lithium tetrafluoroborate). In some embodiments, the treatment includes treatment with lithium tetrafluoroborate followed by treatment with ammonium hydroxide (e.g., when P1 is 2-(trimethylsilyl)ethoxymethyl). In some embodiments, the treatment includes treatment with a base (e.g., P1 is N-pentanoyloxymethyl). In some embodiments, the base is an alkali metal hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the treatment includes treatment with sodium hydroxide or ammonia in a solvent such as methanol or water.

[0794] In some embodiments, a mild two-stage process is employed to deprotect the SEM protecting group. The SEM-protected substrate of formula Ic is treated with lithium tetrafluoroborate (LiBF4) in an aqueous acetonitrile solution for ten to twenty hours. The resulting hydroxymethyl intermediate is then treated with an aqueous ammonium hydroxide (NH4OH) solution at room temperature to provide the compound of formula III.

[0795] In some embodiments, an aqueous solution of sodium hydroxide (NaOH) is used for POM deprotection. Thus, the POM-protected compound of formula Ic is treated with a 1N aqueous solution of sodium hydroxide for two to three hours at room temperature. The desired product of formula III is obtained after a typical acid-base treatment. In some embodiments, the deprotection conditions include treatment with lithium tetrafluoroborate followed by treatment with an aqueous solution of ammonium hydroxide.

[0796] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[0797] Method for converting Formula I amides into Formula III nitriles

[0798] The present invention further provides a method for converting an amide of formula I into a nitrile compound of formula I. The method for converting an amide of formula I involves dehydrating the amide to form a nitrile. The protecting group can then be removed, and the resulting amine can be protonated to form a pharmaceutically acceptable salt. Therefore, in some embodiments, the present invention provides a method comprising converting a compound of formula I:

[0799]

[0800]

[0801] The reaction is carried out under dehydration conditions to form a compound of formula Ia:

[0802]

[0803] in:

[0804] * indicates chiral carbon;

[0805] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0806] R2 is selected from -C(=O)-NH2;

[0807] P1 is a protecting group.

[0808] In some embodiments, the dehydration conditions include trichloroacetyl chloride (in the presence of triethylamine). In some embodiments, the dehydration conditions include any dehydrating agent for amide dehydration, including but not limited to acyl chlorides (e.g., trichloroacetyl chloride), P2O5; ZnCl2 (under microwave conditions); triphenylphosphine and N-chlorosuccinimide; ethyl dichlorophosphate / DBU; and PdCl2. In some embodiments, the dehydration conditions are as described in Kuo, CW.; Zhu, J.-L.; Wu, J. et al., Chem. Commun. 2007, 301; Manjula, K.; Pasha, MA. Syn. Commun. 2007, 37, 1545; Takahashi, T.; Sugimoto, O.; Koshio, J.; Tanji, K. Heterocycles 2006, 68, 1973; Maffioli, SI; Marzorati, E.; Marazzi, A. Organic Letters 2005, 7, 5237; or Iranpoor, N.; Firouzabadi, H.; Aghapour, G. Syn. Commun. 2002, 32, 2535. All of the above references are incorporated herein by reference in their entirety.

[0809] In a further embodiment, the method further includes reacting the compound of formula Ic under deprotection conditions to form the compound of formula III:

[0810]

[0811] in:

[0812] * indicates chiral carbon;

[0813] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0814] P1 is a protecting group.

[0815] Suitable P1 groups and deprotection methods include, but are not limited to, those described above.

[0816] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[0817] Method for converting formula I esters into formula III nitriles

[0818] The present invention further provides a method for converting an ester of formula I into a nitrile compound of formula I. The method for converting an ester of formula I involves saponifying the ester to form an acid, selective ammonolysis, and dehydrating the amide. The protecting group can then be removed, and the resulting amine can be protonated to form a pharmaceutically acceptable salt.

[0819] Therefore, the present invention provides a method comprising making a compound of formula I:

[0820]

[0821] It reacts with metal hydroxides to form compounds of formula Ic:

[0822]

[0823] in:

[0824] * indicates chiral carbon;

[0825] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0826] R2 is -C(=O)OR3;

[0827] R3 is selected from C 1-4 Alkyl; and

[0828] P1 is a protecting group.

[0829] In some embodiments, the metal hydroxide is an alkali metal hydroxide or an alkaline earth hydroxide. In some embodiments, the metal hydroxide is lithium hydroxide.

[0830] In a further embodiment, the method further includes reacting a compound of formula Ic with ammonia or ammonium hydroxide in the presence of a coupling agent to form a compound of formula Ib:

[0831]

[0832] in:

[0833] * indicates chiral carbon;

[0834] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0835] P1 is a protecting group.

[0836] In some embodiments, the coupling agent is N,N-carbonyldiimidazole. In some embodiments, the coupling agent is selected from 1,2-benzisoxazol-3-yldiphenyl phosphate; ClCO2-i-Bu and Et3N; carbodiimide; SOCl2 and Cl-C(O)-C(O)-Cl; p-toluenesulfonyl chloride and DMAP; and ClCO2-i-Bu and triethylamine. In some embodiments, the coupling agent is selected from those of: Ueda, M.; Oikawa, H. J. J. G. Chem. 1985, 50, 760 (1,2-benzisoxazol-3-yldiphenyl phosphate); Lai, M.; Liu, H. J. J. M. Chem. Soc. 1991, 113, 7388 (ClCO2-i-Bu, Et3N); Williams, A.; Ibrahim, I. Chem. Rev. 1991, 81, 589 (carbodiimide); Weiss, MM; Harman Ge, J; Polverino, AJJMed. Chem., 2008, 51, 1668 (SOCl2, Cl-CO-CO-Cl); Hong, CY; and Kishi. YJAm. Chem. Soc., 1991, 113, 9 693 (TsCl, DMAP); and Nitta, H.; Yu, D.; Kudo, M.; Mori, A.; Inoue, SJ Am. Chem. Soc., 1992, 114, 7969 (ClCO2-i-Bu, Et3N).

[0837] In other embodiments, the method further includes reacting the compound of formula Ib under dehydration conditions to form the compound of formula Ia:

[0838]

[0839] in:

[0840] * indicates chiral carbon;

[0841] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0842] P1 is a protecting group.

[0843] In some embodiments, the dehydration conditions include trichloroacetyl chloride (in the presence of triethylamine). In some embodiments, the dehydration conditions include any dehydrating agent for amide dehydration, including but not limited to acyl chlorides (e.g., trichloroacetyl chloride), P2O5; ZnCl2 (under microwave conditions); triphenylphosphine and N-chlorosuccinimide; ethyl dichlorophosphate / DBU; and PdCl2. In some embodiments, the dehydration conditions are as described in Kuo, CW.; Zhu, J.-L.; Wu, J. et al., Chem. Commun. 2007, 301; Manjula, K.; Pasha, MA. Syn. Commun. 2007, 37, 1545; Takahashi, T.; Sugimoto, O.; Koshio, J.; Tanji, K. Heterocycles 2006, 68, 1973; Maffioli, SI; Marzorati, E.; Marazzi, A. Organic Letters 2005, 7, 5237; or Iranpoor, N.; Firouzabadi, H.; Aghapour, G. Syn. Commun. 2002, 32, 2535. The full text of all of the above documents is incorporated herein by reference.

[0844] In a further embodiment, the method further includes reacting the compound of formula Ic under deprotection conditions to form the compound of formula III:

[0845]

[0846] in:

[0847] * indicates chiral carbon;

[0848] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0849] P1 is a protecting group.

[0850] Suitable P1 groups and deprotection methods include, but are not limited to, those described above.

[0851] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[0852] Starting material for hydrogenation (compound of formula II)

[0853] Compound II used in the asymmetric hydrogenation method (above) can be prepared according to Scheme 1, wherein P1 and P2 are each independently protecting groups, and R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 The alkyl group is fluoroalkyl, and R2 is a cyano or alkyl ester. The routes for preparing compounds of formula IV are described below.

[0854] Option 1

[0855]

[0856] This method involves an aza-Michael addition reaction between a suitably substituted acetylene of formula XIV and a protected compound of formula IV, 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (the preparation of compounds of formulas IV and XIV is described below). This reaction can be carried out at room temperature in the presence of a catalytic amount of solid potassium carbonate in DMF to yield the corresponding compound of formula I.

[0857] As shown in Scheme 2, the compound of formula IIa can be treated with acid to form the compound of formula IIb, thereby forming the compound of formula II (where R1 is -C(=O)NH2).

[0858] Option 2

[0859]

[0860] Therefore, the present invention provides a method for preparing compounds of formula II:

[0861]

[0862] Including compounds of formula IV:

[0863]

[0864] Compounds of formula XIV:

[0865]

[0866] The reaction occurs in the presence of a base.

[0867] in:

[0868] * indicates chiral carbon;

[0869] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0870] R2 is selected from -C(=O)O-R3 and cyano;

[0871] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0872] P1 is a protecting group.

[0873] Appropriate P1 protection bases include, but are not limited to, those listed above.

[0874] In some embodiments, the aza-Michael addition is carried out at room temperature in an organic solvent in the presence of a catalytic amount of base. The base may be a solvent or base suitable for the aza-Michael reaction. In some embodiments, the solvent is acetonitrile or dimethylformamide (DMF). In some embodiments, the base is a tetraalkylammonium halide, tetraalkylammonium hydroxide, guanidine, amidine, hydroxide, alkoxide, silicate, alkali metal phosphate, oxide, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine, or an alkali metal salt of a carboxylic acid. In some embodiments, the base is tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, tert-butylammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenylphosphine, triethylphosphine, potassium acetate, or potassium acrylate. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium carbonate. In some embodiments, the base is DBU. In some embodiments, the base is present in a catalytic amount. In some embodiments, the amount of base is about 0.1 to about 5 equivalents, or about 0.5 to about 3 equivalents, or about 0.1 to about 0.5 equivalents. In some embodiments, the reaction is completed in about 1 to about 3 hours.

[0875] In some embodiments, R1 is selected from cyclopentyl, methyl, and trifluoromethyl. In some embodiments, R1 is cyclopentyl or cyclopropyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is methyl. In some embodiments, R1 is trifluoromethyl.

[0876] In some embodiments, the alkali is an alkali metal or alkaline earth metal carbonate. In some embodiments, the alkali is potassium carbonate.

[0877] In some embodiments, the present invention provides compounds of formula II:

[0878]

[0879] in:

[0880] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0881] R2 is selected from -C(=O)-NH2 and -C(=O)O-R3;

[0882] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0883] P1 is a protecting group.

[0884] In some embodiments, P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3. In some embodiments, R1 is cyclopentyl.

[0885] Compounds of formula IIb (where R1 is -C(=O)NH2) can be formed as follows: Compounds of formula IIa:

[0886]

[0887] Treatment with acid to form the racemic form of the IIb compound:

[0888]

[0889] in:

[0890] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0891] P1 is a protecting group.

[0892] In some embodiments, the acid is trifluoroacetic acid, sulfuric acid, or a combination thereof. In some embodiments, the treatment comprises treatment with trifluoroacetic acid (TFA) and sulfuric acid (H2SO4) at room temperature. In some embodiments, the volume ratio of TFA to H2SO4 is about 10:1. In some embodiments, the reaction is completed in about one hour.

[0893] Compounds of formula XIV used in the method described in scheme 1 can be formed by methods such as those described in scheme 3 below. Therefore, compounds of formula XIVa (where R2 of formula XIV is cyano) are prepared by treating the lithium salt of compound C-1 in an organic solvent such as anhydrous THF at about -78°C to about room temperature with cyanoxyphenyl (C-2) generated in situ from phenol and cyanogen bromide, to obtain the corresponding 3-substituted propynenitrile of formula XIVa. Similarly, treating the lithium salt of compound C-1 with the chloroformate shown in formula C-3 yields the 3-substituted propyne ester compound shown in formula XIVb (where R2 of formula XIV is -C(=O)OR3).

[0894] Option 3

[0895]

[0896] II. Asymmetric aza-Michael addition method for preparing Id or VI aldehyde intermediates

[0897] In another aspect, the present invention particularly provides an enantiomeric excess of (R)- or (S)-enantiomers of the compound of formula Id:

[0898]

[0899] Including compounds of formula IV:

[0900]

[0901] Compounds of formula V:

[0902]

[0903] The reaction occurs in the presence of chiral amines and organic acids;

[0904] in:

[0905] * indicates chiral carbon;

[0906] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0907] P1 is a protecting group.

[0908] In a further aspect, the present invention provides a method for preparing an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula VI:

[0909]

[0910] Including compounds of formula V:

[0911]

[0912] Compounds of Formula VII:

[0913]

[0914] The reaction occurs in the presence of chiral amines and organic acids;

[0915] in:

[0916] * indicates chiral carbon;

[0917] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0918] X1 is a halogen.

[0919] While not wishing to be bound by any particular theory, it should be understood that the chiral amine-catalyzed aza-Michael conjugate addition mechanism from N-heterocyclic compounds to α,β-unsaturated aldehydes involves the following pathway. First, the α,β-unsaturated aldehyde of Formula V reacts with a protonated catalyst formed by a combination of a chiral amine and an organic acid, forming an imineonium ion accompanied by dehydration. Due to the chirality of the catalyst, two different imineonium ions with E and Z configurations can be formed. The corresponding E configuration is expected to be the dominant intermediate present, where the Si facet is shielded by the chiral group in the catalyst, leaving the Re facet accessible to the N-heterocyclic compound. Second, the addition of a substituted pyrazole to the imineonium ion yields an enamine intermediate with a positive charge on the protonated pyrazole ring. This proton then transfers from the nitrogen atom in the pyrazole ring to the carbon atom in the enamine to form the imineonium intermediate. Third, the hydrolysis of the imineonium ion leads to catalyst regeneration and product formation. Based on the understanding of the reaction mechanism, the reaction conditions for this organocatalyzed aza-Michael reaction are determined.

[0920] In some embodiments, the presence of the compound of formula V is in excess (e.g., about 1.5 to about 5 equivalents). In some embodiments, the presence of the chiral amine is about 0.02 to about 0.15 equivalents, or about 0.05 to about 0.10 equivalents.

[0921] In some embodiments of any asymmetric aza-Michael addition method, the organic acid is p-toluenesulfonic acid, benzoic acid, or 4-nitrobenzoic acid. In some embodiments, the organic acid is benzoic acid. In some embodiments, the organic acid present is in amounts of about 0.05 to about 0.10 equivalents.

[0922] In some embodiments, the reaction is carried out in an organic solvent selected from chloroform (CHCl3) or toluene. In some embodiments, the reaction is carried out at about room temperature or at a temperature of about 0 to about 5°C. In some embodiments, the reaction is completed in about 10 to about 24 hours. In some embodiments, the reaction conversion reaches more than 95%, wherein the separated yield reaches about 80 to about 90%. Chiral HPLC methods have been developed to determine the chiral purity of each aza-Michael adduct or its derivative.

[0923] In some embodiments of any asymmetric aza-Michael addition method, the chiral amine is the (R)- or (S)-enantiomer of compound A-1:

[0924]

[0925] in:

[0926] X is CY3Y4, Y is CY5Y6; or

[0927] X is S or NY7, Y is CY5Y6; or

[0928] X is CY3Y4, Y is S;

[0929] Q1 and Q2 are each independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated groups, carboxyl groups, C 1-6 Alkyl carboxamide, C 1-6 Alkoxycarbonyl and phenyl; wherein C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkyl carboxamide, C 1-6 Each of the alkoxycarbonyl and phenyl groups may optionally be substituted by one, two, or three independently selected groups from the following: hydroxyl, carboxyl, tri-C 1-6 Alkyl silyl, tri-C 1-6 Alkylsilyloxy, C 6-10 Aryl, C 6-10 Aromatic amino, C 1-9 heteroaryl and C 1-9 heteroaryl amino acids; of which C 6-10 Aryl, C 6-10 Aromatic amino, C 1-9 heteroaryl and C 1-9 Each of the heteroaryl amino groups is optionally selected independently from halogens, C, and D. 1-6 Alkyl and C 1-6 The haloalkyl group is substituted; and

[0930] Y1, Y2, Y3, Y4, Y5, and Y6 are each independently selected from H, hydroxyl, carboxyl, and C groups. 1-6 Alkyl, C1-6 Halogenated, C 1-6 Alkoxycarbonyl and phenyl; or

[0931] Y1 and Y2 combine to form an oxo group; or

[0932] Y3 and Y4 combine to form an oxo group; or

[0933] Y5 and Y6 combine to form an oxo group; or

[0934] Y1 and Y2, together with the carbon atoms they are attached to, form 5- or 6-membered cycloalkyl rings; or

[0935] Q1 and Y5, together with the carbon atoms they are attached to, form 5- or 6-membered cycloalkyl rings.

[0936] In some embodiments of the compound of formula A-1:

[0937] X is CY3Y4, Y is CY5Y6; or

[0938] X is S or NY7, Y is CY5Y6; or

[0939] X is CY3Y4, Y is S;

[0940] Q1 is H or methyl;

[0941] Q2 is selected from H, methyl, isopropyl, butyl, carboxyl, C. 1-5 Alkylaminocarbonyl, methoxycarbonyl, and phenyl; wherein methyl and C 1-5 Each alkylamino carbonyl group may optionally be replaced by one, two, or three independently selected groups from the following: hydroxyl, carboxyl, tri-C 1-6 Alkyl silyl, tri-C 1-4 Alkylsiloxy, phenyl, phenylamino, and indole-3-yl; wherein each of the phenyl and indole-3-yl groups is optionally substituted with one or two groups independently selected from methyl and trifluoromethyl;

[0942] Y1 can be H, hydroxyl, carboxyl, methyl, or methoxycarbonyl.

[0943] Y2 is H or methyl;

[0944] Y3, Y4, Y5, and Y6 are each independently selected from H, hydroxyl, methyl, and phenyl;

[0945] Y7 is H or methyl; or

[0946] Y1 and Y2 combine to form an oxo group; or

[0947] Y3 and Y4 combine to form an oxo group; or

[0948] Y5 and Y6 combine to form an oxo group; or

[0949] Y1 and Y2, together with the carbon atoms they are attached to, form a 6-membered cycloalkyl ring; or

[0950] Q1 and Y5, together with the carbon atoms they are attached to, form a 6-membered cycloalkyl ring.

[0951] In some embodiments of any asymmetric aza-Michael addition method

[0952] Chiral amines are (R)- or (S)-enantiomers of compounds of formula A-2:

[0953]

[0954] in

[0955] * indicates a chiral carbon with an (R)- or (S)- configuration;

[0956] Ar1 and Ar2 are each independently selected from C by 1, 2, 3 or 4 independently. 1-6 Alkyl and C 1-6 C-substituted with alkyl halogen groups 6-10 aryl;

[0957] Each R a Selected independently from C 1-6 Alkyl; and

[0958] R b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated groups.

[0959] In some embodiments, Ar1 and Ar2 are each independently a phenyl group optionally substituted with 1, 2, 3, or 4 groups independently selected from methyl and trifluoromethyl groups; each R a Independently selected from methyl, ethyl, or tert-butyl; and R b For H.

[0960] In some embodiments of any asymmetric aza-Michael addition method, the chiral amine is an (R)- or (S)-enantiomer selected from the following compounds: proline, prolylamide, prolyl-L-leucine, prolyl-L-alanine, prolyl-glycine, prolyl-L-phenylalanine, diphenylpyrrolidine, dibenzylpyrrolidine, N-(1-methylethyl)-pyrrolidine carboxamide, 2-(anilinemethyl)pyrrolidine, 2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, diphenyl(pyrrolidine-2-) 4-(1-methyl)methanol, proline, 4-thiazolidinylcarboxylic 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-benzimidazole-2-carboxylic acid, 4,5-diphenyl-imidazolidine-2-carboxylic acid, N1-methyl-3-phenylpropane-1,2-diamine, 1,2-diphenylethylenediamine, 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-thiazolidin-4-carboxylic acid, tert-leucine methyl ester, 5-benzyl-2,2,3-trimethyl-imidazolin-4-one, proline methyl ester, 4,5-diphenylimidazolidine, 2-cyclohexyl-4,5-diphenylimidazolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{bis-[3,5-dimethylphenyl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{diphenyl-tri... 2-{bis[naphthyl-2-yl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{tert-butyldimethylsilyloxy-diphenyl-methyl}-pyrrolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-triethylsilyloxy-methyl}-pyrrolidine and 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-ethyl-dimethylsilyloxy-methyl}-pyrrolidine; wherein the (R)- or (S)- configuration is on a carbon adjacent to the NH group in the compound.

