Methods and intermediates for preparing JAK inhibitors

Abstract

The present invention relates to processes for preparing ruxolitinib or its salts, and related synthetic intermediates associated therewith.

Description

[Technical Field]

[0001] The present invention relates to methods for preparing ruxolitinib, its salts, and related synthetic intermediate compounds and their salts. Ruxolitinib and its salts are useful as inhibitors of the Janus kinase family of protein tyrosine kinases (JAKs) for the treatment of inflammatory diseases, myeloproliferative disorders, and other diseases. [Background technology]

[0002] Protein kinases (PKs) are a group of enzymes that regulate diverse and important biological processes, including cell proliferation, survival, and differentiation, organogenesis and morphogenesis, angiogenesis, and tissue repair and regeneration, among others. 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 contexts. In addition to their function in normal tissues / organs, many protein kinases also play more specialized roles in many human diseases, including cancer. When dysregulated, a subset of protein kinases (also called oncogenic protein kinases) can cause tumor formation and growth and even contribute to tumor maintenance and progression (Blume-Jensen P. et al., Nature 2001, 411(6835):355-365). To date, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug discovery.

[0003] Protein kinases can be classified as receptor and non-receptor. Receptor tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion, 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 family 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).

[0004] Pathways involving JAKs and signal transducers and activators of transcription (STATs) are involved in the signal transduction of a wide range of cytokines. Cytokines are small polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. Generally, cytokine receptors lack intrinsic tyrosine kinase activity and therefore require receptor-associated kinases to propagate phosphorylation cascades. JAKs perform this function. Cytokines bind to their receptors, causing them to dimerize, allowing JAKs to phosphorylate specific tyrosine motifs within the cytokine receptor as well as each other. STATs that recognize these phosphotyrosine motifs are recruited to the receptor and are then activated by JAK-dependent tyrosine phosphorylation events. Upon activation, STATs dissociate from their receptors, dimerize, translocate to the nucleus, 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).

[0005] The JAK family plays a role in regulating the cytokine-dependent proliferation and function of cells involved in immune responses. The JAK / STAT pathway, particularly all four members of the JAK family, is thought to play a role in the pathogenesis of asthma responses, chronic obstructive pulmonary disease, bronchitis, and other related lower respiratory tract inflammatory diseases. Furthermore, several cytokines signaling through JAK kinases have been implicated in upper respiratory tract inflammatory diseases or conditions, such as those affecting the nose and paranasal sinuses (e.g., rhinitis and sinusitis), whether or not they are classical allergic responses. The JAK / STAT pathway has also been implicated in a role not only in chronic allergic responses, but also in ocular inflammatory diseases / conditions, including, but not limited to, iritis, uveitis, scleritis, and conjunctivitis. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.

[0006] Blocking signal transduction at the level of JAK kinases holds promise for the development of treatments for human cancers. Inhibition of JAK kinases is also expected to have therapeutic benefits in patients suffering from skin immune disorders and skin sensitization, such as psoriasis. Therefore, inhibitors of Janus kinases or related kinases are widely sought, and several publications have reported on a class of effective compounds. For example, the JAK inhibitor ruxolitinib, ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile), has been reported in U.S. Patent Application Publication Nos. 2007 / 0135461, 2010 / 190981, and 2008 / 0312259, the disclosures of which are incorporated herein by reference.

[0007] In light of the increasing demand for compounds for the treatment of disorders associated with the inhibition of kinases, such as Janus kinases, new, more efficient routes to ruxolitinib, its salts, and related intermediates are needed. The methods and compounds described herein help meet these and other needs. Summary of the Invention

[0008] The present disclosure provides, inter alia, methods for preparing ruxolitinib, its salts, and related synthetic intermediate compounds and salts of the intermediates.

[0009] Thus, the present disclosure provides a compound of formula 3: [ka] or a salt thereof, by reacting (i) a salt of formula 2a and (ii) a compound of formula 2b: [ka] with a reagent selected from In the formula, X - is the counter anion.

[0010] The present disclosure further provides a salt of formula 2c: [ka] The compound of formula 3: [ka] to form ruxolitinib or a salt thereof.

[0011] The present disclosure also provides a salt of formula 2c: [ka] The salt of formula 3a: [ka] to form ruxolitinib or a salt thereof.

[0012] The present disclosure further provides: (a) Salt of formula 2d: [ka] with a base to form a salt of formula 2c: [ka] and forming (b) converting a salt of formula 2c into a salt of formula 3a: [ka] to form ruxolitinib or a salt thereof; The present invention provides a method for preparing ruxolitinib or a salt thereof, comprising:

[0013] In some embodiments of the above method, the salt of formula 2d is (a) A compound of formula 2P: [ka] with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 1aP: [ka] and forming (b) deprotecting the compound of Formula 1aP to give a compound of Formula 1a: [ka] or a salt thereof; and (c) reacting a compound of formula 1a or a salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form a salt of formula 2d; prepared by a method comprising: In the formula, P 1 is an amino protecting group.

[0014] In some embodiments of the above method, the salt of formula 2d is (a) A compound of formula 22P: [ka] with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 23P: [ka] and forming (b) reducing a compound of formula 23P to give a compound of formula 1a: [ka] or a salt thereof; and (c) reacting a compound of formula 1a or a salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form a salt of formula 2d; prepared by a method comprising: In the formula, P 2 is an amino protecting group.