[0961] In some of the above embodiments, the chiral amine is an (R)-enantiomer. In any embodiment of the asymmetric aza-Michael addition method, the chiral amine is selected from one of the following compounds:

[0962]

[0963] In some embodiments, the enantiomer excess is from about 85% to about 95%. In some embodiments, the enantiomer excess is equal to or greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.

[0964] In some embodiments, the present invention provides a composition comprising an enantiomerically excess of the (R)- or (S)-enantiomer of a compound of formula I:

[0965]

[0966] in:

[0967] * indicates chiral carbon;

[0968] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[0969] R2 is selected from -C(=O)-NH2, -C(=O)O-R3, -C(=O)OH and -C(=O)H;

[0970] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[0971] P1 is a protecting group.

[0972] In some embodiments, P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3. In some embodiments, R1 is cyclopentyl.

[0973] In other embodiments, the present invention provides compositions comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula IX:

[0974]

[0975] in:

[0976] * indicates chiral carbon;

[0977] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0978] R c and Rd Each independently for C 1-6 Alkyl; or

[0979] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[0980] In some embodiments, R1 is cyclopentyl.

[0981] Method for converting aldehyde intermediates of formula I or VI into nitrile compounds

[0982] On the other hand, the present invention provides a method for preparing nitrile compounds from a compound of formula Id. Therefore, in some embodiments, the present invention provides a method comprising: […].

[0983]

[0984]

[0985] Treatment with ammonia or ammonium hydroxide and iodine to form a compound of formula Ia:

[0986]

[0987] in:

[0988] * indicates chiral carbon;

[0989] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0990] P1 is a protecting group.

[0991] In some embodiments, the treatment is completed by treating the chiral aldehyde of Formula I in an organic solvent such as tetrahydrofuran (THF) with an excess of aqueous ammonium solution (NH4OH) and a stoichiometric amount of iodine (I2). In some embodiments, the reaction is completed at room temperature over about 1 to about 2 hours. Under these reaction conditions, the chirality of the chiral aldehyde remains unchanged. The chirality of the chiral nitrile can be verified by chiral HPLC analysis.

[0992] In some embodiments, the method further includes reacting the compound of formula Ic under deprotection conditions to form the compound of formula III:

[0993]

[0994] in:

[0995] * indicates chiral carbon;

[0996] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[0997] P1 is a protecting group.

[0998] Suitable P1 groups include, but are not limited to, those described above.

[0999] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[1000] On the other hand, the present invention provides a method for preparing nitrile compounds from compounds of formula VI. Therefore, in some embodiments, the present invention provides a method comprising: […].

[1001]

[1002] Treatment with ammonia or ammonium hydroxide and iodine to form a compound of formula VIII:

[1003]

[1004] in:

[1005] * indicates chiral carbon;

[1006] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1007] X1 is a halogen.

[1008] In some embodiments, the method further includes reacting the compound of formula VIII with the compound of formula B-1:

[1009]

[1010] To form compounds of formula IX:

[1011]

[1012] in:

[1013] * indicates chiral carbon;

[1014] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1015] Rc and R d Each is independently selected from H and C 1-6 Alkyl; or

[1016] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1017] In some embodiments, the compound of formula B-1 is 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bis[1,3,2-dioxoboropentyl].

[1018] In a further embodiment, the method further includes reacting the compound of formula IX with the compound of formula X:

[1019]

[1020] The reaction proceeds in the presence of a palladium catalyst and a base to form a compound of formula Ic:

[1021]

[1022] in

[1023] * indicates chiral carbon;

[1024] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1025] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[1026] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycle; X2 is a toluenesulfonate group, trifluoromethanesulfonate group, iodo group, chloro group, or bromo group; and

[1027] P1 is a protecting group.

[1028] In other embodiments, the method further includes reacting the compound of formula IX with the compound of formula XI:

[1029]

[1030] The reaction proceeds in the presence of a palladium catalyst, a base, and a solvent to form a compound of formula III:

[1031]

[1032] in:

[1033] * indicates chiral carbon;

[1034] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1035] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[1036] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 An alkyl-substituted 5- to 6-membered heterocycle; and X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group.

[1037] In some embodiments, X2 is a bromo group, an iodo group, or a chlorine group. In some embodiments, X2 is a chlorine group.

[1038] The Suzuki coupling reaction can be initiated using a variety of palladium (0) and palladium (II) catalysts and can be carried out under conditions known in the art (see, for example, Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483, the entire contents of which are incorporated herein by reference). In some embodiments, the palladium catalyst is Pd(PPh3)4 and Pd(dppf)2Cl2. In some embodiments, the palladium catalyst is tetrakis(triphenylphosphine)palladium (0) or tetrakis(tris(o-tolyl)phosphine)palladium (0). In some embodiments, the palladium catalyst is tetrakis(triphenylphosphine)palladium (0).

[1039] In some embodiments, the palladium catalyst loading is approximately 1 × 10⁻⁶. -4 The amount is approximately 0.1 equivalents. In some embodiments, the palladium catalyst loading is approximately 0.0010 to approximately 0.0015 equivalents. In some embodiments, the stoichiometric ratio of compound X or XI to compound IX is approximately 1:1.05 to approximately 1:1.35.

[1040] In some embodiments, the solvent includes water and an organic solvent. In some embodiments, the organic solvent is 1,4-dioxane, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene, or ethanol, or a combination thereof. In some embodiments, the organic solvent includes DME. In some embodiments, the organic solvent includes DMF.

[1041] In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is potassium carbonate (K₂CO₃). In some embodiments, two to five equivalents of the base (e.g., K₂CO₃) are used.

[1042] In some embodiments, the Suzuki coupling reaction is carried out at a temperature of about 80 to about 100°C. In some embodiments, the reaction is carried out for two to twelve hours. In some embodiments,

[1043] Compound XII may optionally be isolated from the treated aqueous solution of the Suzuki coupling reaction mixture or used directly. Suitable P2 protecting groups include, but are not limited to, the protecting groups of amines described in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, pp. 696–887 (particularly pp. 872–887) (2007), the full text of which is incorporated herein by reference.

[1044] In other embodiments, the method further includes reacting the compound of formula Ia under deprotection conditions to form the compound of formula III:

[1045]

[1046] * indicates chiral carbon;

[1047] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1048] P1 is a protecting group.

[1049] Suitable P1 groups and deprotection methods include, but are not limited to, those described above.

[1050] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[1051] Starting materials for the aza-Michael addition method

[1052] Compounds of formula IV can be formed by methods similar to those described below. 3-substituted acrolein of formula V can then be prepared according to scheme 4. Therefore, treating C-4 aldehydes (e.g., reacting with (triphenylphosphine)acetaldehyde) under typical Wittig conditions yields the corresponding compounds of formula V.

[1053] Option 4

[1054]

[1055] III. Synthesis and Racemic Resolution of Pyrazole Intermediates

[1056] Chiral compounds of formula III can be prepared by chiral column separation (e.g., by chiral preparative chromatography) of a protected racemic derivative of formula IX pyrazole borate, followed by Suzuki coupling of the IX chiral intermediate with an unprotected pyrrolo[2,3-d]pyrimidine of formula XI (Scheme 5). Alternatively, the chiral intermediate of formula (S)-IX or (R)-IX can be reacted with a protected pyrrolo[2,3-d]pyrimidine of formula X under Suzuki coupling conditions, followed by deprotection to remove the P1 protecting group, thereby yielding the chiral compound of formula III (Scheme 5). Racemic substituted pyrazole borate derivatives of formula IX can be generated via Michael addition reaction between a pyrazole borate derivative of formula XV and a Michael acceptor of formula D-1 (Scheme 5).

[1057] Option 5

[1058]

[1059] Therefore, in some embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of the formula IX compound:

[1060]

[1061] The composition comprising passing a racemic mixture of a compound containing form IX through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of (R)- or (S)-enantiomers of the compound containing form IX;

[1062] in:

[1063] * indicates chiral carbon;

[1064] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1065] R c and R dEach independently for C 1-6 Alkyl; or

[1066] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1067] In some embodiments, chromatography is performed in batch or continuous mode using a chiral stationary phase and a mobile phase, in isocratic or gradient mode.

[1068] In some embodiments, the chiral chromatography unit is a preparative high-performance liquid chromatography (HPLC) system packed with a chiral column filled with a chiral stationary phase. In some embodiments, the chiral stationary phase packed with a chiral stationary phase comprises amylose tris(3,5-dimethylphenyl carbamate) immobilized on silica gel (which can be "… "IA" is derived from Daicel. In some embodiments, a chiral column is filled with a chiral stationary phase comprising cellulose tris(3,5-dimethylphenyl carbamate) coated on silica gel (which can be " "ChiralcelOD" is derived from Daicel. In some embodiments, the chromatographic unit employs a continuous chromatographic method, such as simulated moving bed (SMB) chromatography or the Varicol process, using a unit packed with a set of eight columns, each column filled with a chiral stationary phase. In some embodiments, the unit is packed with 3 to 12 columns, 5 to 10 columns, or 5 to 8 columns, each column filled with a chiral stationary phase, and in some cases, the same chiral stationary phase. In some embodiments, a chiral stationary phase made of amylose tris(carbamate-3,5-dimethylphenyl) immobilized on silica gel (which can be " "IA" is derived from Daicel. In some embodiments, a chiral stationary phase (which can be "IA") is used, made of cellulose tris(3,5-dimethylphenyl carbamate) coated on silica gel. "OD" is derived from Daicel's packed column. In some embodiments, the chiral stationary phase is a cellulose-modified chiral stationary phase (CSP, Chiral Technologies). In some embodiments, the chiral stationary phase is a silica-based stationary phase coated with 4-(3,5-dinitrobenzoamide)tetrahydrophenanthrene (which can be "(S,S"). 1” (from Regis Technologies). In some embodiments, the mobile phase comprises ethanol and hexane. In some embodiments, the mobile phase comprises ethanol and hexane in a ratio of about 1:9. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, the amount of ethanol present is about 10 vol% to about 100 vol%, or about 10 vol% to about 25 vol%, or about 15 vol%. In some embodiments, the mobile phase comprises about 15 vol% ethanol and about 85 vol% hexane. In some embodiments, the mobile phase comprises ethanol and hexane, wherein the amount of ethanol present is about 25 vol% to about 10 vol%. In some embodiments... The mobile phase comprises isopropanol and hexane, wherein the isopropanol is present in an amount of about 25 vol% to about 10 vol%. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, the isopropanol is present in an amount of about 10 vol% to about 25 vol%. In some embodiments, the mobile phase comprises methyl-tert-butyl ether and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, the methyl-tert-butyl ether is present in an amount of about 10 vol% to about 100 vol%, preferably about 50 vol% to about 100 vol%, and most preferably about 90 vol% to about 100 vol%. In some embodiments, the mobile phase comprises ethyl acetate and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, ethyl acetate is present in an amount of about 10 vol% to about 100 vol%, about 50 vol% to about 100 vol%, or about 75 vol%. In some embodiments, the mobile phase comprises tetrahydrofuran and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, tetrahydrofuran is present in an amount of about 10 vol% to about 100 vol%, about 10 vol% to about 50 vol%, or about 25 vol%. In some embodiments, the chromatographic unit is held... At room temperature. In some embodiments, the mobile phase is passed through at a flow rate of about 1 mL / min to about 20 mL / min. In some embodiments, the mobile phase is passed through at a flow rate of about 1 mL / min. In some embodiments, the mobile phase is passed through at a flow rate of about 18 mL / min. In some embodiments, the eluent is monitored by ultraviolet (UV) spectroscopy. In some embodiments, the eluent is monitored by UV spectroscopy at about 220 nm. The elution of the desired enantiomer is detected by UV spectroscopy, thereby determining the portion of the collected eluent containing the enantiomer-enriched composition. The %ee (enantiomer excess) of the composition can then be determined by analytical chiral HPLC.

[1069] In some embodiments, the chromatographic method employed is batch preparative chromatography, supercritical fluid chromatography (SFC), cyclojet chromatography, continuous multilayer column chromatography, simulated moving bed chromatography, or varicol chromatography. TM Method or PowerFeed method.

[1070] In some embodiments, the chiral stationary phase comprises an interacting agent, which is an enantiomeric resolving agent, immobilized to an inert support material by, for example, chemical bonding or by reducing solubility via crosslinking. Suitable inert support materials can be macroporous, such as crosslinked polystyrene, polyacrylamide, polyacrylate, alumina, diatomite, quartz, kaolin, magnesium oxide, titanium dioxide, or silica gel. In some embodiments, the inert support material is silica gel.

[1071] In some embodiments, the chiral stationary phase is a member of amylose or cellulose polysaccharides selected from cellulose benzoate derivatives, such as cellulose tris(3,5-dimethylphenyl)carbamate (which can be "…"). OD or " "IB" is derived from Daicel Chemical Industries, Ltd. (Daicel), where carbamate derivatives are bonded to the cellulose backbone; cellulose tribenzoate derivatives, such as cellulose tri-4-methylbenzoate (which can " "OJ" is derived from Daicel; cellulose tricinnamate (can be " "OK" is derived from Daicel; amylase phenyl and benzyl carbamate derivatives, such as amylose tri[(S)-α-methylbenzyl carbamate] (can " "AS" is derived from Daicel; amylose tris(3,5-dimethylphenyl)carbamate (can be " AD" or " "IA" is derived from Daicel, wherein a carbamate derivative is bonded to the amylose backbone; 3,4-substituted phenyl carbamate or 4-substituted phenyl carbamate of amylose; and amylose tricinnamate. In some embodiments, the chiral stationary phase includes IA or Chiralpak AD. In some embodiments, the chiral stationary phase includes OD. In some embodiments, the chiral stationary phase is a member of the Pirkle phase family, such as a 3,5-dinitrobenzoyl derivative of phenylglycine (available from Regis Technologies Inc. under the name "phenylglycine"); a 3,5-dinitrobenzoyl derivative of leucine (available from Regis Technologies Inc. under the name "Leucine"); N-3,5-dinitrobenzoyl-3-amino-3-phenyl-2-(1,1-dimethylethyl)-propionate (available from Regis Technologies Inc. under the name "β-GEM 1"); N-3,5-dinitrobenzoyl-amino-2,2-dimethyl-4-pentenylphosphonate dimethyl ester (available from Regis Technologies Inc. under the name "α-BURKE 2"); 3-(3,5-dinitrobenzoylamino)-4-phenyl-β-lactam (available from Regis Technologies Inc. under the name "PIRKLE 1-J"). (Inc.); 3,5-dinitrobenzoyl derivatives of diphenylethylenediamine (available from Regis Technologies Inc. under the name "ULMO"); 4-(3,5-dinitrobenzoylamino)tetrahydrophenanthrene (available from Regis Technologies Inc. under the name "(S,S)"); 1” and “(R,R)” 1”, or “(S,S)” 2” and “(R,R)” 2” (obtained from Regis Technologies Inc.); 3,5-dinitrobenzoyl derivative of 1,2-diaminocyclohexane (obtainable from Regis Technologies Inc., “DACH-DNB”). In some embodiments, the chiral stationary phase comprises (S,S) 1" or "(R,R)" 1.

[1072] In some embodiments, the particle size of the chiral stationary phase is typically 1 to 300 μm, 2 to 100 μm, 5 to 75 μm, or 10 to 30 μm.

[1073] In some embodiments, the mobile phase is a nonpolar, polar proton or aprotic solvent, or a mixture thereof. In some embodiments, the mobile phase is a mixture of carbon dioxide and a polar proton solvent. Suitable nonpolar solvents include, for example, hydrocarbons such as n-pentane, n-hexane, hexane, n-heptane, heptane, cyclohexane, and methylcyclohexane. Suitable proton or aprotic solvents include, for example, alcohols, particularly methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol; ethers, such as methyl tert-butyl ether; esters, such as ethyl acetate; halogenated hydrocarbons; and acetonitrile. In some embodiments, the nonpolar solvent is n-heptane. In some embodiments, the proton or aprotic solvent is ethanol, 2-propanol, or methyl tert-butyl ether. In some embodiments, the mobile phase is a mixture of heptane and ethanol. In some embodiments, the amount of ethanol present in the mobile phase is about 10% to about 100%, about 10% to about 25%, or about 15%. In some embodiments, the mobile phase is a mixture of heptane and 2-propanol. In some embodiments, the amount of 2-propanol present in the mobile phase is about 10% to about 100%, about 10% to about 25%, or about 20%. In some embodiments, the mobile phase is a mixture of heptane and methyl tert-butyl ether. In some embodiments, the amount of methyl tert-butyl ether present in the mobile phase is about 10% to about 100%, about 75% to about 100%, or about 90% to about 100%.

[1074] In some embodiments, the temperature range for performing chromatography is from about 0°C to 50°C, from about 10°C to 30°C, or about 25°C.

[1075] In some embodiments, the enantiomeric purity of the desired enantiomeric sample is greater than about 90%, greater than about 98%, or greater than about 99.0%. In some embodiments, the yield of the desired enantiomeric sample is greater than about 70%, greater than about 90%, or greater than about 95%.

[1076] In some embodiments, the production rate of the desired enantiomer is greater than about 0.1 kg, 0.4 kg or 0.8 kg of pure enantiomer per kilogram of stationary phase per day.

[1077] In some embodiments, the separated enantiomers are recovered after evaporation under reduced pressure as a concentrated oil.

[1078] In some embodiments, the mobile phase used in the chiral chromatography method is recycled.

[1079] In some embodiments, the unwanted enantiomers are racemized and reused as racemic feed for chiral separation.

[1080] In some embodiments, the compound of formula IX has the formula:

[1081] In some embodiments, the excess of enantiomers is equal to or greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.

[1082] In some embodiments, the recovery rate of the desired enantiomer is 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, preferably greater than 90% or 95%.

[1083] In some embodiments, the method further includes using a compound of formula IX:

[1084]

[1085] Compounds of formula XI:

[1086]

[1087] The reaction is carried out in the presence of a palladium catalyst, a base, and a solvent, wherein the reaction conditions and time are sufficient to form a composition comprising an enantiomer in excess of the (R)- or (S)-enantiomer of formula III:

[1088]

[1089] in:

[1090] * indicates chiral carbon;

[1091] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1092] R c and R d Each independently for C 1-6 Alkyl; or

[1093] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles; and

[1094] X2 is a toluenesulfonate group, trifluoromethanesulfonate group, iodo group, chlorine group, or bromine group.

[1095] In some embodiments, the method further includes using a compound of formula IX:

[1096]

[1097] Compound X:

[1098]

[1099] The reaction is carried out in the presence of a palladium catalyst, a base, and a solvent, wherein the reaction conditions and time are sufficient to form a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of formula Ia:

[1100]

[1101] in:

[1102] * indicates chiral carbon;

[1103] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1104] R c and R d Each independently for C 1-6 Alkyl; or

[1105] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles;

[1106] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group; and

[1107] P1 is a protecting group.

[1108] In some embodiments, X2 is a bromo group, an iodo group, or a chlorine group. In some embodiments, X2 is a chlorine group.

[1109] The Suzuki coupling reaction can be initiated using a variety of palladium(0) and palladium(II) catalysts, and can be carried out under conditions known in the art (see, for example, Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483, the entire contents of which are incorporated herein by reference). In some embodiments, the palladium catalyst is Pd(PPh3)4 and Pd(dppf)2Cl2.

[1110] In some embodiments, the palladium catalyst is tetrakis(triphenylphosphine)palladium(0) or tetrakis(tris(o-tolyl)phosphine)palladium(0). In some embodiments, the palladium catalyst is tetrakis(triphenylphosphine)palladium(0).

[1111] In some embodiments, the palladium catalyst loading is approximately 1 x 10⁻⁶. -4 The amount is approximately 0.1 equivalents. In some embodiments, the palladium catalyst loading is approximately 0.0010 to approximately 0.0015 equivalents. In some embodiments, the stoichiometric ratio of compound X or XI to compound IX is approximately 1:1.05 to approximately 1:1.35.

[1112] In some embodiments, the solvent includes water and an organic solvent. In some embodiments, the organic solvent is 1,4-dioxane, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene, or ethanol, or a combination thereof. In some embodiments, the organic solvent includes DME. In some embodiments, the organic solvent includes DMF.

[1113] In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is potassium carbonate (K₂CO₃). In some embodiments, two to five equivalents of the base (e.g., K₂CO₃) are used.

[1114] In some embodiments, the Suzuki coupling reaction is carried out at a temperature of about 80 to about 100°C. In some embodiments, the reaction is carried out for two to twelve hours. In some embodiments, the compound of formula Ia or III may optionally be isolated from the treated aqueous solution of the Suzuki coupling reaction mixture or used directly.

[1115] Appropriate P1 groups and deprotection conditions are provided above.

[1116] In some embodiments, the present invention provides a method for preparing racemic derivatives of compound IX.

[1117]

[1118] Including compounds of formula XV:

[1119]

[1120] With compound of formula D-1:

[1121]

[1122] The reaction takes place in the presence of a base to produce a compound of formula IX;

[1123] in:

[1124] * indicates chiral carbon;

[1125] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C1-6 fluoroalkyl; and

[1126] R c and R d Each independently for C 1-6 Alkyl; or

[1127] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1128] In some embodiments, the aza-Michael addition is carried out in an organic solvent at room temperature and in the presence of a catalytic amount of base. The base may be a solvent or base suitable for the aza-Michael reaction. In some embodiments, the solvent is acetonitrile or dimethylformamide (DMF). In some embodiments, the base is a tetraalkylammonium halide, tetraalkylammonium hydroxide, guanidine, amidine, hydroxide, alkoxide, silicate, alkali metal phosphate, oxide, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine, or an alkali metal salt of a carboxylic acid. In some embodiments, the Michael addition catalyst is tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, tert-butylammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenylphosphine, triethylphosphine, potassium acetate, or potassium acrylate. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium carbonate. In some embodiments, the base is DBU. In some embodiments, the base is present in a catalytic amount. In some embodiments, the amount of base is about 0.1 to about 5 equivalents or about 0.5 to about 3 equivalents. In some embodiments, the reaction is completed in about 10 to about 24 hours.

[1129] In some embodiments, the method further comprises treating the compound of formula Ia under deprotection conditions sufficient to provide an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula III:

[1130]

[1131] in:

[1132] * indicates chiral carbon;

[1133] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C1-6 fluoroalkyl; and

[1134] P1 is a protecting group.

[1135] Suitable P1 groups and deprotection methods include, but are not limited to, those described above.

[1136] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[1137] IV. Chiral enrichment of racemic products of formula Ia and racemization of undesirable enantiomers of formula Ia

[1138] The racemic compound of formula Ia can be formed via the Michael addition method described in Scheme 6 below. Therefore, the compound of formula IV can be reacted with acrylonitrile of formula D-1 to form the racemic compound of formula Ia. The racemic compound of formula Ia can then be separated by chiral column chromatography to obtain a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia. The protecting group can then be removed to produce an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula III.

[1139] Option 6

[1140]

[1141] Therefore, in some embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia:

[1142]

[1143] The composition comprising passing a racemic derivative of a compound containing form Ia through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of (R)- or (S)-enantiomers of the compound containing form Ia.

[1144] in:

[1145] * indicates chiral carbon;

[1146] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1147] P1 is a protecting group.

[1148] In some embodiments, the chiral chromatography unit is a preparative high-performance liquid chromatography (HPLC) system packed with a chiral column filled with a chiral stationary phase. In some embodiments, the chiral column is... IA. In some embodiments, the chiral column is OD-H. In some embodiments, the chromatographic unit is a simulated moving bed (SMB) chromatographic unit containing a set of eight columns, each column being packed with a chiral stationary phase. In some embodiments, the chiral stationary phase is a cellulose-modified chiral stationary phase (CSP, Chiral Technologies). In some embodiments, the mobile phase comprises ethanol and hexane. In some embodiments, the mobile phase comprises ethanol and hexane in a volume ratio of about 1:9. In some embodiments, the mobile phase comprises about 15 vol% ethanol and about 85 vol% hexane. In some embodiments, the mobile phase comprises ethanol and hexane, wherein ethanol is present in an amount of about 25 vol% to about 10 vol%. In some embodiments, the mobile phase comprises isopropanol and hexane, wherein isopropanol is present in an amount of about 25 vol% to about 10 vol%. In some embodiments, the chromatographic unit is maintained at room temperature. In some embodiments, the mobile phase is passed through at a flow rate of about 1 mL / min to about 20 mL / min. In some embodiments, the mobile phase is passed through at a flow rate of about 1 mL / min. In some embodiments, the mobile phase is passed through at a flow rate of about 18 mL / min. In some embodiments, the eluent is monitored by ultraviolet (UV) spectroscopy. In some embodiments, the eluent is monitored at approximately 220 nm by ultraviolet spectroscopy. The elution of the desired enantiomer is detected by UV spectroscopy, thereby determining the portion of the collected eluent containing the enantiomer-enriched composition. The %ee (enantiomer excess) of the composition can then be determined by analytical chiral HPLC.

[1149] In some embodiments, the excess of enantiomers is equal to or greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.

[1150] In some embodiments, chiral chromatography is performed using a preparative high-performance liquid chromatography (HPLC) system equipped with a column packed with a chiral stationary phase. In some embodiments, a chiral stationary phase (which can be "...") is used, which is made by immobilizing amylose tris(carbamate-3,5-dimethylphenyl) on silica gel. "IA" is derived from Daicel. In some embodiments, a chiral stationary phase (which can be "IA") is used, prepared by coating cellulose tris(3,5-dimethylphenyl carbamate) onto silica gel. "OD" is derived from Daicel. In some embodiments, the chromatographic method is a continuous chromatographic method, such as simulated moving bed (SMB) chromatography or the Varicol method, which uses a unit packed with a group of 3 to 12, preferably 5 to 10, most preferably 5 to 8 columns, each column packed with the same chiral stationary phase. In some embodiments, the column is packed with a chiral stationary phase made by immobilizing amylose tris(3,5-dimethylphenyl carbamate) on silica gel (which can be "…"). "IA" is derived from Daicel. In some embodiments, the column is packed with a chiral stationary phase, which is made by coating cellulose tris(3,5-dimethylphenyl carbamate) onto silica gel (which can be " "OD" is derived from Daicel. In some embodiments, the chiral stationary phase is a silica-based stationary phase coated with 4-(3,5-dinitrobenzoylamino)tetrahydrophenanthrene (which can be "(S,S"). 1” (from Regis Technologies). In some embodiments, the mobile phase comprises ethanol and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, ethanol is present in an amount from about 10 vol% to about 100 vol%, from about 10 vol% to about 25 vol%, or about 15 vol%. In some embodiments, the mobile phase comprises isopropanol and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, isopropanol is present in an amount from about 10 vol% to about 25 vol%. In some embodiments, the mobile phase comprises methyl-tert-butyl ether and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, methyl-tert-butyl ether is present in an amount from about 10 vol% to about 100 vol%, from about 50 vol%, or about 10 vol%. The amount of ethyl acetate is from about 10% to about 100% by volume, or from about 90% to about 100% by volume. In some embodiments, the mobile phase comprises ethyl acetate and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, the amount of ethyl acetate is from about 10% to about 100% by volume, from about 50% to about 100% by volume, or from about 75% by volume. In some embodiments, the mobile phase comprises tetrahydrofuran and hexane. In some embodiments, hexane is replaced by heptane, n-heptane, cyclohexane, or methylcyclohexane. In some embodiments, tetrahydrofuran is from about 10% to about 100% by volume, from about 10% to about 50% by volume, or from about 25% by volume. In some embodiments, the chromatographic unit is operated at a temperature of about 5°C to about 50°C, about 10°C to about 30°C, or about 25°C, or at ambient temperature.

[1151] In some embodiments, the chromatographic method employed is batch preparative chromatography, supercritical fluid chromatography (SFC), cyclojet chromatography, continuous multilayer column chromatography, simulated moving bed chromatography, or varicol chromatography. TM Method or PowerFeed method.

[1152] In some embodiments, the chiral stationary phase comprises an interacting agent, which is an enantiomeric resolving agent, immobilized to an inert support material by, for example, chemical bonding or by reducing solubility via crosslinking. Suitable inert support materials can be macroporous, such as crosslinked polystyrene, polyacrylamide, polyacrylate, alumina, diatomite, quartz, kaolin, magnesium oxide, titanium dioxide, or silica gel. In some embodiments, the inert support material is silica gel.

[1153] In some embodiments, the chiral stationary phase is a member of amylose or cellulose polysaccharides selected from cellulose benzoate derivatives, such as cellulose tris(3,5-dimethylphenyl)carbamate (which can be "…"). OD or " "IB" is derived from Daicel Chemical Industries, Ltd. (Daicel), where carbamate derivatives are bonded to the cellulose backbone; cellulose tribenzoate derivatives, such as cellulose tri-4-methylbenzoate (which can " "OJ" is derived from Daicel; cellulose tricinnamate (can be " "OK" is derived from Daicel; amylase phenyl and benzyl carbamate derivatives, such as amylose tri[(S)-α-methylbenzyl carbamate] (can " "AS" is derived from Daicel; amylose tris(3,5-dimethylphenyl)carbamate (can be " AD" or " "IA" is derived from Daicel, wherein a carbamate derivative is bonded to the amylose backbone; 3,4-substituted phenyl carbamate or 4-substituted phenyl carbamate of amylose; and amylose tricinnamate. In some embodiments, the chiral stationary phase includes IA or Chiralpak AD. In some embodiments, the chiral stationary phase includes OD. In some embodiments, the chiral stationary phase is a member of the Pirkle phase family, such as a 3,5-dinitrobenzoyl derivative of phenylglycine (available from Regis Technologies Inc. under the name "phenylglycine"); a 3,5-dinitrobenzoyl derivative of leucine (available from Regis Technologies Inc. under the name "Leucine"); N-3,5-dinitrobenzoyl-3-amino-3-phenyl-2-(1,1-dimethylethyl)-propionate (available from Regis Technologies Inc. under the name "β-GEM 1"); N-3,5-dinitrobenzoyl-amino-2,2-dimethyl-4-pentenylphosphonate dimethyl ester (available from Regis Technologies Inc. under the name "α-BURKE 2"); 3-(3,5-dinitrobenzoylamino)-4-phenyl-β-lactam (available from Regis Technologies Inc. under the name "PIRKLE 1-J"). (Inc.); 3,5-dinitrobenzoyl derivatives of diphenylethylenediamine (available from Regis Technologies Inc. under the name "ULMO"); 4-(3,5-dinitrobenzoylamino)tetrahydrophenanthrene (available from Regis Technologies Inc. under the name "(S,S)"); 1” and “(R,R)” 1”, or “(S,S)” 2” and “(R,R)” 2” (obtained from Regis Technologies Inc.); 3,5-dinitrobenzoyl derivative of 1,2-diaminocyclohexane (obtainable from Regis Technologies Inc., “DACH-DNB”). In some embodiments, the chiral stationary phase comprises (S,S) 1" or "(R,R)" 1.

[1154] In some embodiments, the particle size of the chiral stationary phase is typically 1 to 300 μm, 2 to 100 μm, 5 to 75 μm, or 10 to 30 μm.

[1155] In some embodiments, the mobile phase is a nonpolar, polar proton or aprotic solvent, or a mixture thereof. In some embodiments, the mobile phase is a mixture of carbon dioxide and a polar proton solvent. Suitable nonpolar solvents include, for example, hydrocarbons such as n-pentane, n-hexane, hexane, n-heptane, heptane, cyclohexane, and methylcyclohexane. Suitable proton or aprotic solvents include, for example, alcohols, particularly methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol; ethers, such as methyl tert-butyl ether; esters, such as ethyl acetate; halogenated hydrocarbons; and acetonitrile. In some embodiments, the nonpolar solvent is n-heptane. In some embodiments, the proton or aprotic solvent is ethanol, 2-propanol, or methyl tert-butyl ether. In some embodiments, the mobile phase is a mixture of heptane and ethanol. In some embodiments, the amount of ethanol present in the mobile phase is about 10% to about 100%, about 10% to about 25%, or about 15%. In some embodiments, the mobile phase is a mixture of heptane and 2-propanol. In some embodiments, the amount of 2-propanol present in the mobile phase is about 10% to about 100%, about 10% to about 25%, or about 20%. In some embodiments, the mobile phase is a mixture of heptane and methyl tert-butyl ether. In some embodiments, the amount of methyl tert-butyl ether present in the mobile phase is about 10% to about 100%, about 75% to about 100%, or about 90% to about 100%. In some embodiments, the chromatography is performed at a temperature of about 0°C to 50°C, about 10°C to 30°C, or about 25°C.

[1156] In some embodiments, the enantiomeric purity of the desired enantiomeric sample is greater than about 90%, greater than about 98%, or greater than about 99.0%. In some embodiments, the yield of the desired enantiomeric sample is greater than about 70%, greater than about 90%, or greater than about 95%.

[1157] In some embodiments, the production rate of the desired enantiomer is greater than about 0.1 kg, 0.4 kg or 0.8 kg of pure enantiomer per kilogram of stationary phase per day.

[1158] In some embodiments, the separated enantiomers are recovered after evaporation under reduced pressure as a concentrated oil.

[1159] In some embodiments, the mobile phase used in the chiral chromatography method is recycled.

[1160] In some embodiments, the unwanted enantiomers are racemized and reused as racemic feed for chiral separation.

[1161] In some embodiments, the recovery rate of the desired enantiomer is at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or preferably greater than 90% or 95%.

[1162] Alternatively, the racemic compound of formula Ia can be reacted with a chiral acid (E-1) (such as (+)-dibenzoyl-D-tartaric acid) to form a chiral salt (E-2) (Scheme 7). After crystallization, filtration, and treatment with an alkali, a composition is produced containing an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia. The protecting group can then be removed to produce an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula III.

[1163] Option 7

[1164]

[1165] Therefore, in some embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia:

[1166]

[1167] include:

[1168] (a) Reacting a composition containing a racemic derivative 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;

[1169] (b) A composition for isolating an enantiomerically excess of a chiral salt of the (R)- or (S)-enantiomer of a compound of formula Ia; and

[1170] (c) Treating a chiral salt with a base to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia:

[1171] in:

[1172] * indicates chiral carbon;

[1173] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1174] P1 is a protecting group.

[1175] Any chiral acid suitable for chiral resolution can be used. In some embodiments, the chiral acid is selected from the optically active forms of the following acids: mandelic acid, 2-chloromandelic acid, camphor sulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphor sulfonic acid, dibenzoyl tartaric acid, di-p-toluyl tartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]hept-1-methylenesulfonic acid, and 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methylenesulfonic acid. In some embodiments, the chiral acid is (+)-dibenzoyl-D-tartaric acid.

[1176] In some embodiments, the solvent includes acetonitrile, tetrahydrofuran, acetone, or a combination thereof. In some embodiments, the solvent is acetonitrile, tetrahydrofuran, and acetone in a ratio of about 90:15:15 (15.0 mL, 0.204 mol).

[1177] In some embodiments, the excess of enantiomers is equal to or greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.

[1178] In some embodiments, separation involves cooling the solvent to precipitate the chiral salt. In some embodiments, separation involves adding a second solvent to precipitate the chiral salt. In some embodiments, separation includes filtering the solvent to recover the chiral salt. In some embodiments, the solvent includes acetonitrile, tetrahydrofuran, acetone, or combinations thereof. In some embodiments, the reaction is carried out at a temperature of about room temperature to about 60°C.

[1179] This method can utilize any base suitable for preparing a chiral salt. In some embodiments, the base is an alkali metal or alkaline earth metal hydroxide or a carbonate. In some embodiments, the base is an alkali metal hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the process includes adding an aqueous solution of the base to a solution of the chiral salt, followed by separating the solution from the aqueous solution. In some embodiments, the method further includes removing the solvent.

[1180] In addition to the chiral enrichment methods described above, the undesired enantiomer of formula Ia can be converted into a racemic compound, followed by a base-catalyzed reverse Michael addition to form a compound of formula IV, which is then reacted with acrylonitrile of formula D-1 to produce the racemic Michael adduct of formula Ia, as shown in Scheme 8. Alternatively, the undesired enantiomer of formula Ia can be epimerized in the presence of the Michael acceptor of formula D-1 to obtain the racemic product of formula Ia, as shown in Scheme 8. The racemic product can then be resolved by the chiral column separation and chiral salt method described above to obtain the desired enantiomer.

[1181] Option 8

[1182]

[1183] Therefore, the present invention provides a method for preparing compositions comprising racemic compounds of formula Ia:

[1184]

[1185] include:

[1186] a) A composition comprising an enantiomer excess of the (R)- or (S)-enantiomer of a compound of formula Ia in the form of a compound of formula D-1.

[1187]

[1188] The treatment is carried out under conditions where the first base is present and sufficient to form a compound of formula IV:

[1189]

[1190] as well as

[1191] (b) Reacting compound IV with compound D-1 in the presence of a second base;

[1192] in:

[1193] * indicates chiral carbon;

[1194] P1 is a protecting group; and

[1195] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[1196] In some embodiments, the first base is an alkali metal or alkaline earth metal base. In some embodiments, the first base is an alkali metal or alkaline earth metal alkane oxide, hydroxide, or carbonate. In some embodiments, the first base is an alkali metal or alkaline earth carbonate. In some embodiments, the first base is an alkaline earth carbonate. In some embodiments, the first base is cesium carbonate. In some embodiments, the first base is an alkali metal tert-butoxide. In some embodiments, the first base is potassium tert-butoxide.

[1197] In some embodiments, the second step is carried out at room temperature in an organic solvent in the presence of a second base in a catalytic amount. The second base may be a suitable solvent or a second base used for the aza-Michael reaction. In some embodiments, the solvent is acetonitrile or dimethylformamide (DMF). In some embodiments, the second base is a tetraalkylammonium halide, tetraalkylammonium hydroxide, guanidine, amidine, hydroxide, alkoxide, silicate, alkali metal phosphate, oxide, tertiary amine, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydrogen phosphate, phosphine, or an alkali metal salt of a carboxylic acid. In some embodiments, the base is tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, tert-butylammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium silicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydrogen phosphate, triphenylphosphine, triethylphosphine, potassium acetate, or potassium acrylate. In some embodiments, the second base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium carbonate. In some embodiments, the second base is DBU. In some embodiments, the base is present in a catalytic amount. In some embodiments, the amount of the second base is about 0.1 to about 5 equivalents, or about 0.5 to about 3 equivalents, or about 0.1 to about 0.5 equivalents. In some embodiments, the reaction is completed in about 1 to about 3 hours.

[1198] Alternatively, the present invention further provides a method for preparing a composition comprising a racemic compound of formula Ia:

[1199]

[1200] This includes compositions containing an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula Ia as compounds of formula D-1:

[1201]

[1202] The treatment is carried out under the condition that a base is present and sufficient to form a racemic compound of formula Ia;

[1203] in:

[1204] * indicates chiral carbon;

[1205] P1 is a protecting group; and

[1206] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[1207] In some embodiments, the alkali is an alkali metal or alkaline earth metal alkali. In some embodiments, the alkali is an alkali metal or alkaline earth metal alkane oxide, hydroxide, or carbonate. In some embodiments, the alkali is an alkali metal or alkaline earth carbonate. In some embodiments, the alkali is an alkaline earth carbonate. In some embodiments, the alkali is cesium carbonate. In some embodiments, the alkali is an alkali metal tert-butoxide. In some embodiments, the alkali is potassium tert-butoxide.

[1208] Racemic derivatives of compound Ia:

[1209]

[1210] It can be prepared by the following method, which includes preparing a compound of formula IV:

[1211]

[1212] Compound D-1:

[1213]

[1214] The treatment is carried out under conditions sufficient to form a racemic compound of formula Ia;

[1215] in:

[1216] * indicates chiral carbon;

[1217] P1 is a protecting group; and

[1218] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[1219] The 3-substituted acrylonitrile of formula D-1 was prepared according to Scheme 9. The olefination of the aldehyde (cyclopentanecarboxy ...

[1220] Option 9

[1221]

[1222] Therefore, in some embodiments, compound D-1 can be prepared by the following method:

[1223]

[1224] This method involves making a compound of formula D-2:

[1225]

[1226] Reaction with Wittig-type reagents having the formula -CH2CN ylide in the presence of a base;

[1227] Where R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[1228] As used herein, the term "Wittig-type reagent" refers to the reagent used in Wittig, Wadsworth-Emmons, and Horner-Wittig reactions described in the art (see, for example, Carey and Sundberg, Advanced Organic Chemistry, Part B: Reactions and Synthesis, 4th ed., Kluwer Academic / Plenum Publishers: New York, pp. 111-119 (2001); and March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 3rd ed., John Wiley & Sons: New York, pp. 845-855 (1985), the full text of which is incorporated herein by reference). Exemplary Wittig-type reagents containing cyanomethyl or cyanomethyl ylide groups include, but are not limited to, the general formula (R'O)₂P(=O)-LR. 1 、R”3P(+)-L(-)-R 1 、R”3P(+)-LR 1 X;R”2P(=O)-LR 1 and (R'N)2P(=O)-LR 1 Compounds in which R' is C 1-6 Alkoxy or optionally substituted phenyl; R” is optionally substituted phenyl; L is -CH2- or -CH-; R 1X is a cyano group; X is an anion (e.g., a halide anion, such as a chloride ion). In some embodiments, the Wittig-type reagent is diethyl cyanomethyl phosphate. In some embodiments, the reaction of the compound of formula D-2 with the Wittig-type reagent is carried out in the presence of a base. In some embodiments, the base is a strong base. In some embodiments, the base is potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium ethoxide, sodium hydroxide, potassium carbonate, or sodium carbonate. In some embodiments, the base is an alkali metal alkoxide. In some embodiments, in some examples, the base is an alkali metal tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the alkeneation of the aldehyde of formula D-2 with the Wittig-type reagent is carried out in an organic solvent (such as THF) at a temperature of about 0 to about 5°C and under the influence of a base (such as potassium tert-butoxide). In some embodiments, the base present is about 1 to about 1.2 equivalents, or about 1.05 to about 1.1 equivalents, relative to the compound of formula D-2. In some embodiments, the Wittig-type reagent present is about 1 to about 1.2 equivalents, or about 1.05 to about 1.1 equivalents, relative to the compound of formula D-2. In some embodiments, the Wittig-type reagent is (methoxymethyl)triphenylphosphonium chloride.

[1229] In other embodiments, the method further includes reacting the compound of formula Ia under deprotection conditions to form the compound of formula III:

[1230]

[1231]

[1232] Suitable P1 groups and deprotection methods include, but are not limited to, those described above.

[1233] In some embodiments, the method further includes reacting the compound of formula III with phosphoric acid to form a phosphate of the compound of formula III.

[1234] V. Pathways for the formation of intermediate compounds

[1235] i) High-yield pathway for formula IV intermediates

[1236] Compounds of formula IV are important intermediates in the various synthetic routes of compounds of formula III described above. These compounds are typically formed via Suzuki coupling. Suzuki coupling of the protected 7H-pyrrolo[2,3-d]pyrimidine derivative of formula X with the unprotected pyrazole borate derivative of formula XV using a palladium catalyst resulted in lower yields (Scheme 10). Without wishing to be bound by any particular theory, it is believed that the lower yields are due to interference from the unprotected amine functional groups in the Suzuki coupling reaction.

[1237] Option 10

[1238]

[1239] Therefore, a novel method for preparing compound IV has been developed, involving the use of a protected pyrazole borate derivative of formula XIII (Scheme 11). Thus, compound XIII can be generated, and then reacted with a protected 7H-pyrrolo[2,3-d]pyrimidine derivative of formula X to form compound XII, followed by deprotection to obtain compound IV. In some embodiments, compound XIII can be formed by in-situ protection of pinacol pyrazole borate. For example, when P2 is 1-(ethoxy)ethyl, pinacol pyrazole-4-ylboronic acid can be reacted in-situ with a vinyl ether to generate the protected compound XIII. The Suzuki coupling reaction between the protected pinacol pyrazole borate of formula XIII and compound X is then carried out smoothly under typical Suzuki reaction conditions, resulting in compound IV in high yield after acidic treatment of the corresponding coupling intermediate of formula XII.

[1240] In other embodiments, the compound of formula XIII is a separated and well-characterized compound. For example, using a separated and well-characterized compound of formula XIII (where P2 is 1-(ethoxy)ethyl and the borate ester moiety is a pinacol group) can yield the product of formula XII and subsequently the compound of formula IV in better yield and purity.

[1241] Option 11

[1242]

[1243] In other embodiments, compound X can be generated in situ from compound XI, followed by reaction with compound XIII. This eliminates the need for separation and purification of compound X during large-scale production. For example, when P1 is SEM, compound XI can be reacted with sodium hydride and SEM chloride to generate compound X in situ (Scheme 12).

[1244] Option 12

[1245]

[1246] Therefore, the present invention provides a method for preparing compound XII:

[1247]

[1248] Including compounds of formula X:

[1249]

[1250] Compounds of formula XIII:

[1251]

[1252]

[1253] The reaction takes place in the presence of a palladium catalyst, a base, and a solvent to form a compound of formula XII.

[1254] in:

[1255] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[1256] P1 and P2 are each an independent protecting base;

[1257] R c and R d Each independently is H or C 1-6 Alkyl; or

[1258] R c and R d Together with the oxygen and boron atoms they are attached to, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1259] In some embodiments, the method further includes a method for preparing a compound of formula IV:

[1260]

[1261] This includes reacting a compound of formula XII under deprotection conditions to produce a compound of formula IV;

[1262] in:

[1263] P1 and P2 are each an independent protecting base; and

[1264] R c and R d Each independently is H or C 1-6 Alkyl; or

[1265] R c and R d Together with the oxygen and boron atoms they are attached to, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1266] In some embodiments, the compound of formula XIII is:

[1267] In some embodiments, X2 is a chloro group, a bromo group, or an iodo group. In some embodiments, X2 is a chloro group.

[1268] The Suzuki coupling reaction can be initiated using a variety of palladium (0) and palladium (II) catalysts, and can be carried out under conditions known in the art (see, for example, Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483, the entire contents of which are incorporated herein by reference). In some embodiments, the palladium catalyst is Pd(PPh3)4 and Pd(dppf)2Cl2. In some embodiments, the palladium catalyst is tetrakis(triphenylphosphine)palladium (0) or tetrakis(tris(o-tolyl)phosphine)palladium (0). In some embodiments, the palladium catalyst is tetrakis(triphenylphosphine)palladium (0).

[1269] In some embodiments, the palladium catalyst loading is approximately 1 x 10⁻⁶. -4 The amount is approximately 0.1 equivalents. In some embodiments, the palladium catalyst loading is approximately 0.0010 to approximately 0.0015 equivalents. In some embodiments, the stoichiometric ratio of compound X to compound XIII is approximately 1:1.05 to approximately 1:1.35.

[1270] In some embodiments, the solvent includes water and an organic solvent. In some embodiments, the organic solvent is 1,4-dioxane, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene, or ethanol, or a combination thereof. In some embodiments, the organic solvent includes DME. In some embodiments, the organic solvent includes DMF.

[1271] In some embodiments, the base is an inorganic base. In some embodiments, the base is an organic base. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is potassium carbonate (K₂CO₃). In some embodiments, two to five equivalents of the base (e.g., K₂CO₃) are used.

[1272] In some embodiments, the Suzuki coupling reaction is carried out at a temperature of about 80 to about 100°C. In some embodiments, the reaction is carried out for two to twelve hours. In some embodiments, the compound of formula XII may optionally be isolated from the aqueous solution of the Suzuki coupling reaction mixture or used directly.

[1273] In some embodiments, compound X is selected from those in scheme 13 and may be formed from compound XI as a starting material. In some embodiments, X2 is chlorinated. In some embodiments, compound X is isolated or generated in situ, and is used as a starting material for the subsequent Suzuki reaction with or without further purification. In some embodiments, the P1 protecting group is one of those listed above.

[1274] Option 13

[1275]

[1276] Suitable P2 protecting groups include, but are not limited to, protecting groups of amines described in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, pp. 696-887 (particularly pp. 872-887) (2007), the full text of which is incorporated herein by reference. In some embodiments, P2 is a protecting group that can be selectively removed without substituting the P1 protecting group. In some embodiments, P2 is a protecting group that can be removed under acidic conditions at room temperature, at a temperature of about 15°C to about 40°C, or at a temperature of about 15°C to about 30°C. In some embodiments, P2 is a deprotected group under acidic conditions at room temperature. In some embodiments, P2 is 1-(ethoxy)ethyl, tri(C 1-6 Alkyl)silyl (e.g., tert-butyldimethylsilyl or triisopropylsilyl), p-methoxybenzyl (PMB), triphenylmethyl (Tr), diphenylmethyl, hydroxymethyl, methoxymethyl (MOM), diethoxymethyl, or tert-butyldimethylsilylmethyl. In some embodiments, P2 is 1-(ethoxy)ethyl.

[1277] The treatment of compound XII to remove the P2 group can be accomplished by methods known in the art for removing specific protecting groups from amines, such as those described in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, pp. 696-887 (particularly pp. 872-887) (2007), the entire text of which is incorporated herein by reference. In some embodiments, the treatment comprises treating compound XII under acidic conditions (e.g., hydrochloric acid or trifluoroacetic acid) and at room temperature, at a temperature of about 15°C to about 40°C, or at a temperature of about 15°C to about 30°C. In some embodiments, the treatment comprises treating compound XII with an aqueous solution of hydrochloric acid of about 1N to about 5N at a temperature of about 10°C to about 30°C.

[1278] Suitable P1 groups include, but are not limited to, those described above.

[1279] Compound X can be formed by protecting compound XI. Therefore, in some embodiments, the method for preparing compound X includes treating compound XI:

[1280]

[1281] By adding protecting groups, a compound of formula X is formed.

[1282]

[1283] in:

[1284] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group; and

[1285] P1 is a protecting group.

[1286] In some embodiments, prior to treatment with an electrophile (such as methyl pivalate (POM-Cl) or trimethylsilyl ethoxymethyl chloride (SEM-Cl)), the compound X1 may be deprotonated in an organic solvent (such as THF, 1,4-dioxane, 1,2-dimethoxyethane (DME), or N,N-dimethylacetamide (DMAC)) with a base (preferably sodium hydride (NaH)) to add a protecting group P1. The protected compound X is isolated or generated in situ and may be used as a starting material for the subsequent Suzuki reaction with or without further purification.

[1287] In other methods described herein, intermediates formed by the methods described herein may be used, as appropriate.

[1288] ii. Preparation of C-9 borate pinacol ester

[1289] The present invention further provides a method for preparing pinacol esters of formula XVI pyrazole borate that can be used in the methods described herein. A specific subgroup of compounds of formula XVI is 4-substituted pyrazole borate derivatives of formula XIIIa, which can be used to replace the above-described compounds of formula XIII.

[1290]

[1291] Compound XVI can be prepared by the method shown in Scheme 14. First, the pyrazole is reacted with a halogenating agent to give a monohalogenated or dihalogenated pyrazole of Formula XIX (where X3 is an iodo group or a bromo group, and m is 1 or 2). Then, the compound of Formula XIX is protected to give a protected monohalogenated or dihalogenated pyrazole of Formula XVIII. The compound of Formula XVIII can then be treated with an alkyl Grignard reagent or an alkyl lithium reagent, followed by treatment with a 2-alkoxy-4,4,5,5-tetramethyl-1,3,2-dioxapentylborane reagent of Formula XVII to form the desired pinacol ester of Formula XVI. In some embodiments, the P3 protecting group is an aqueous protecting group stable to the Grignard reaction or lithium reaction (e.g., where P3 is 1-(ethoxy)ethyl). In other cases, P3 is an aqueous protecting group unstable to the Grignard reaction or alkyl lithium reaction. In this case, an additional protecting step will be required to add the protecting group P3. In some embodiments, for ease of handling, P3 is selected from the groups listed above for P2.

[1292] Option 14

[1293]

[1294] Therefore, in some embodiments, the present invention provides a method for preparing XVI compounds:

[1295]

[1296] include:

[1297] (a) Making compound XVIII

[1298]

[1299] With about 1 or more equivalent of C 1-6 Alkyl Grignard reagents or C 1-6 The reaction is carried out with an alkyllithium reagent, followed by treatment with about one or more equivalents of a compound of formula XVII:

[1300]

[1301] as well as

[1302] (b) Optionally, the product of step (a) is protected again to obtain compound XVI;

[1303] in:

[1304] P3 is a protecting group;

[1305] X3 is a halogen;

[1306] R4 is C 1-6 Alkyl; and

[1307] m is an integer selected from 1 and 2.

[1308] In some embodiments, the ratio of the compound of formula XVIII to the Grignard reagent or lithium reagent is about 1:1 to about 1:2.0, about 1:1 to about 1:1.8, or about 1:1 to about 1.2. Typically, the reaction is carried out in an aprotic organic solvent. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the ratio of the compound of formula XVIII to the compound of formula XVII is about 1:1 to about 1:5, about 1:1 to about 1:3, or about 1:1.5 to about 1:2.5.

[1309] In some embodiments, the Grignard reagent is used in step (a) at a temperature of -30°C to about room temperature, about -30°C to about 0°C, or about -25°C to about -5°C. In some embodiments, the lithium reagent is used in step (a) at a temperature of about -80°C to about -60°C or about -78°C.

[1310] In some embodiments, the Grignard reagent is isopropyl magnesium bromide or its adduct.

[1311] In some embodiments, R4 is C 1-4 Alkyl group. In some embodiments, R4 is C4. 1-3 Alkyl group. In some embodiments, R4 is methyl or isopropyl. In some embodiments, X3 is iodo or bromo. In some embodiments, m is 2. In some embodiments, m is 1.

[1312] In some cases, the compound of formula XVIII may be known (see, for example, Abe et al., Heterocycles, 2005, 66, 229-240; Korolev et al., Tet. Lett. 2005, 46, 5751-5754; Vasilevsky, Heterocycles, 2003, 60(4), 879-886; and WO 2008 / 082198, all of which are incorporated herein by reference in their entirety). In other embodiments, the method further includes a method for preparing a compound of formula XVIII, including a compound of formula XIX:

[1313]

[1314] in:

[1315] P3 is a protecting group;

[1316] X3 is a halogen; and

[1317] m is an integer selected from 1 and 2.

[1318] In some cases, the disubstituted or monosubstituted compounds of formula XIX may be known (see, for example, WO 2007 / 043677; Vasillevsky, Heterocycles, 2003, 60(4), 879-886; WO 2008 / 013925; and Huttel et al., Ann. 1959, 625, 55, all of which are incorporated herein by reference in their entirety). In some embodiments, the method further includes a method for preparing a compound of formula XIX, comprising reacting a 1H-pyrazole with a halogenating agent;

[1319] in:

[1320] X3 is a halogen; and

[1321] m is an integer selected from 1 and 2.

[1322] In some embodiments, X3 is an iodide or a bromine group. In some embodiments, the halogenating agent is selected from N-bromosuccinimide (NBS) or N-iodosuccinimide, wherein X3 is a bromine or an iodide group.

[1323] In other methods described herein, intermediates formed by the methods described herein may be used, as appropriate.

[1324] iii. Preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine

[1325] Compounds of formula XI are useful intermediates in some of the synthetic methods described herein. In some embodiments, the present invention provides a method for preparing compounds of formula XI, namely 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (XIa), wherein X2 is a chlorine group (Scheme 15).

[1326]

[1327] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (XIa) is synthesized by acid treatment of compound F-1. Compound F-1 can be synthesized by treating compound F-2 with a Wittig reagent having the formula CH2OCH3. Compound F-2 can be formed as follows: starting with commercially available 4,6-dihydroxypyrimidine (compound F-4), compound F-3 is formed by Vilsmeier formylation-chlorination, followed by selective ammonolysis to form compound F-2.

[1328] Option 15

[1329]

[1330] Therefore, in some embodiments, the present invention provides a method for preparing compounds of formula XIa:

[1331]

[1332] Including compounds of formula F-1:

[1333]

[1334] The compound was treated with an acid under conditions sufficient to form compound D-1.

[1335] In some embodiments, the acid is a strong acid. In some embodiments, the acid is a concentrated aqueous solution of hydrochloric acid (about 18 M). In some embodiments, these conditions include carrying out the reaction in a solvent at reflux temperature. In some embodiments, the reaction is completed in about 5 to about 15 hours.

[1336] In some embodiments, the method further includes a method for preparing a compound of formula F-1, including making a compound of formula F-2:

[1337]

[1338] It reacts with about 1 or more equivalents of a Wittig-type reagent having the formula -CH2OCH3 ylide in the presence of a base.

[1339] As used herein, the term "Wittig-type reagent" refers to the reagent used in Wittig reactions, Wadsworth-Emmons reactions, and Horner-Wittig reactions as described in the art (see, for example, Carey and Sundberg, Advanced Organic Chemistry, Part B: Reactions and Synthesis, 4th ed., Kluwer Academic / Plenum Publishers: New York, pp. 111-119 (2001); and March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 3rd ed., John Wiley & Sons: New York, pp. 845-855 (1985), the full text of which is incorporated herein by reference). Exemplary Wittig-type reagents containing cyanomethyl or cyanomethyl ylide groups include, but are not limited to, the general formula (R'O)₂P(=O)-LR. 1 、R”3P(+)-L(-)-R 1 、R”3P(+)-LR 1 X;R”2P(=O)-LR 1 and (R'N)2P(=O)-LR 1 Compounds in which R' is C 1-6 Alkoxy or optionally substituted phenyl; R” is optionally substituted phenyl; L is -CH2- or -CH-; R 1X is a methoxy group; X is an anion (e.g., a halide anion, such as a chloride ion). In some embodiments, the Wittig-type reagent is diethyl methoxymethyl phosphate. In some embodiments, the compound of formula F-1 reacts with the Wittig-type reagent in the presence of a base. In some embodiments, the base is a strong base. In some embodiments, the base is potassium tert-butoxide, sodium tert-butoxide, sodium hydride, sodium ethoxide, sodium hydroxide, potassium carbonate, or sodium carbonate. In some embodiments, the base is an alkali metal alkoxide. In some embodiments, the base is an alkali metal tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the alkenelation of the aldehyde of formula F-1 with the Wittig-type reagent is carried out in an organic solvent (such as THF) at a temperature of about 0 to about 5°C and under the influence of a base (such as potassium tert-butoxide). In some embodiments, the base present is about 1 to about 1.2 equivalents, or about 1.05 to about 1.1 equivalents, relative to the compound of formula F-1. In some embodiments, the Wittig-type reagent present is about 1 to about 1.2 equivalents, or about 1.05 to about 1.1 equivalents, relative to the compound of formula F-1. In some embodiments, the Wittig-type reagent is (methoxymethyl)triphenylphosphonium chloride.

[1340] In some embodiments, the method further includes a method for preparing a compound of formula F-2, including making a compound of formula F-3:

[1341]

[1342] It reacts with about 2 or more equivalents of ammonia in a solvent.

[1343] In some embodiments, the solvent is methanol. In some embodiments, the base is present in approximately two equivalents relative to the compound of formula F-2.

[1344] In some embodiments, the method further includes a method for preparing a compound of formula F-3, including making a compound of formula F-4:

[1345]

[1346] It reacts with chlorinating agents.

[1347] In some embodiments, the chlorinating agent is phosphorus oxychloride. In some embodiments, the chlorinating agent present relative to the compound of formula F-3 is about or greater than about 2 equivalents, about or greater than about 3 equivalents, or about or greater than about 4 equivalents, or about 3 to about 5 equivalents.

[1348] In other methods described herein, intermediates formed by the methods described herein may be used, as appropriate. Detailed Implementation

[1350] In some embodiments, the present invention provides a method for preparing a composition comprising an enantiomer of formula III' compound in an enantiomer excess of 90% or greater (R)-enantiomer:

[1351]

[1352] include:

[1353] (a) Compound of formula XI':

[1354]

[1355] Treatment with sodium hydride and N-pentanoyloxymethyl chloride to form compound X':

[1356]

[1357]

[1358] (b) Using compound X' with compound XIII':

[1359]

[1360] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII':

[1361]

[1362] (c) Reacting the compound of formula XII' under deprotection conditions to obtain the compound of formula IV':

[1363]

[1364] (d) To make compounds of formula IV” and compounds of formula XIV':

[1365]

[1366] The reaction was carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene to give compound II':

[1367]

[1368] (e) Reacting compound II' with hydrogen in the presence of [Rh(COD)2]CF3SO3 and a chiral phosphine ligand selected from the following:

[1369]

[1370] To form compounds of formula I':

[1371] as well as

[1372] (f) Reacting the compound of formula I' under deprotection conditions to form the compound of formula III';

[1373] * indicates chiral carbon.

[1374] In some embodiments of step (e):

[1375] The solvent is 2,2,2-trifluoroethanol (TFE);

[1376] The hydrogenation catalyst loading is from about 0.005 to about 0.01 mol%.

[1377] The ratio of the compound of formula II to the hydrogenation catalyst is approximately 20,000 / 1 to approximately 10,000 / 1;

[1378] The hydrogen pressure is approximately 7 to approximately 60 bar;

[1379] The reaction was carried out at a temperature of approximately room temperature to approximately 75°C;

[1380] The reaction proceeds to the point where the conversion rate of compound II to compound III is approximately equal to or greater than 99.5%; and

[1381] The reaction takes approximately 10 to 25 hours.

[1382] In some embodiments, the method further includes preparing a compound of formula XI':

[1383]

[1384] include:

[1385] (i) To make F-4 compound:

[1386]

[1387] It reacts with 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:

[1388]

[1389] (ii) Reacting compound F-3 with approximately two equivalents of ammonia in methanol to form compound F-2:

[1390]

[1391] (iii) Mixing compound F-2 with about 1 to about 1.5 equivalents of [Ph3P] +The Wittig-type reagent of (CH2OCH3)]Cl- (where Ph is phenyl) reacts in the presence of about 1 to about 1.5 equivalents of potassium tert-butoxide to form a compound of formula F-1:

[1392] as well as

[1393] (iv) In tetrahydrofuran, the compound of formula F-1 is refluxed with concentrated hydrochloric acid aqueous solution to form the compound of formula XI'.

[1394] In some embodiments, the method further includes preparing a compound of formula XIII':

[1395]

[1396] include:

[1397] (i) React 1H-pyrazole with N-bromosuccinimide to form a compound of formula XIX';

[1398]

[1399] (ii) Protected XIX compounds to form XVIII' compounds:

[1400] as well as

[1401] (iii) Reacting the compound of formula XVIII' with about one or more equivalents of isopropyl magnesium chloride, followed by treatment with about one or more equivalents of the compound of formula XVII':

[1402]

[1403] To form compound XIII'.

[1404] In some embodiments, the method further includes preparing a compound of formula XIII':

[1405]

[1406] include:

[1407] (i) Protect 4-iodo-1H-pyrazole to form a compound of formula XVIII”:

[1408] as well as

[1409] (ii) Reacting the compound of formula XVIII” with about one or more equivalents of isopropyl magnesium chloride in tetrahydrofuran, followed by treatment with about one or more equivalents of the compound of formula XVII':

[1410]

[1411] To form compound XIII'.

[1412] In a further embodiment, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1413]

[1414] include:

[1415] (a) Compound of formula XI':

[1416]

[1417] Treatment with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form a compound of formula X”:

[1418]

[1419] (b) Using compound X” with compound XIII':

[1420]

[1421] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII”:

[1422]

[1423] (c) Reacting the compound of formula XII” under deprotection conditions to form the compound of formula IV”:

[1424]

[1425]

[1426] (d) To make compound IV” and compound D-1':

[1427]

[1428] The reaction is carried out under conditions sufficient to form a racemic mixture containing compound I”:

[1429]

[1430] (e) Passing the composition containing the racemic derivative of compound I" through a chiral chromatographic unit using a mobile phase, and collecting the composition containing an enantiomeric excess of the (R)-enantiomer of compound I"; and

[1431] (f) Reacting the compound of formula I” with lithium tetrafluoroborate, followed by reacting with an aqueous solution of ammonium hydroxide, to form a composition containing an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1432] * represents chiral carbon.

[1433] In other embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1434]

[1435] include:

[1436] (a) A composition containing an enantiomer excess of the (S)-enantiomer of a compound of formula I”:

[1437]

[1438] Compound of formula D-1':

[1439]

[1440] In the presence of cesium carbonate, the mixture is treated in acetonitrile under conditions sufficient to form a racemic product of formula I”.

[1441] (b) Passing the composition containing the racemic derivative of compound I" through a chiral chromatographic unit using a mobile phase, and collecting the composition containing an enantiomeric excess of the (R)-enantiomer of compound I"; and

[1442] (c) Reacting the compound of formula I” with lithium tetrafluoroborate, followed by reacting with an aqueous solution of ammonium hydroxide, to form a composition containing an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1443] * represents chiral carbon.

[1444] In other embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1445]

[1446] include:

[1447] (a) Compound of formula XI':

[1448]

[1449] Treatment with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form a compound of formula X”:

[1450]

[1451] (b) Using the compound of formula X” with the compound of formula XIII':

[1452]

[1453] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII”:

[1454]

[1455] (c) Reacting the compound of formula XII” under deprotection conditions to form the compound of formula IV”:

[1456]

[1457] (d) Mixing the compound of formula IV” with the compound of formula D-1':

[1458]

[1459] The reaction is carried out under conditions sufficient to form a racemic compound containing formula I”:

[1460]

[1461] (e) passing the composition comprising the racemic derivative of the compound of formula I” through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I”; and

[1462] (f) React the compound of formula I” with boron trifluoride diethyl ether, followed by reaction with an aqueous solution of ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1463] * represents chiral carbon.

[1464] In other embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1465]

[1466] include:

[1467] (a) A composition containing an enantiomer excess of the (S)-enantiomer of a compound of formula I”:

[1468]

[1469] Using compound D-1':

[1470]

[1471] The mixture is treated in acetonitrile in the presence of cesium carbonate to a condition sufficient to form a racemic product of formula I”.

[1472] (b) passing the composition comprising the racemic derivative of the compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[1473] (c) React the compound of formula I” with boron trifluoride diethyl ether, followed by reaction with an aqueous solution of ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1474] * represents chiral carbon.

[1475] In other embodiments, the present invention provides a method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1476]

[1477] Includes: compounds of formula I”:

[1478]

[1479] The compound is reacted with boron trifluoride diethyl ether, followed by an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III'; wherein * is a chiral carbon.

[1480] In other embodiments, the present invention provides a method for preparing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate, 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.

[1481] In other embodiments, the present invention provides a method for purifying (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate, comprising recrystallizing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate from a solvent mixture comprising methanol, 2-propanol, and n-heptane. In some embodiments, 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 in methanol.

[1482] The present invention also includes the following exemplary embodiments:

[1483] 1. A method for preparing a composition containing a compound of formula I:

[1484]

[1485] Including compounds of formula II:

[1486]

[1487] Reacts with hydrogen in the presence of a hydrogenation catalyst;

[1488] in:

[1489] * indicates chiral carbon;

[1490] 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.

[1491] 2. The method according to embodiment 1, wherein the composition comprises an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula I; and the hydrogenation catalyst is a ruthenium or rhodium catalyst having L1; wherein L1 is a chiral phosphine ligand.

[1492] 3. The method according to embodiment 2, wherein the excess of the enantiomer is equal to or greater than about 90%.

[1493] 4. The method according to embodiment 2, wherein the excess of the enantiomer is equal to or greater than about 99%.

[1494] 5. The method according to embodiment 2, wherein the chiral phosphine ligand is selected from one of the following:

[1495] 6. The method according to embodiment 2, wherein the composition comprises an enantiomer excess of the (S)-enantiomer of the compound of formula I.

[1496] 7. The method according to embodiment 6, wherein L1 is selected from one of the following ligands:

[1497]

[1498] 8. The method according to embodiment 2, wherein the composition comprises an enantiomer excess of the (R)-enantiomer of the compound of formula I.

[1499] 9. The method according to embodiment 8, wherein L1 is selected from one of the following ligands:

[1500]

[1501] 10. The method according to any one of embodiments 2 to 9, wherein the product is a compound of formula Ia:

[1502]

[1503] in:

[1504] * indicates chiral carbon;

[1505] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1506] P1 is a protecting group.

[1507] 11. The method according to any one of embodiments 2 to 9, wherein R2 is -C(=O)-NH2.

[1508] 12. The method according to embodiment 11 further comprises reacting the compound of formula I under dehydration conditions to form compound of formula Ia:

[1509]

[1510] in:

[1511] * indicates chiral carbon;

[1512] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1513] P1 is a protecting group.

[1514] 13. The method according to embodiment 12, wherein the dehydration conditions include trichloroacetyl chloride in the presence of triethylamine.

[1515] 14. The method according to any one of embodiments 2 to 9, wherein R2 is -C(=O)O-R3.

[1516] 15. The method according to any one of embodiments 2 to 9, wherein R2 is -C(=O)OCH3.

[1517] 16. The method according to embodiment 14 or 15 further comprises reacting the compound of formula I with a metal hydroxide to form a compound of formula Ic:

[1518]

[1519] in:

[1520] * indicates chiral carbon;

[1521] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1522] P1 is a protecting group.

[1523] 17. The method according to embodiment 16, wherein the metal hydroxide is an alkali metal hydroxide or an alkaline earth hydroxide.

[1524] 18. The method according to embodiment 16, wherein the metal hydroxide is lithium hydroxide.

[1525] 19. The method according to any one of embodiments 16 to 18, further comprising reacting the compound of formula Ic with ammonia or ammonium hydroxide in the presence of a coupling agent to form a compound of formula Ib:

[1526]

[1527] in:

[1528] * indicates chiral carbon;

[1529] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1530] P1 is a protecting group.

[1531] 20. The method according to embodiment 19, wherein the coupling agent is N,N-carbonyldiimidazole.

[1532] 21. The method according to any one of embodiments 19 to 20, further comprising reacting the compound of formula Ib under dehydration conditions to form the compound of formula Ia:

[1533]

[1534] in:

[1535] * indicates chiral carbon;

[1536] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1537] P1 is a protecting group.

[1538] 22. The method according to any one of embodiments 2 to 21, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1539] 23. The method according to any one of embodiments 2 to 22, wherein R1 is cyclopentyl.

[1540] 24. A method for preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula Id:

[1541]

[1542] Including compounds of formula IV:

[1543]

[1544] Compounds of formula V:

[1545]

[1546] The reaction occurs in the presence of chiral amines and organic acids.

[1547] in:

[1548] * indicates chiral carbon;

[1549] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1550] P1 is a protecting group.

[1551] 25. A method for preparing a composition containing an enantiomeric excess of (R)- or (S)-enantiomers of a compound of formula VI:

[1552]

[1553] Including compounds of formula V:

[1554]

[1555] Compounds of Formula VII:

[1556]

[1557] The reaction occurs in the presence of chiral amines and organic acids.

[1558] Where: * indicates chiral carbon;

[1559] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1560] X1 is a halogen.

[1561] 26. The method according to embodiment 24 or 25, wherein the organic acid is p-toluenesulfonic acid.

[1562] 27. The method according to any one of embodiments 24 to 26, wherein the chiral amine is an (R)- or (S)-enantiomer of a compound of formula A-1:

[1563]

[1564] Among them: Q1

[1565] X is CY3Y4 and Y is CY5Y6; or

[1566] X is S or NY7, and Y is CY5Y6; or

[1567] X is CY3Y4, and Y is S;

[1568] Q1 and Q2 are each independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated groups, carboxyl groups, C 1-6 Alkyl carboxamide, C 1-6 Alkoxycarbonyl and phenyl; wherein the C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkyl carboxamide, C 1-6 Each of the alkoxycarbonyl and phenyl groups is optionally selected independently by one, two, or three groups from hydroxyl, carboxyl, tri-C 1-6 Alkyl silyl, tri-C 1-6 Alkylsilyloxy, C 6-10 Aryl, C 6-10 Aromatic amino, C1-9 heteroaryl and C 1-9 Substitution of a heteroaryl amino group; wherein the C 6-10 Aryl, C 6-10 Aromatic amino, C 1-9 heteroaryl and C 1-9 Each of the heteroaryl amino groups is optionally selected independently from halogens, C, and D. 1-6 Alkyl and C 1-6 The alkyl halogroup is substituted; and each of Y1, Y2, Y3, Y4, Y5, and Y6 is independently selected from H, hydroxyl, carboxyl, C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxycarbonyl and phenyl; or

[1569] Y1 and Y2 combine to form an oxo group; or

[1570] Y3 and Y4 combine to form an oxo group; or

[1571] Y5 and Y6 combine to form an oxo group; or

[1572] Y1 and Y2, together with the carbon atoms they are attached to, form 5- or 6-membered cycloalkyl rings; or

[1573] Q1 and Y5, together with the carbon atoms they are attached to, form 5- or 6-membered cycloalkyl rings.

[1574] 28. The method according to any one of embodiments 24 to 26, wherein the chiral amine is an (R)- or (S)-enantiomer of compound A-2:

[1575]

[1576] in

[1577] * indicates a chiral carbon with an (R)- or (S)- configuration;

[1578] Ar1 and Ar2 are each independently selected from C by 1, 2, 3 or 4 independently. 1-6 Alkyl and C 1-6 C-substituted with alkyl halogen groups 6-10 Aryl;

[1579] Each R a Selected independently from C 1-6 Alkyl; and

[1580] R b Selected from H, C 1-6 Alkyl and C 1-6 Halogenated groups.

[1581] 29. The method according to implementation scheme 28, wherein:

[1582] Ar1 and Ar2 are each independently a phenyl group optionally substituted with 1, 2, 3 or 4 groups independently selected from methyl and trifluoromethyl groups;

[1583] Each R a Independently selected from methyl, ethyl, or tert-butyl;

[1584] R b For H.

[1585] 30. The method according to any one of embodiments 24 to 26, wherein the chiral amine is an (R)- or (S)-enantiomer selected from the group consisting of: proline, prolylamide, prolyl-L-leucine, prolyl-L-alanine, prolylglycine, prolyl-L-phenylalanine, diphenylpyrrolidine, dibenzylpyrrolidine, N-(1-methylethyl)-pyrrolidine carboxamide, 2-(anilinemethyl)pyrrolidine, 2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, diphenyl(pyrrolidine-2- Methanol, proline, 4-thiazolidinylcarboxylic 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-benzimidazole-2-carboxylic acid, 4,5-diphenyl-imidazolidine-2-carboxylic acid, N1-methyl-3-phenylpropane-1,2-diamine, 1,2-diphenylethylenediamine, 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-thiazolidin-4-carboxylic acid, tert-leucine methyl ester, 5-benzyl-2,2,3-trimethyl-imidazolin-4-one, proline methyl ester, 4,5-diphenylimidazolidine, 2-cyclohexyl-4,5-diphenylimidazolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{bis-[3,5-dimethylphenyl]-trimethylsilyloxy-methyl}-pyrrolidine, 2-{diphenyl-trimethyl... Silalkoxy-methyl}-pyrrolidine, 2-{bis[naphthyl-2-yl]-trimethylsilalkoxy-methyl}-pyrrolidine, 2-{tert-butyldimethylsilalkoxy-diphenyl-methyl}-pyrrolidine, 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-triethylsilalkoxy-methyl}-pyrrolidine and 2-{bis-[3,5-bis(trifluoromethyl)phenyl]-ethyl-dimethylsilalkoxy-methyl}-pyrrolidine; wherein the (R)- or (S)- configuration is on a carbon adjacent to the NH group in the compound.

[1586] 31. The method according to any one of embodiments 27 to 30, wherein the chiral amine is an (R)-enantiomer.

[1587] 32. The method according to any one of embodiments 24 to 26, wherein the chiral amine is selected from one of the following compounds:

[1588] 33. The method according to any one of embodiments 24 to 32, wherein the excess of the enantiomer is equal to or greater than about 90%.

[1589] 34. The method according to any one of embodiments 24 to 32, wherein the excess of the enantiomer is equal to or greater than about 99%.

[1590] 35. The method according to embodiment 24, further comprising treating the compound of formula Id with ammonia or ammonium hydroxide and iodine to form the compound of formula Ia:

[1591]

[1592] in:

[1593] * indicates chiral carbon;

[1594] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1595] P1 is a protecting group.

[1596] 36. The method according to embodiment 25 further comprises treating the compound of formula VI with ammonia or ammonium hydroxide and iodine to form the compound of formula VIII:

[1597]

[1598] in:

[1599] * indicates chiral carbon;

[1600] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1601] P1 is a protecting group; and

[1602] X1 is a halogen.

[1603] 37. The method according to embodiment 36 further comprises reacting the compound of formula VIII with the compound of formula B-1:

[1604]

[1605] To form compounds of formula IX:

[1606]

[1607] in:

[1608] * indicates chiral carbon;

[1609] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1610] X1 is a halogen group; and

[1611] R c and R d Each is independently selected from H and C 1-6 Alkyl; or

[1612] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1613] 38. The method according to embodiment 37, wherein the compound of formula B-1 is 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bis[1,3,2-dioxoboropentyl].

[1614] 39. The method according to embodiment 37 or 38 further comprises reacting the compound of formula IX with the compound of formula X:

[1615]

[1616] The reaction proceeds in the presence of a palladium catalyst and a base to form a compound of formula Ia:

[1617]

[1618] in:

[1619] * indicates chiral carbon;

[1620] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1621] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[1622] P1 is a protecting group; and

[1623] R c and R d Each is independently selected from H and C1-6 Alkyl; or

[1624] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1625] 40. The method according to any one of embodiments 24, 26 to 35 and 24 to 39, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1626] 41. The method according to any one of embodiments 24 to 40, wherein R1 is cyclopentyl.

[1627] 42. A composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula IX:

[1628]

[1629] in:

[1630] * indicates chiral carbon;

[1631] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1632] R c and R d Each independently for C 1-6 Alkyl; or

[1633] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1634] 43. The composition according to embodiment 42, wherein R1 is cyclopentyl.

[1635] 44. A method for preparing a composition according to embodiment 42 or 43, comprising passing the composition containing a racemic form of the IX compound through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of the (R)- or (S)-enantiomer of the IX compound.

[1636] 45. The method according to embodiment 44, wherein the mobile phase comprises ethanol and hexane, wherein the ethanol is present in an amount of about 25 vol% to about 10 vol%.

[1637] 46. ​​The method according to embodiment 42 or 45, wherein the chromatographic unit is a simulated moving bed (SMB) chromatographic unit having a set of eight columns or chiral column units, wherein each column is filled with a chiral stationary phase.

[1638] 47. The method according to embodiment 46, wherein the chiral stationary phase is a cellulose-modified chiral stationary phase.

[1639] 48. The method according to any one of embodiments 44 to 47, wherein the compound of formula IX is as follows:

[1640]

[1641] 49. The method according to any one of embodiments 44 to 48 further comprises making a compound of formula IX:

[1642]

[1643] Compounds of formula XI:

[1644]

[1645] The reaction is carried out in the presence of a palladium catalyst, a base, and a solvent to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of formula III:

[1646]

[1647] in:

[1648] * indicates chiral carbon;

[1649] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[1650] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1651] R c and R d Each independently for C 1-6 Alkyl; or

[1652] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms.1-4 Alkyl-substituted 5- to 6-membered heterocycles.

[1653] 50. The method according to any one of embodiments 44 to 48 further comprises making a compound of formula IX:

[1654]

[1655] Compound X:

[1656]

[1657] Under certain conditions, in the presence of a palladium catalyst, a base, and a solvent, a reaction is carried out for a sufficient period of time to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of formula Ia:

[1658]

[1659] in:

[1660] * indicates chiral carbon;

[1661] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1662] R c and R d Each independently for C 1-6 Alkyl; or

[1663] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles;

[1664] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group; and

[1665] P1 is a protecting group.

[1666] 51. A method for preparing a composition containing a racemic compound of formula Ia:

[1667]

[1668] include:

[1669] a) A composition comprising an enantiomer in excess of the (R)- or (S)-enantiomer of a compound of formula Ia as compound D-1:

[1670]

[1671] The treatment is carried out in the presence of the first base, under conditions sufficient to form compound IV:

[1672]

[1673] as well as

[1674] (b) Reacting compound IV with compound D-1 in the presence of a second base;

[1675] in:

[1676] * indicates chiral carbon;

[1677] P1 is a protecting group; and

[1678] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[1679] 52. The method according to embodiment 51, wherein the first base is cesium carbonate.

[1680] 53. The method according to embodiment 51 or 52, wherein the second base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[1681] 54. A method for preparing a composition containing a racemic compound of formula Ia:

[1682]

[1683] This includes compositions containing an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula Ia as compounds of formula D-1:

[1684]

[1685] The treatment is carried out in the presence of a base, under conditions sufficient to form the racemic compound of formula Ia;

[1686] in:

[1687] * indicates chiral carbon;

[1688] P1 is a protecting group; and

[1689] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[1690] 55. The method according to embodiment 54, wherein the base is potassium tert-butoxide.

[1691] 56. The method according to any one of embodiments 51 to 55, further comprising preparing a composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia:

[1692]

[1693] The composition comprising passing a racemic derivative of a compound containing form Ia through a chiral chromatographic unit using a mobile phase and collecting an enantiomeric excess of (R)- or (S)-enantiomers of the compound containing form Ia.

[1694] in:

[1695] * indicates chiral carbon;

[1696] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1697] P1 is a protecting group.

[1698] 57. The method according to embodiment 56, wherein the mobile phase comprises isopropanol and hexane, wherein the isopropanol is present in an amount of about 25 vol% to about 10 vol%.

[1699] 58. The method according to any one of embodiments 56 to 57, wherein the chromatographic unit is a simulated moving bed (SMB) chromatographic unit having a set of eight columns or chiral column units, wherein each column is filled with a chiral stationary phase.

[1700] 59. The method according to any one of embodiments 51 to 58, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1701] 60. The method according to any one of embodiments 51 to 60, wherein R1 is cyclopentyl.

[1702] 61. A method for preparing a composition comprising an enantiomeric excess of a (R)- or (S)-enantiomer of a compound of formula Ia:

[1703]

[1704] include:

[1705] (a) Reacting a composition containing a racemic derivative 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;

[1706] (b) Separating the composition, said composition comprising an enantiomerically excess of a chiral salt of the (R)- or (S)-enantiomer of the compound of formula Ia; and

[1707] (c) Treat the chiral salt with an alkali to form a composition containing an enantiomeric excess of the (R)- or (S)-enantiomer of the compound of formula Ia;

[1708] in:

[1709] * indicates chiral carbon;

[1710] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1711] P1 is a protecting group.

[1712] 62. The method according to embodiment 61, wherein the chiral acid is selected from optically active forms of mandelic acid, 2-chloromandelic acid, camphor sulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphor sulfonic acid, dibenzoyl tartaric acid, di-p-toluyl tartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]hept-1-methylenesulfonic acid and 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methylenesulfonic acid.

[1713] 63. The method according to embodiment 61, wherein the chiral acid is (+)-dibenzoyl-D-tartaric acid.

[1714] 64. The method according to any one of embodiments 61 to 63, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1715] 65. The method according to any one of embodiments 61 to 64, wherein R1 is cyclopentyl.

[1716] 66. A method for preparing compound XII:

[1717]

[1718] Including compounds of formula X:

[1719]

[1720] Compounds of formula XIII:

[1721]

[1722]

[1723] The reaction takes place in the presence of a palladium catalyst, a base, and a solvent to form a compound of formula XII.

[1724] in:

[1725] * indicates chiral carbon;

[1726] X2 is a toluenesulfonate group, a trifluoromethanesulfonate group, an iodo group, a chloro group, or a bromo group;

[1727] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl; and

[1728] R c and R d Each independently is H or C 1-6 Alkyl; or

[1729] R c and R d Together with the oxygen atoms they are attached to and the boron atoms attached to those oxygen atoms, they form a group optionally bounded by 1, 2, 3, or 4 carbon atoms. 1-4 Alkyl-substituted 5- to 6-membered heterocycles; and

[1730] P1 and P2 are each an independent protective base.

[1731] 67. The method according to embodiment 66, wherein the compound of formula XIII is as follows:

[1732]

[1733] 68. The method according to any one of embodiments 66 to 67, wherein P1 is -CH2OC(=O)-C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1734] 69. The method according to any one of embodiments 66 to 68, wherein P2 is 1-(ethoxy)ethyl.

[1735] 70. The method according to any one of embodiments 10, 12, 13, 21, 35, 39, 50 and 56 to 63, further comprising reacting the compound of formula Ia under deprotection conditions to form the compound of formula III:

[1736]

[1737] * indicates chiral carbon;

[1738] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C1-6 fluoroalkyl; and

[1739] P1 is a protecting group.

[1740] 71. The method according to embodiment 70, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1741] 72. The method according to embodiment 70 or 71, wherein R1 is cyclopentyl.

[1742] 73. The method according to embodiment 70 or 71, wherein the compound of formula III is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile.

[1743] 74. The method according to any one of embodiments 70 to 73 further comprises reacting the compound of formula III with phosphoric acid to form a phosphate of said compound of formula III.

[1744] 75. A method for preparing compound XVI:

[1745]

[1746] include:

[1747] (a) Making compound XVIII

[1748]

[1749] With about 1 or more equivalent of C 1-6 Alkyl Grignard reagents or C 1-6 The reaction is carried out with an alkyllithium reagent, followed by treatment with about one or more equivalents of a compound of formula XVII:

[1750]

[1751] as well as,

[1752] (b) Optionally, the product of step (a) is protected again to obtain compound XVI;

[1753] in:

[1754] P3 is a protecting group;

[1755] X3 is a halogen;

[1756] R4 is C 1-6 Alkyl; and

[1757] m is an integer selected from 1 and 2.

[1758] 76. The method according to embodiment 75, wherein X3 is an iodine group or a bromine group.

[1759] 77. The method according to embodiment 75 or 76, wherein P3 is 1-(ethoxy)ethyl.

[1760] 78. The method according to any one of embodiments 75 to 77, wherein the compound of formula XVI is as follows:

[1761]

[1762] 79. The method according to any one of embodiments 75 to 78, further comprising a method for preparing a compound of formula XVIII, including a protected compound of formula XIX:

[1763]

[1764] in:

[1765] P3 is a protecting group;

[1766] X3 is a halogen;

[1767] And m is an integer selected from 1 and 2.

[1768] 80. The method according to any one of embodiments 75 to 79, further comprising preparing the compound of formula XIX by a method comprising reacting 1H-pyrazole with a halogenating agent, wherein:

[1769] X3 is a halogen; and

[1770] m is an integer selected from 1 and 2.

[1771] 81. The method according to any one of embodiments 75 to 80, wherein the halogenating agent is selected from N-bromosuccinimide or N-iodosuccinimide.

[1772] 82. A method for preparing compounds of formula XIa:

[1773]

[1774] Including compounds of formula F-1:

[1775]

[1776] The mixture was treated with an acid under conditions sufficient to form a compound of formula XIa.

[1777] 83. The method according to embodiment 82, wherein the acid is a concentrated hydrochloric acid aqueous solution.

[1778] 84. The method according to any one of embodiments 82 to 83, further comprising preparing the compound of formula F-1 by a method comprising causing the compound of formula F-2:

[1779]

[1780] It reacts with about 1 or more equivalents of a Wittig-type reagent having the formula -CH2OCH3 ylide in the presence of a base.

[1781] 85. The method according to any one of embodiments 82 to 84, further comprising preparing the compound of formula F-1 by a method comprising causing the compound of formula F-3:

[1782]

[1783] It reacts with about 2 or more equivalents of ammonia in a solvent.

[1784] 86. The method according to any one of embodiments 82 to 85, further comprising preparing the compound of formula F-1 by a method comprising causing the compound of formula F-4:

[1785]

[1786] It reacts with chlorinating agents.

[1787] 87. A composition comprising an enantiomeric excess of the (R)- or (S)-enantiomer of a compound of formula I:

[1788]

[1789] in:

[1790] * indicates chiral carbon;

[1791] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1792] R2 is selected from -C(=O)-NH2, -C(=O)O-R3, -C(=O)OH and -C(=O)H;

[1793] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[1794] P1 is a protecting group.

[1795] 88. The composition according to embodiment 87, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1796] 89. The composition according to embodiment 87 or 88, wherein R1 is cyclopentyl.

[1797] 90. A compound of formula II:

[1798]

[1799] in:

[1800] R1 is selected from C 3-7 cycloalkyl, C 1-6 Alkyl and C 1-6 fluoroalkyl;

[1801] R2 is selected from -C(=O)-NH2 and -C(=O)O-R3;

[1802] R3 is selected from C 1-4 Alkyl or C 1-4 fluoroalkyl; and

[1803] P1 is a protecting group.

[1804] 91. The compound according to embodiment 90, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

[1805] 92. The compound according to embodiment 90 or 91, wherein R1 is cyclopentyl.

[1806] 93. A method for preparing a composition comprising a compound of formula III' in an enantiomeric excess of 90% or more (R)-enantiomers:

[1807]

[1808] include:

[1809] (a) Compound of formula XI':

[1810]

[1811] Treatment with sodium hydride and N-pentanoyloxymethyl chloride to form compound X':

[1812]

[1813]

[1814] (b) The compound of formula X' is converted into compound of formula XIII':

[1815]

[1816] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII':

[1817]

[1818] (c) Reacting the compound of formula XII' under deprotection conditions to obtain the compound of formula IV':

[1819]

[1820] (d) Mixing the compound of formula IV" with the compound of formula XIV':

[1821]

[1822] The reaction was carried out in the presence of 1,8-diaza-bicyclo[5.4.0]undec-7-ene to give compound II':

[1823]

[1824] (e) Reacting the compound of formula II' with hydrogen in the presence of [Rh(COD)2]CF3SO3 and a chiral phosphine ligand selected from the following:

[1825]

[1826] To form compounds of formula I':

[1827] as well as

[1828] (f) Reacting the compound of formula I' under deprotection conditions to form the compound of formula III';

[1829] * indicates chiral carbon.

[1830] 94. The method according to embodiment 93 further includes preparing the compound of formula XI':

[1831]

[1832] include:

[1833] (i) To make F-4 compound:

[1834]

[1835] It reacts with 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:

[1836]

[1837] (ii) Reacting the F-3 compound with about two equivalents of ammonia in methanol to form a compound of formula F-2:

[1838]

[1839] (iii) Mixing the compound of formula F-2 with about 1 to about 1.5 equivalents of formula [Ph3P] + The Wittig-type reagent of (CH2OCH3)]Cl- reacts in the presence of about 1 to about 1.5 equivalents of potassium tert-butoxide, wherein Ph is a phenyl group, to form a compound of formula F-1:

[1840] as well as

[1841] (iv) The compound of formula F-1 is refluxed in tetrahydrofuran with concentrated hydrochloric acid aqueous solution to form compound of formula XI'.

[1842] 95. The method according to embodiment 93 further comprises preparing the compound of formula XIII':

[1843]

[1844] include:

[1845] (i) Reacting 1H-pyrazole with N-bromosuccinimide to form a compound of formula XIX';

[1846]

[1847] (ii) Protect the compound of formula XIX to form compound of formula XVIII':

[1848] as well as

[1849] (iii) Reacting the compound of formula XVIII' with about one or more equivalents of isopropyl magnesium chloride, followed by treatment with about one or more equivalents of the compound of formula XVII':

[1850]

[1851] To form compound XIII'.

[1852] 96. The method according to embodiment 93 further comprises preparing the compound of formula XIII':

[1853]

[1854] include:

[1855] (i) Protect 4-iodo-1H-pyrazole to form a compound of formula XVIII":

[1856] as well as

[1857] (ii) Reacting the compound of formula XVIII" with about one or more equivalents of isopropyl magnesium chloride in tetrahydrofuran, followed by treatment with about one or more equivalents of the compound of formula XVII':

[1858]

[1859] To form compound XIII'.

[1860] 97. The method according to embodiment 93, wherein in step (e):

[1861] The solvent is 2,2,2-trifluoroethanol (TFE);

[1862] The hydrogenation catalyst is loaded in an amount of about 0.005 to about 0.01 mol%.

[1863] The ratio of the compound of formula II to the hydrogenation catalyst is from about 20,000 / 1 to about 10,000 / 1;

[1864] The hydrogen pressure is approximately 7 to approximately 60 bar;

[1865] The reaction was carried out at a temperature of approximately room temperature to approximately 75°C;

[1866] The reaction is run until the conversion of compound II to compound III is approximately equal to or greater than 99.5%; and

[1867] The reaction takes approximately 10 to 25 hours.

[1868] 98. A method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1869]

[1870] include:

[1871] (a) Compound of formula XI':

[1872]

[1873] Treatment with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form compound X":

[1874]

[1875] (b) The compound of formula X" is converted into compound of formula XIII':

[1876]

[1877] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII":

[1878]

[1879] (c) Reacting the compound of formula XII" under deprotection conditions to form the compound of formula IV":

[1880]

[1881] (d) Mixing the compound of formula IV" with the compound of formula D-1':

[1882]

[1883] The reaction is carried out under conditions sufficient to form a racemic compound containing formula I":

[1884]

[1885] (e) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[1886] (f) React the compound of formula I" with lithium tetrafluoroborate, and then with an aqueous solution of ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1887] * represents chiral carbon.

[1888] 99. A method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1889]

[1890] include:

[1891] (a) A composition containing an enantiomer excess of the (S)-enantiomer of a compound of formula I":

[1892]

[1893] Compound of formula D-1':

[1894]

[1895] The mixture is treated in acetonitrile in the presence of cesium carbonate under conditions sufficient to form a racemic product of formula I".

[1896] (b) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[1897] (c) React the compound of formula I" with lithium tetrafluoroborate, and then with an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1898] * represents chiral carbon.

[1899] 100. A method for preparing a composition comprising an enantiomeric excess of (R)-enantiomer of a compound of formula III':

[1900]

[1901] include:

[1902] (a) Compound of formula XI':

[1903]

[1904] Treatment with sodium hydride and 2-(trimethylsilyl)ethoxymethyl to form compound X":

[1905]

[1906]

[1907] (b) The compound of formula X" is converted into compound of formula XIII':

[1908]

[1909] Treatment was carried out in the presence of Pd(triphenylphosphine)4, potassium carbonate, and a solvent to form a compound of formula XII":

[1910]

[1911] (c) Reacting the compound of formula XII" under deprotection conditions to form the compound of formula IV":

[1912]

[1913] (d) Mixing the compound of formula IV" with the compound of formula D-1':

[1914]

[1915]

[1916] The reaction is carried out under conditions sufficient to form a racemic compound containing formula I":

[1917]

[1918] (e) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[1919] (f) React the compound of formula I" with boron trifluoride diethyl ether, and then with an aqueous solution of ammonium hydroxide to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1920] * represents chiral carbon.

[1921] 101. A method for preparing a composition comprising an enantiomeric excess of the (R)-enantiomer of a compound of formula III':

[1922]

[1923] include:

[1924] (a) A composition containing an enantiomer excess of the (S)-enantiomer of a compound of formula I":

[1925]

[1926] Compound of formula D-1':

[1927]

[1928] The mixture is treated in acetonitrile in the presence of cesium carbonate under conditions sufficient to form a racemic product of formula I".

[1929] (b) passing the composition comprising the racemic compound of formula I" through a chiral chromatographic unit using a mobile phase, and collecting the composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula I"; and

[1930] (c) React the compound of formula I" with boron trifluoride diethyl ether, followed by an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III';

[1931] * represents chiral carbon.

[1932] 102. A method for preparing a composition comprising an enantiomeric excess of (R)-enantiomer of a compound of formula III':

[1933]

[1934] Includes: compounds of formula I:

[1935]

[1936] The compound is reacted with boron trifluoride ether, followed by an aqueous solution of ammonium hydroxide, to form a composition comprising an enantiomeric excess of the (R)-enantiomer of the compound of formula III'; wherein * is a chiral carbon.

[1937] 103. A method for preparing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate, 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.

[1938] 104. A method for purifying (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate, comprising recrystallizing (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate from a solvent mixture comprising methanol, 2-propanol and n-heptane.

[1939] 105. The method according to embodiment 104, wherein the 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 in methanol.

[1940] The invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that many non-critical parameters can be changed or modified to obtain substantially the same results.

[1941] Example

[1942]

[1943] [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methylpentanoate (5). Sodium hydride (NaH, 60 wt% in mineral oil, 32.82 g, 0.82 mol, 1.20 equivalent) and anhydrous 1,2-dimethoxyethane (DME, 500 mL, 4.8 mol) were packed into a dried 3L four-necked round-bottom flask equipped with a stir bar, septum, thermocouple, 500 mL feeding funnel, and nitrogen inlet, and the resulting mixture was cooled to 0–3 °C. A dried 1L round-bottom flask was filled with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1,105.0 g, 0.684 mol) and 1,2-dimethoxyethane (DME, 750 mL, 7.2 mol). The resulting slurry was then added in portions over 30 minutes via a wide-bore sleeve at 5–12 °C. The resulting reaction mixture was heterogeneous. After the addition, the cold bath was removed, and the mixture was gradually heated to room temperature and stirred at room temperature for 1 hour, then cooled to 0–5 °C. Chloromethyl pivalate (pivaloyloxymethyl chloride, POM-Cl, 112 mL, 0.752 mol, 1.1 equivalents) was added dropwise to the reaction mixture over 30 minutes while stirring at 0–5 °C. The addition of chloromethyl pivalate was mildly exothermic, raising the reaction temperature to as high as 14 °C. After adding chloromethyl tervastatin, the cooling bath was removed, and the reaction mixture was brought to room temperature and stirred at room temperature for 90 minutes. When the reaction was confirmed to be complete (e.g., by TLC and LCMS), the reaction was carefully quenched with water (100 mL). This quenched reaction mixture containing crude POM-protected chlorodeazopurine (2) was used directly for subsequent Suzuki coupling reactions without further treatment and purification.

[1944] 4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)–1H-pyrazole (3,200 g, 0.75 mol, 1.10 equivalents) and potassium carbonate (K2CO3, 189 g, 1.37 mol, 2.0 equivalents) were added to the quenched reaction mixture containing crude POM-protected chlorodenitrifying purine (2) prepared above at room temperature. The resulting mixture was degassed by passing a nitrogen stream through the solution for 15 minutes, then treated with tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 7.9 g, 0.68 mmol, 0.01 equivalents), and the resulting reaction mixture was heated under reflux (approximately 82 °C) for 10 hours. When the reaction was confirmed to be complete (e.g., by TLC (1:1 hexane / ethyl acetate) and LCMS), the reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 L) and water (1 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 500 mL). The combined organic layers were washed with water (2 × 1 L) and brine (1 L), and then concentrated under reduced pressure to give crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methylpentanoteate (4), which was used directly for subsequent deprotection reactions without further purification.

[1945] A solution of crude {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methylpentanoate (4) in THF (1 L, 12.3 mol) was added to a 500 mL aqueous solution of 4N HCl. The resulting reaction mixture was then stirred at room temperature for 5 hours. When the reaction was confirmed to be complete (e.g., by TLC and LCMS), the reaction mixture was cooled to 0–5 °C and the pH was adjusted to 9–10 with 2 L of 1M aqueous sodium hydroxide (NaOH). The mixture was concentrated under reduced pressure to remove most of the THF, and the resulting suspension was stirred at room temperature for 2 hours. The solid was collected by filtration, washed with water (3 × 500 mL), and dried under vacuum to give crude [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methylpentanotelate (5, 157.5 g, theoretically 204.43 g, 77% yield, via three steps) as a white to off-white solid, which was confirmed to be of sufficient purity to carry out subsequent reactions without further purification (>98% by area, as determined by HPLC). For 5: 1H NMR(DMSO-d6,400MHz)δppm13.42(br s,1H),8.76(s,1H),8.67(s,1H),8.33(s,1H),7.68(d,1H,J=3.8Hz),7.11(d,1H,J=3.8Hz),6.21(s,2H),1.06(s,9H); 13 C 15 H 17 N5O2(MW,299.33),LCMS(EI)m / e 300(M + +H).

[1946]

[1947] Cyanoxybenzene (6). Phenol (20.0 g, 0.210 mol), diethyl ether (Et₂O, 290 mL), and cyanogen bromide (BrCN, 23.0 g, 0.210 mol, 1.0 equivalent) were added to a dried 500 mL three-necked round-bottom flask equipped with a top stirrer, septum, thermocouple, and nitrogen inlet at room temperature. The resulting solution was cooled to 0–3 °C, and then triethylamine (TEA, 61.9 mL, 0.442 mol, 2.1 equivalent) was added dropwise over 25 minutes via syringe. The addition of triethylamine to the reaction mixture was mildly exothermic, raising the reaction temperature to up to 15 °C. After the addition of triethylamine, the reaction mixture became a white slurry at 5–15 °C and was vigorously stirred at 0 °C for 2 hours. When the reaction was confirmed to be complete (e.g., by TLC and LCMS), the reaction mixture was diluted with pentane (150 mL, 1.30 mol). The precipitated triethylamine hydrochloride was filtered off and washed with diethyl ether and pentane (1:1 volume ratio, 200 mL). The filtrate was then concentrated under reduced pressure to remove most of the solvent, and the residue containing crude cyanoxybenzene (6) was used directly in subsequent reactions without further purification, assuming a theoretical yield.

[1948] 3-Cyclopentylpropynenitrile (8). Cyclopentylacetylene (7, 15.0 g, 0.143 mol) and anhydrous tetrahydrofuran (THF, 170 mL, 2.10 mol) were added to a dried 500 mL three-necked round-bottom flask equipped with a stir bar, nitrogen inlet, 125 mL feeding funnel, and thermocouple at room temperature. The resulting solution was then cooled to –78 °C, and a 2.5 M solution of n-butyllithium in hexane (63.1 mL, 0.158 mol, 1.1 equivalents) was added dropwise over 25 minutes. The resulting cyclopentylacetylene lithium solution was stirred at -78 °C for 15 minutes, and then a solution of crude cyanoxybenzene (6, 25.0 g, 0.210 mol, 1.5 equivalents) in anhydrous tetrahydrofuran (THF, 30.0 mL, 0.400 mol) was added dropwise through a sleeve at -78 °C. The resulting reaction mixture was stirred at -78°C for another 10 minutes, then the cooling bath was removed, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for 1–2 hours. When the reaction was confirmed to be complete, the reaction mixture was quenched with 6N sodium hydroxide aqueous solution (NaOH, 200 mL) and 20% salt aqueous solution (200 mL). The aqueous solution was treated with ethyl acetate (EtOAc, 200 mL), and the two layers were separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (SiO2, 0 to 5% ethyl acetate / hexane gradient elution) to give 3-cyclopentylpropynitrile (8, 14.3 g, theoretically 17.0 g, 84% yield, in two steps) as a yellow to orange oil. For 8: 1 H NMR(DMSO-d6,400MHz) δ2.97(m,1H),1.97(m,2H),1.64(m,4H),1.56(m,2H).

[1949]

[1950] 4-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentavate (9). At room temperature, a 500 mL round-bottom flask equipped with a stir bar and a nitrogen inlet was charged with 3-cyclopentylpropynitrile (8, 8.50 g, 0.0713 mol, 1.52 equivalents), N,N-dimethylformamide (DMF, 84 mL, 1.08 mol), and [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methylpentavate (5, 14.0 g, 0.0468 mol) and solid potassium carbonate (K₂CO₃, 0.329 g, 0.00238 mol, 0.05 equivalents). The resulting reaction mixture was then stirred at room temperature for 60 minutes. When TLC and HPLC confirmed the completion of the reaction, the reaction mixture was quenched with 20% saline solution (75 mL), and the resulting solution was extracted with ethyl acetate (EtOAc, 3 × 75 mL). The combined organic extracts were washed with 20% saline solution (75 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 0 to 20% ethyl acetate / hexane gradient elution) to give 4-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentovalerate (9, 16.4 g, theoretically 19.6 g, 83.7% yield) as a white solid. For 9: 1 H NMR(DMSO-d6,300MHz)δ9.09(s,1H),8.84(s,1H),8.63(s,1H),7.78(d,1H,J=3.8Hz) ,7.17(d,1H,J=3.8Hz),6.24(s,2H),5.82(s,1H),3.55(m,1H),1.92(m,2H),1.59(br m,6H),1.06(s,9H);C 23 H 26 N6O2(MW,418.49),LCMS(EI)m / e 419(M + +H).

[1951] (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate (10). At room temperature, a 200 mL round-bottom flask equipped with a stir bar and a nitrogen inlet was filled with 4-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate (9, 8.00 g, 0.0191 mol), trifluoroacetic acid (TFA, 40.6 mL, 0.528 mol), and concentrated sulfuric acid (H₂SO₄, 3.77 mL, 0.0707 mol). The resulting reaction mixture was stirred at room temperature for 60 minutes. Once TLC and HPLC confirmed the completion of the reaction, the reaction mixture was quenched with water (30.1 mL, 1.67 mol). The quenched reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0–5 °C. The cold solution was then treated with 3N sodium hydroxide aqueous solution (NaOH, 223 mL) to adjust the pH to 8, followed by treatment with ethyl acetate (EtOAc, 200 mL). The two layers were separated, and the aqueous solution was then extracted with ethyl acetate (EtOAc, 2 × 50 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (100 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 0 to 100% ethyl acetate / hexane gradient elution) to give (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxyprop-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanoate (10, 6.79 g, theoretically 8.34 g, 81.4% yield) as a pale yellow solid. For 10: 1 H NMR(DMSO-d6,300MHz)δ8.77(s,1H),8.68(s,1H),8.41(s,1H),7.71(d,1H,J=3.8Hz),7.51(br.s,1H),7.09(br C 23 H 28 N6O3(MW,436.51),LCMS(EI)m / e 437(M + +H).

[1952]

[1953] (4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanoate (11). At room temperature, a 25 mL round-bottom flask equipped with a stir bar was filled with (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanoate (10, 1.15 g, 2.63 mmol), tetrahydrofuran (THF, 20.0 mL, 246 mmol), and 10% carbon-supported palladium (50% wet, 130 mg). The resulting reaction mixture was degassed three times, each time backfilled with hydrogen, and then hydrogenated under a stable stream of hydrogen released from a hydrogen cylinder. The reaction was checked after 17 hours and found to be complete. The reaction mixture was then filtered through a diatomaceous earth bed to remove the catalyst, and the diatomaceous earth bed was washed with a small volume of tetrahydrofuran (THF). The combined filtrates were concentrated under reduced pressure to give crude (4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate (11, 1.15 g, theoretically 1.153 g, 99% yield), a yellow to brown oil, which solidified upon standing in vacuum at room temperature. This crude product (11) was confirmed to be sufficiently pure (>98%, by HPLC analysis) to be suitable for subsequent steps without further purification. For 11: 1 H NMR(DMSO-d6,300MHz)δppm 8.73(s,1H),8.60(s,1H),8.27(s,1H),7.70(d,1H,J=3.8Hz),7.32(bs, 1H),7.09(d,1H,J=3.8Hz),6.75(bs,1H),6.21(s,2H),4.56(td,1H,J=4 .0,9.8Hz),2.86(dd,1H,J=10.5,5.6Hz),2.63(dd,1H,J=4.0,15.3Hz),2.32(m,1H),1.77(m,1H),1.56-1.19(m,7H),1.06(s,9H); LCMS(EI)m / e 439(M + +H); C 23 H 30 N6O3(MW,438.52),LCMS(EI)m / e 439(M + +H).

[1954] (R)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentovatate ((R)-11) and (S)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentovatate ((S)-11).

[1955] The general screening procedure for asymmetric hydrogenation, using the substrate (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate (10), yields the optically enriched product (4-(1-(3-amino-1-cyclopentyl-3-oxypropyl]-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-11 or (S)-11): Under nitrogen, the substrate (10), catalyst (metal, ligand, and catalyst precursor), and an oxygen-free solvent are loaded into a 300 mL autoclave containing a glass vial (20 mL). Prepare a solution (4-6 mL). Charge the autoclave with hydrogen to the desired pressure and stir at room temperature or heat in an oil bath. After releasing the hydrogen, concentrate the reaction mixture under reduced pressure. Purify the residue by elution with a silica gel pad using a mixture of ethyl acetate and methanol (v / v = 9 / 1) to give the product (4-(1-(3-amino-1-cyclopentyl-3-oxypropyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-11 or (S)-11), for determination of chemical conversion (HPLC and chiral HPLC), LC / MS and NMR spectroscopy, and enantiomeric excess (%ee, by chiral HPLC).

[1956] The enantiomeric excess (%ee) of the product was determined by chiral HPLC analysis. IA column. The mobile phase was a mixture of hexane and ethanol (v / v = 90 / 10). The flow rate was 1 mL / min, and the UV detection wavelength was set to 254 nm. The substrate (10), the undesired enantiomer ((S)-11, the first peak), and the desired enantiomer ((R)-11, the second peak) were fully separated at retention times of 46 min, 36 min, and 38 min, respectively.

[1957] For (R)-11 or (S)-11: 1H NMR(DMSO-d6,300MHz)δppm 8.73(s,1H),8.60(s,1H),8.27(s,1H),7.70(d,1H,J=3.8Hz),7.32(bs, 1H),7.09(d,1H,J=3.8Hz),6.75(bs,1H),6.21(s,2H),4.56(td,1H,J=4 .0,9.8Hz),2.86(dd,1H,J=10.5,5.6Hz),2.63(dd,1H,J=4.0,15.3Hz),2.32(m,1H),1.77(m,1H),1.56-1.19(m,7H),1.06(s,9H); LCMS(EI)m / e 439(M + +H); C 23 H 30 N6O3(MW,438.52),LCMS(EI)m / e 439(M + +H).

[1958] The table below summarizes the analysis and reaction conditions for this asymmetric hydrogenation.

[1959]

[1960]

[1961] The structures of the chiral phosphine ligands used in this study are listed below.

[1962]

[1963] The following describes a representative preparative asymmetric hydrogenation procedure and how crystallization can be used to improve the chiral purity of the product.

[1964] (S)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((S)-11). Under nitrogen, a solution of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxypropyl-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate (10,215 mg) in a mixture of dichloromethane (CH2Cl2, 12.5 mL) and trifluoroethanol (CF3CH2OH, 0.25 mL) was treated with the catalyst Rh(COD)(SSRR-TangPhos)BF4 (8.8 mg), and the reaction mixture was then pressurized to 40 bar with hydrogen. Under this hydrogen pressure, the reaction mixture was stirred at 50°C for 20 hours. When HPLC analysis showed that the substrate had been completely consumed, the reaction mixture was cooled to room temperature. Chiral HPLC analysis determined that the enantiomeric excess of the reaction mixture was 88% ee (first peak 94%, (S)-11; second peak 6%, (R)-11). The reaction mixture was filtered through a thin silica gel pad, which was then washed with dichloromethane (5 mL). The filtrate was then concentrated to dryness under reduced pressure. The resulting foamy solid (180 mg) was packed into a mixture of heptane (5 mL) and ethyl acetate (EtOAc, 5 mL). A white solid precipitated upon stirring at 20°C. The slurry was stirred at 20°C for 16 hours. The solid was collected by filtration, and chiral HPLC analysis of the collected solid (52 mg) showed an enantiomeric excess of 66.0%, biased towards the first peak (first peak 83.0%, (S)-11; second peak 17.0%, (R)-11). The resulting filtrate was then evaporated to dryness. Chiral HPLC analysis of the resulting oil (108 mg) showed an enantiomeric excess of 99.6%, biased towards the first peak (first peak 99.83%, (S)-11; second peak 0.17%, (R)-11). This result indicates in principle that the optical purity of the asymmetric hydrogenation product can be significantly improved by selectively removing a smaller amount of enantiomeric material through precipitation of a suitable solvent system (e.g., ethyl acetate / heptane).

[1965] (R)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-11). Under nitrogen atmosphere, a solution of (10,500 mg) of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxypropyl-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate (10,500 mg) in methanol (MeOH, 8.0 mL) was treated with the catalyst Ru(COD)(SL-A153-1)(CF3CO2)2 (6.6 mg). The reaction mixture was then pressurized to 50 bar with hydrogen. Under this hydrogen pressure, the reaction mixture was stirred at 30 °C for 21 hours. When HPLC analysis showed that the substrate had been completely consumed, the reaction mixture was cooled to room temperature. Chiral HPLC analysis determined that the enantiomeric excess of the reaction mixture was 98% ee (second peak 99%, (R)-11; first peak 1%, (S)-11). The reaction mixture was then filtered through a thin silica gel pad, which was washed with methanol (5 mL). The filtrate was concentrated to dryness under reduced pressure. Analysis of the resulting foamy solid (470 mg) by chiral HPLC showed an enantiomeric excess of 98.0%, biased towards the second peak (second peak 99.0%, (R)-11; first peak 1.0%, (S)-11).

[1966]

[1967] (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-12). Method A: At room temperature, (R)-(4-(1-(3-amino-1-cyclopentyl-3-oxypropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-11, 413 mg, 0.942 mmol), N,N-dimethylformamide (DMF, 10 mL, 129 mmol) and triethylamine (TEA, 0.525 mL, 3.77 mmol, 4.0 equivalent) were packed into a 50 mL round-bottom flask equipped with a stir bar and a nitrogen inlet. The resulting mixture was then cooled to 0–5 °C in an ice bath, and trichloroacetyl chloride (0.315 mL, 2.82 mmol, 3.0 equivalence) was added dropwise via syringe at room temperature. The resulting reaction mixture was then stirred at 0–5 °C for 90 min. When TLC and HPLC confirmed the completion of the reaction, the reaction mixture was treated with ethyl acetate (EtOAc, 25 mL) and 20% saline solution (20 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 × 25 mL). The combined organic extracts were washed with 20% saline solution (35 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residual brown oily crude product was purified by rapid chromatography (SiO2, 0 to 50% ethyl acetate / hexane gradient elution) to give (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-12, 278 mg, theoretically 396.1 mg, 70.2% yield), which solidified upon standing in vacuum at room temperature. For (R)-12: achiral purity (99.1 area%, detected by HPLC at 220 nm); chiral purity (99.6 area%, analyzed by chiral HPLC; 99.2% ee); 1 HNMR(DMSO-d6,400MHz)δppm 8.84(s,1H),8.78(s,1H),8.39(s,1H),7.74(d,1H,J=3.7Hz,),7.11(d,1H,J=3.8Hz),6.23(s,2H),4.53(ddd,1H,J=9.9 C 23 H 28N6O2(MW,420.51),LCMS(EI)m / e 421.4(M + +H).

[1968] (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base). Method A: At room temperature, (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methylpentanate ((R)-12, 278 mg, 0.661 mmol) and methanol (MeOH, 2.50 mL, 37.0 mmol) were added to a 25 mL round-bottom flask equipped with a stir bar and a nitrogen inlet. The resulting homogeneous reaction solution was then treated with 0.10 M aqueous sodium hydroxide solution (NaOH, 1.5 mL, 0.15 mmol, 2.3 equivalents) at room temperature. The resulting reaction mixture was stirred at room temperature for 22 hours. When the reaction was confirmed to be complete, the reaction mixture was diluted with 20% saline solution (10 mL) and ethyl acetate (EtOAc, 25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 25 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 0 to 100% ethyl acetate / hexane gradient elution) to give (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base, 188 mg, theoretically 202.5 mg, 92.8% yield) as a colorless oil, which solidified upon standing under vacuum at room temperature. For (R)-13 (free base): 1 H NMR(DMSO-d6,400MHz)δppm12.1(bs,1H),8.80(d,1H,J=0.42Hz),8.67(s,1H),8.37(s,1H),7.59(dd,1H,J=2.34,3.51Hz),6.98(dd,1H,J=1 .40,3.44Hz),4.53(td,1H,J=19.5,4.63Hz),3.26(dd,1H,J=9.77,17.2Hz),3.18(dd,1H,J=4.32,17.3Hz),2.40(m,1H),1.79(m,1H),1.65to 1.13(m,7H);C 17 H 18 N6(MW,306.37)LCMS(EI)m / e 307(M + +H).

[1969] (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate ((R)-14, phosphate). At 60-65 °C, a solution of phosphoric acid (186.2 g, 1.9 mol, 1.10 equivalents) in isopropanol (1.6 L) was added to a solution of (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base, 572 g, 1.87 mol) in isopropanol (IPA, 8 L). No exothermic reaction was observed upon addition of the phosphoric acid solution, and a precipitate formed almost immediately. The resulting mixture was then heated at 76 °C for 1.5 h, then gradually cooled to ambient temperature and stirred overnight at room temperature. The mixture was filtered, and the solid was washed with a mixture of heptane and isopropanol (1 / 1, v / v, 3 L), then transferred back to the original flask and stirred in heptane (8 L) for one hour. The solid was collected by filtration, washed with heptane (1 L), and dried to constant weight in a convection oven at 40 °C and under vacuum to give (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate ((R)-14, phosphate, 634.2 g, theoretically 755 g, 84% yield) as a white to grayish-white crystalline solid. For (R)-14 (phosphate): melting point 197.6 °C; 1 H NMR(DMSO-d6,500MHz)δppm12.10(s,1H),8.78(s,1H),8.68(s,1H),8.36(s 1H),7.58(dd,1H,J=1.9,3.5Hz),6.97(d,1H,J=3.6Hz),4.52(td,1H,J=3.9,9.7Hz),3.25(dd,1H,J=9.8,17.2Hz),3.1 6(dd,1H,J=4.0,17.0Hz),2.41,(m,1H),1.79(m,1H),1.59(m,1H),1.51(m,2H),1.42(m,1H),1.29(m,2H),1.18(m,1H); 13 C NMR(DMSO-d6,125MHz)δppm 152.1,150.8,149.8,139.2,131.0,126.8,120.4,118.1,112.8,99.8,62.5,44.3,29.1,29.0,24.9,24.3,22.5; C 17 H 18 N6 (MW, 306.37, free base) LCMS (EI) m / e 307 (M + +H, base peak), 329.1 (M) ++Na).

[1970]

[1971] 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (17). 4-chloropyrrolo[2,3-d]pyrimidine (1,10.08 g, 65.6 mmol) in sodium hydride (NaH, 60 wt% oil distribution, 4.05 g, 101.3 mmol, 1.54 equivalents) was slowly added to a suspension of 1,2-dimethoxyethane (DME, 20.0 mL, 192.4 mmol) while maintaining the temperature below 5°C (-7°C to 5°C). A large amount of gas was released immediately upon introduction of the substrate (1) solution. The resulting reaction mixture was stirred at 0–5 °C for 30 minutes, and then trimethylsilylethoxymethyl chloride (SEM-Cl, 12.56 g, 75.3 mmol, 1.15 equivalents) was slowly added while keeping the reaction temperature below 5 °C. After the addition, the reaction mixture was stirred at 0 °C for 1 hour, and then heated to room temperature for 23 hours. When HPLC and TLC confirmed the completion of the reaction, the reaction mixture was quenched with water (46 mL) at room temperature, and the quenched reaction mixture containing the desired product (15) was used directly for the next step of the Suzuki coupling reaction without further treatment and purification.

[1972] At room temperature, 1,2-dimethoxyethane (DME, 38 mL), potassium carbonate powder (K₂CO₃, 23.56 g, 170.5 mmol, 2.6 equivalents), and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)-1H-pyrazole (3, 18.60 g, 69.89 mmol, 1.06 equivalents) were added to the quenched reaction mixture containing crude 4-chloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (15, 18.63 g, 65.64 mmol) obtained from the previous reaction as described above. The resulting mixture was degassed four times, each time backfilled with nitrogen, and then treated at room temperature with tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4, 244.2 mg, 0.21 mmol, 0.003 equivalents). The resulting reaction mixture was degassed four times, each time backfilled with nitrogen, and then heated to 80 °C for 4–8 hours. When TLC and HPLC confirmed the completion of the reaction, the reaction mixture was gradually cooled to room temperature and filtered through a short bed of diatomaceous earth (10 g). The diatomaceous earth bed was washed with ethyl acetate (EtOAc, 20 mL). The two filtrates were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 × 30 mL). The combined organic extracts were washed with a saturated aqueous solution of NaCl (20 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure. The residue containing the desired crude Suzuki coupling product (16) was then transferred to a 500 mL round-bottom flask with THF (22 mL) for use in subsequent deprotection reactions without further purification.

[1973] A solution (22 mL) of the crude Suzuki coupling product (16) in THF was treated with water (108 mL) and a 10% aqueous HCl solution (prepared by mixing 19.6 mL of concentrated HCl with 64 mL of H2O). The resulting reaction mixture was stirred at room temperature for 4–6 hours. When TLC and HPLC confirmed the completion of the deprotection reaction, a 30% aqueous sodium hydroxide (NaOH) solution (prepared by dissolving 10.4 g of NaOH in 21.0 mL of H2O) was slowly added to the reaction mixture while keeping the temperature below 25 °C. After 10 minutes, the solid gradually dissolved and reprecipitated. The mixture was stirred at room temperature for 1–2 hours, and then the solid was collected by filtration and washed with H2O (50 mL). The wet filter cake was transferred to a 250 mL three-necked flask and treated with acetonitrile (MeCN, 112 mL) at room temperature. The mixture was heated under reflux for 2 hours, then gradually cooled to room temperature and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with MeCN (36 mL), and dried in a vacuum oven at 40–45 °C to give 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (17, 15.3 g, theoretically 20.7 g, 73.9% yield, via three steps), as a white crystalline solid (99.4% by area, as determined by HPLC). For 17: 1 H NMR(DMSO-d6,400MHz)δppm 13.41(bs,1H),8.74(s,1H),8.67(bs,1H),8.35(bs,1H),7.72(d,1H,J=3.7Hz),7.10(d ,1H,J=3.7Hz),5.61(s,2H),3.51(t,2H,J=8.2Hz),0.81(t,2H,J=8.2Hz),0.13(s,9H);C 15 H 21 N5OSi(MW,315.45),LCMS(EI)m / e 316(M + +H).

[1974]

[1975] Methyl 3-cyclopentylpropynate (18). 2.50 M n-butyllithium (66.0 mL, 165 mmol, 1.1 equivalence) in hexane was added to a stirred solution of cyclopentylacetylene (7, 17.49 mL, 150.0 mmol) in anhydrous tetrahydrofuran (THF, 200 mL, 2466 mmol). The resulting emulsion suspension was stirred at -78 °C for 30 min. Methyl chloroformate (17.6 mL, 225 mmol, 1.5 equivalence) was then added. The reaction mixture became a clear solution. The cooling bath was then removed, and the reaction mixture was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture became a suspension again. When TLC (5% EtOAc / hexane, KMnO4 staining) confirmed the completion of the reaction, the reaction mixture was quenched with saturated NH4Cl aqueous solution (150 mL) and extracted with diethyl ether (Et2O, 2 × 200 mL). The combined organic layers were washed with a saturated aqueous NaCl solution, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was distilled under vacuum (99-101 °C / 16 mbar) to give methyl 3-cyclopentylpropynate as a colorless oil (18, 21.856 g, theoretically 22.83 g, 96% yield). For 18: 1 H NMR (CDCl3, 400MHz) δppm 3.74 (s, 3H), 2.73 (m, 1H), 1.95 (m, 2H), 1.72 (m, 4H), 1.57 (m, 2H).

[1976]

[1977] (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19). At room temperature, solid potassium carbonate (K₂CO₃, 318 mg, 2.30 mmol) was added to a stirred solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin (17, 7.260 g, 23.01 mmol) and 3-cyclopentylprop-2-acetylenenitrile (8, 6.140 g, 34.52 mmol, 1.5 equivalents) in N,N-dimethylformamide (DMF, 40.0 mL, 516 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. When LCMS confirmed the completion of the reaction, the reaction mixture was quenched with water (80 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with water (80 mL) and brine (50 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (SiO2, 0–30% EtOAc / hexane gradient elution) to give (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 8.256 g, theoretically 10.0 g, 82.6% yield). For 19: 1 H NMR(CDCl3,300MHz)δppm 9.15(bs,1H),8.96(s,1H),8.56(s,1H),7.51(d,1H,J=3.5Hz),6.93(d,1H,J=3.5Hz),5.75(s,2H),5.29(s,1H), 3.62(m,1H),3.60(t,2H,J=8.2Hz),2.16(m,2H),1.81(m,4H),1.59(m,2H),0.98(t,2H,J=8.2Hz),0.00(s,9H); 23 H 30 N6OSi(MW,434.61),LCMS(EI)m / e 435.2(M + +H).

[1978] (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile ((R)-20) and (S)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile ((S)-20).

[1979] The general screening procedure for asymmetric hydrogenation, using the substrate (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19), yields the optically enriched product 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile ((R)-20 or (S)-20): Under nitrogen, the substrate (19), catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) are loaded into a 300 mL autoclave with a glass vial (20 mL). Hydrogen was introduced into the autoclave to achieve the desired pressure, and the mixture was stirred at room temperature or heated in an oil bath. After the hydrogen was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by elution with a silica gel pad using a mixture of ethyl acetate and methanol (v / v = 9 / 1) to give the product 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile ((R)-20 or (S)-20), for determination of chemical conversion (HPLC and chiral HPLC), LC / MS and NMR spectrometry, and enantiomeric excess (%ee, analyzed by chiral HPLC).

[1980] The enantiomeric excess (%ee) of the product was determined by chiral HPLC analysis. A chiral HPLC method was developed that uses... An OD-H column (4.6 × 250 mm, 5 μm) was purchased from Chiral Technologies, Inc. and filled with silica gel coated with cellulose tris(3,5-dimethylphenyl cellulose). The two enantiomers (R)-20 or (S)-20 were separated at room temperature using a mobile phase of 1 mL / min consisting of 10% ethanol and 90% hexane, with a resolution greater than 3.0. UV detection was performed at 220 nm. The retention times of the (S)-enantiomer ((S)-20) and (R)-enantiomer ((R)-20) were 10.3 min (first peak) and 13.1 min (second peak), respectively.

[1981] For (R)-20 or (S)-20: 1 H NMR(DMSO-d6,400MHz)δppm 8.83(s,1H),8.75(s,1H),8.39(s,1H),7.77(d,1H,J=3.7Hz),7.09(d,1H,J=3.7Hz),5.63(s,2H),4.53(td,1H,J=19.4,4.0Hz),3.5 C 23 H 32 N6OSi(MW,436.63),LCMS(EI)m / e437(M + +H) and 459(M) + +Na).

[1982] The table below summarizes the analysis and reaction conditions for this asymmetric hydrogenation.

[1983]

[1984]

[1985] The structures of the chiral phosphine ligands used in this study are listed below.

[1986]

[1987] The following describes a representative preparative asymmetric hydrogenation procedure.

[1988] (S)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile ((S)-20). Under nitrogen, a solution of (Z)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19,116 mg) in dichloromethane (CH2Cl2, 4.0 mL) was treated with the catalyst [Ru(p-methylisopropylbenzene)(S-C3-TunePhos)Cl]Cl (8.5 mg), and the reaction mixture was then pressurized to 60 bar with hydrogen. Under this hydrogen pressure, the reaction mixture was stirred at 75 °C for 19 hours. When HPLC analysis showed that the substrate had been completely consumed, the reaction mixture was cooled to room temperature. Chiral HPLC analysis determined an enantiomeric excess of 34.1% ee in the reaction mixture (first peak 67.05%, (S)-20; second peak 32.95%, (R)-20). The reaction mixture was then filtered through a thin silica gel pad, which was washed with dichloromethane (CH2Cl2, 5 mL). The filtrate was concentrated to dryness under reduced pressure. Analysis of the resulting foamy solid (107 mg) by chiral HPLC showed an enantiomeric excess of 34.1%, biased towards the first peak (first peak 67.05%, (S)-20; second peak 32.95%, (R)-20).

[1989]

[1990] (E)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl acrylate (21). At room temperature, 1,8-diazabicyclo[5.4.0]undecyl-7-ene (DBU, 2.92 mL, 19.2 mmol, 0.5 equivalent) was added to a stirred suspension of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin (17, 12.08 g, 38.31 mmol) and methyl 3-cyclopentylprop-2-alkynyl ester (18, 8.970 g, 45.97 mmol, 1.2 equivalents) in acetonitrile (76 mL, 1400 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. When LCMS confirmed the completion of the reaction, the reaction mixture was extracted with water (50 mL) and 1N HCl aqueous solution (20 mL). After treatment with 1N HCl aqueous solution, the quenched reaction mixture was adjusted to pH 4. The mixture was then extracted with EtOAc (2 × 100 mL), and the combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by combiflash (SiO2, 0-50% EtOAc / hexane gradient elution) to give (E)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl acrylate (21, 6.838 g, theoretically 17.92 g, yield 38%) as a colorless, extremely viscous oil. For 19: 1 H NMR(CDCl3,400MHz)δppm 8.93(s,1H),8.55(bs,1H),8.44(s,1H),7.49(d,1H,J=3.5Hz),6.86(d,1H,J=3.5Hz),6.34(s,1H),5.74(s,2H),4.56( C 24 H 33 N5O3Si(MW,467.64), LCMS(EI)m / e 468.2(M + +H).

[1991] (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-yl)methyl propionate ((R)-22) and (S)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-yl)methyl propionate ((S)-22).

[1992] The general screening procedure for asymmetric hydrogenation, using the substrate (E)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl acrylate (21), yields the optically enriched product 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl propionate ((R)-22 or (S)-22): Under nitrogen, the substrate (21), catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) are loaded into a 300 mL autoclave with a glass vial (20 mL). Hydrogen was introduced into the autoclave to achieve the desired pressure, and the mixture was stirred at room temperature or heated in an oil bath. After the hydrogen was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by elution with a silica gel pad using a mixture of ethyl acetate and methanol (v / v = 9 / 1) to give the product methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionate ((R)-22 or (S)-22), for determination of chemical conversion (HPLC and chiral HPLC), LC / MS and NMR spectrometry, and enantiomeric excess (%ee, by chiral HPLC).

[1993] The enantiomeric excess (%ee) of the product was determined by chiral HPLC analysis. A chiral HPLC method was developed that uses... An OD-H column (4.6 × 250 mm, 5 μm) was purchased from Chiral Technologies, Inc., and filled with silica gel coated with cellulose tris(3,5-dimethylphenyl cellulose). The two enantiomers (R)-22 or (S)-22 were separated at room temperature using a mobile phase of 1 mL / min prepared from 15% ethanol and 85% hexane with a resolution greater than 3.0. UV detection was performed at 254 nm. The retention times of the (S)-enantiomer ((S)-22) and (R)-enantiomer ((R)-22) were 5.3 min (first peak) and 8.2 min (second peak), respectively.

[1994] For (R)-22 or (S)-22: C 24 H 35 N5O3Si(MW,469.65), LCMS(EI)m / e 470(M + +H) and 492(M) + +Na).

[1995] The table below summarizes the analysis and reaction conditions for this asymmetric hydrogenation.

[1996]

[1997]

[1998] The structures of the chiral phosphine ligands used in this study are listed below.

[1999]

[2000] The following describes a representative preparative asymmetric hydrogenation procedure.

[2001] Methyl (S)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionate ((S)-22). Under nitrogen atmosphere, a solution of methyl (E)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21,109 mg) in ethyl acetate (EtOAc, 5.0 mL) was treated with the catalyst [Rh(COD)(+)-DuanPhos](BF4) (5.5 mg), and the reaction mixture was then pressurized to 20 bar with hydrogen. Under this hydrogen pressure, the reaction mixture was stirred at room temperature for 19 hours. When HPLC analysis showed that the substrate had been completely consumed, the reaction mixture was cooled to room temperature. Chiral HPLC analysis determined an enantiomeric excess of 97.9% ee in the reaction mixture (first peak 98.95%, (S)-22; second peak 1.05%, (R)-22). The reaction mixture was then filtered through a thin silica gel pad, which was washed with ethyl acetate (EtOAc, 5 mL). The filtrate was concentrated to dryness under reduced pressure. Analysis of the resulting foamy solid (98 mg) by chiral HPLC showed an enantiomeric excess of 97.9%, biased towards the first peak (first peak 98.95%, (S)-22; second peak 1.05%, (R)-22).

[2002] Methyl (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionate ((R)-22). Under nitrogen, a solution of methyl (E)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21,815 mg) in tetrahydrofuran (THF, 8.0 mL) was treated with the catalyst [Rh(COD)(-)-DuanPhos](BF4) (4.6 mg), and the reaction mixture was then pressurized to 50 bar with hydrogen. Under this hydrogen pressure, the reaction mixture was stirred at 35 °C for 22 hours. When HPLC analysis showed that the substrate was almost completely consumed, the reaction mixture was cooled to room temperature. Chiral HPLC analysis determined an enantiomeric excess of 94.7% ee in the reaction mixture (second peak 97.35%, (R)-22; first peak 2.65%, (S)-22). The reaction mixture was then filtered through a thin silica gel pad, which was washed with tetrahydrofuran (THF, 5 mL). The filtrate was concentrated to dryness under reduced pressure. Analysis of the resulting foamy solid (778 mg) by chiral HPLC showed an enantiomeric excess of 94.7%, biased towards the second peak (second peak 97.35%, (R)-22; first peak 2.65%, (S)-22).

[2003]

[2004] (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid ((R)-23). ​​At room temperature, a solution of lithium hydroxide monohydrate (LiOH-H2O, 265 mg, 6.31 mmol, 1.2 equivalents) in water (15 mL) was added to a stirred solution of (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid ((R)-22, 2.47 g, 5.26 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 3 hours. When the LCMS indicated the reaction was complete, the reaction mixture was acidified to pH 5 with 1N HCl aqueous solution and then extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure to give (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid ((R)-23, 2.40 g, theoretically 2.40 g, 100% yield) as a colorless oil, which solidified upon standing under vacuum at room temperature. For (R)-23: 1 H NMR(CDCl3,300MHz)δppm 8.95(s,1H),8.95(bs,1H),8.36(s,1H),7.57(d,1H,J=3.7Hz),6.99(d,1 H,J=3.7Hz),5.74(s,2H),4.65(dt,1H,J=3.1,10.3Hz),3.58(t,2H,J=8.2 Hz),3.24(dd,1H,J=16.5,10.3Hz),3.04(dd,1H,J=16.2,3.1Hz),2.59(m, 1H), 2.00 (m, 1H), 1.77-1.24 (m, 7H), 0.97 (t, 2H, J = 8.2Hz), 0.00 (s, 9H); C 23 H 33 N5O3Si(MW,455.63), LCMS(EI)m / e 456.1(M + +H).

[2005] (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionamide ((R)-24). At room temperature, N,N-carbonyldiimidazole (CDI, 21 mg, 0.13 mmol, 3.0 equivalence) was added to a stirred solution of (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid ((R)-23, 20 mg, 0.044 mmol) in DMF (1 mL). The reaction mixture was then stirred at room temperature, and the formation of the acylimidazole was tracked by TLC (acid consumed to a higher Rf spot with 30% EtOAc / hexane). When TLC showed that the acylimidazole conversion was complete, ammonia was then bubbled through the stirred solution for 30 minutes to obtain the amide (which was then subjected to LCMS). Excess ammonia was evaporated by vigorously bubbling nitrogen through the solution. The crude product (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionamide ((R)-24) from DMF was directly used in the following reaction to convert the amide ((R)-24) into the corresponding nitrile ((R)-20).

[2006] (3R)-cyclopentyl-3-{4-[7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((R)-20). Method A: At 0 °C, dichloromethane (1 mL) and triethylamine (0.12 mL, 0.88 mmol, 20.0 equivalent) were added to a stirred solution of (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionamide ((R)-24, 20 mg, 0.044 mmol) in DMF (1 mL), followed by the addition of trichloroacetyl chloride (0.052 mL, 0.462 mmol, 10.5 equivalent). The resulting reaction mixture was stirred at 0 °C for 1 hour. When LCMS indicated completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (NaHCO3, 5 mL) and then extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-75% EtOAc / hexane gradient elution) to give (3R)-cyclopentyl-3-{4-[7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((R)-20, 10 mg, theoretically 19 mg, 53% yield). For (R)-20: 1 H NMR(DMSO-d6,400MHz)δppm 8.83(s,1H),8.75(s,1H),8.39(s,1H),7.77(d,1H,J=3.7Hz),7.09(d,1H,J=3.7Hz),5.63(s,2H),4.53(td,1H,J=19.4,4.0Hz),3.5 C 23 H 32 N6OSi(MW,436.63),LCMS(EI)m / e 437(M + +H) and 459(M) + +Na).

[2007] (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base). Method B: At room temperature, water (400 mL) was added to a solution of (3R)-cyclopentyl-3-{4-[7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((R)-20, 463 g, 1.06 mol, 98.6% ee) in acetonitrile (4.5 L), followed immediately by the addition of lithium tetrafluoroborate (LiBF4, 987.9 g, 10.5 mol, 10.0 equivalent). The reaction temperature was observed to drop from ambient temperature to 12 °C upon the addition of water, and then rise to 33 °C during the addition of lithium tetrafluoroborate (LiBF4). The resulting reaction mixture was heated under reflux (approximately 80°C) overnight. The liquid was quenched in ethyl acetate / water and examined by LCMS and TLC (95:5 ethyl acetate / methanol, v / v). When LCMS and TLC analysis showed both the hydroxymethyl intermediate ((R)-25) and the completely deprotected substance ((R)-13, free base) but no starting material ((R)-20) remaining, the reaction mixture was gradually cooled to <5°C, and then 20% aqueous ammonium hydroxide (NH4OH, 450 mL) was gradually added to adjust the pH of the reaction mixture to 9 (verified by pH bar). The cold bath was removed, and the reaction mixture was gradually warmed to room temperature and stirred overnight at room temperature. The liquid was quenched in ethyl acetate / water and examined by LCMS and TLC (95:5 ethyl acetate / methanol, v / v) to confirm complete deprotection. When LCMS and TLC showed confirmed completion of the reaction, the reaction mixture was filtered, and the solids were washed with acetonitrile (1 L). The combined filtrates were then concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (EtOAc, 6 L) and semi-saturated brine (3 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were washed with semi-saturated sodium bicarbonate (NaHCO3, 3 L) and brine (3 L), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure to give a crude product as an orange oil. The crude product was then purified by rapid column chromatography (SiO2, 40 to 100% ethyl acetate / heptane gradient elution) to give a white foamy product (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-13, free base, 273 g, theoretically 324.9 g, 84% yield). This substance was then subjected to... 19 F NMR analysis was performed to ensure the absence of lithium tetrafluoroborate (LiBF4) residue, and chiral HPLC was used for further analysis. The enantiomeric purity was confirmed by OD (90:10 hexane / ethanol), and it was used to prepare the corresponding phosphates without further purification. For (R)-13 (free base): 1 H NMR(DMSO-d6,400MHz)δppm 12.1(bs,1H),8.80(d,1H,J=0.42Hz),8.67(s,1H),8.37(s,1H),7.59(dd,1H,J=2.34,3.51Hz), 6.98(dd,1H,J=1.40,3.44Hz), 4.53(td,1H,J=19.5,4.63Hz),3.26(dd,1H,J=9.77,17.2Hz),3.18(dd,1H,J=4.32,17.3Hz),2.40(m,1H),1.79(m,1H),1.65to 1.13(m,7H);C 17 H 18 N6(MW,306.37)LCMS(EI)m / e 307(M + +H).

[2008]

[2009] (2E)-3-cyclopentylpropenal (28). At room temperature, cyclopentane carboxycarboxyaldehyde (26, 21.36 mL, 200.0 mmol) was added to a stirred suspension of triphenylphosphine(27, 62.75 g, 200.0 mmol, 1.0 equivalent) in anhydrous benzene (400 mL, 4476 mmol). The resulting reaction mixture was then stirred at 80 °C for 16 hours. When TLC and HPLC confirmed the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was then purified directly by Combiflash (SiO2) elution with a 0–10% EtOAc / hexane gradient to give (2E)-3-cyclopentylpropenal (28, 14.4 g, theoretically 24.84 g, 58% yield) as a yellow oil. For 28: 1 ¹H NMR (DMSO-d⁶, 400MHz) δppm 1 H NMR (CDCl3, 400MHz) δ9.49 (d, 1H, J = 7.8Hz), 6.82 (dd, 1H, J = 15.6, 7.8Hz), 6.08 ( dd,1H,J=15.6,8.0Hz),2.72(m,1H),1.89(m,2H),1.67(m,4H),1.44(m,2H); C8H 12 O(MW,124.18)LCMS(EI)m / e 125(M + +H).

[2010]

[2011] (2R)-1-Ethyl-2-methylpyrrolidine-1,2-dicarboxylic acid ester ((R)-30). Ethyl chloroformate (28.4 mL, 288 mmol, 2.4 equivalents) was added to a stirred suspension of D-proline ((R)-29 (13.955 g, 120.0 mmol) and potassium carbonate (K₂CO₃ (33.17 g, 240.0 mmol, 2.0 equivalents)) in anhydrous methanol (MeOH, 240 mL, 5925 mmol) at 0 °C. The resulting reaction mixture was then stirred at room temperature for 18 hours...

Claims

1. Compounds of formula Ia: or a pharmaceutically acceptable salt thereof; in: * is 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.

2. The compound according to claim 1, wherein P1 is -CH2OC(=O)C(CH3)3 or -CH2OCH2CH2Si(CH3)3.

3. The compound according to claim 1 or 2, wherein P1 is -CH2OCH2CH2Si(CH3)3. The compound according to claim 3 , wherein R 1 is cyclopentyl.

5. The compound according to claim 1, wherein the compound of formula Ia is a compound of formula I″: or a pharmaceutically acceptable salt thereof.

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