[0015] In some embodiments of the above method, the salt of Formula 3a is (a) A compound of formula 6a: [ka] with hydrazine to give a compound of formula 7a: [ka] and forming Formula (b) 7a with L-tartaric acid to form a salt of formula 3a; It is prepared by a method comprising:

[0016] The present disclosure further provides: (a) [ka] or its salts, or (b) [ka] or (c) [ka] or (d) [ka] or its salts, or (e) [ka] or its salts, or (f) [ka] or its salts, or (g) [ka] or its salts, or (h) [ka] or its salts, or (i) [ka] (In the formula, X - is Cl - a counter anion other than (j) [ka] or (k) [ka] or (l) [ka] or (m) [ka] or (n) [ka] or (o) [ka] The present invention provides a compound or salt selected from:

[0017] The present disclosure still further provides a salt of Formula 2d selected from Form I and Form II: [ka] The present invention provides a crystalline form of

[0018] The present disclosure also provides a salt of formula 3a: [ka] Also provided is a crystalline form of [Brief explanation of the drawings]

[0019] [Figure 1] 1 is an X-ray powder diffraction (XRPD) pattern of Compound 2d, Form I. [Figure 2] 1 is a differential scanning calorimetry (DSC) thermogram of Compound 2d, Form I. [Figure 3] 1 is a thermogravimetric analysis (TGA) thermogram of Compound 2d, Form I. [Figure 4] 1 is an XRPD pattern of Compound 2d, Form II. [Figure 5] 1 is a DSC thermogram of Compound 2d, Form II. [Figure 6] 1 is a TGA thermogram of Compound 2d, Form II. [Figure 7] 1 is an XRPD pattern of the hexafluorophosphate salt of compound 2. [Figure 8] 1 is a DSC thermogram of the hexafluorophosphate salt of Compound 2. [Figure 9] 1 is a TGA thermogram of the hexafluorophosphate salt of Compound 2. [Figure 10A] 1 is the X-ray single crystal structure of compound 3a, showing one molecule. [Figure 10B] 1 is an X-ray single crystal structure of compound 3a showing the repeating unit of compound 3a. [Figure 11] 1 is an XRPD pattern of compound 3a. [Figure 12] 1 is a DSC thermogram of compound 3a. [Figure 13] 1 is a TGA thermogram of compound 3a.

[0020] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure provides methods for preparing ruxolitinib, also known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, and intermediates thereof, as well as salts and crystalline forms of ruxolitinib and intermediates. Ruxolitinib (also known as INCB018424) is sold as the phosphate salt under the trade names JAKAFI and JAKAVI and has the following structure: [ka] It has.

[0022] (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is also referred to in the present disclosure as Compound 1. This compound and various methods for preparing this compound are disclosed in U.S. Patent Application Publication Nos. 2007 / 0135461, 2010 / 190981, and 2008 / 0312259, which are hereby incorporated by reference.

[0023] The present disclosure provides: Compounds of Formula 3: [ka] or a salt thereof, by reacting (i) a salt of formula 2a or a salt thereof, and (ii) a compound of formula 2b: [ka] with a reagent selected from In the formula, X - is the counter anion.

[0024] The present disclosure provides: Compounds of Formula 3: [ka] or a salt thereof, by reacting (i) a salt of formula 2a, and (ii) a compound of formula 2b: [ka] with a reagent selected from In the formula, X - is the counter anion.

[0025] In some embodiments, the reagent is a salt of Formula 2a.

[0026] In some embodiments, the reagent is a compound of formula 2b.

[0027] In some embodiments, the reagent is a salt of a salt of Formula 2a, wherein X - is Cl - is.

[0028] In some embodiments, the reagent is the hydrochloride salt of a salt of formula 2a, wherein X - is Cl - is.

[0029] In some embodiments, the compound of Formula 3 or salt thereof is a chiral salt of the compound of Formula 3.

[0030] Chiral salts can be prepared by reacting the compound of formula 3 with an optically active form of an acid selected from mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyltartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid, and 2-acrylamido-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid.

[0031] In some embodiments, the chiral salt is the L-(+)-tartrate salt of the compound of formula 3. In some embodiments, the compound of formula 3 or a salt thereof is represented by formula 3a: [ka] It has.

[0032] In some embodiments, about 1 to about 1.5 molar equivalents of a reagent ((i) a salt of Formula 2a, or (ii) a compound of Formula 2b) are utilized relative to the compound of Formula 3 or a salt thereof. For example, about 1.25 molar equivalents of a reagent are utilized relative to the compound of Formula 3 or a salt thereof. For example, about 1 molar equivalent of a reagent is utilized relative to the compound of Formula 3 or a salt thereof.

[0033] In some embodiments, the reaction of the reagent ((i) a salt of Formula 2a, or (ii) a compound of Formula 2b) with the compound of Formula 3 or its salt is carried out in solvent component S1. Solvent component S1 can include a polar protic solvent or a polar aprotic solvent. In some embodiments, solvent component S1 includes water. In some embodiments, solvent component S1 includes an alcohol. In some embodiments, solvent component S1 includes a compound of Formula C 1-6In some embodiments, solvent component S1 comprises alkyl-OH. In some embodiments, solvent component S1 is ethanol. In some embodiments, solvent component S1 comprises dimethylformamide. In some embodiments, solvent component S1 comprises water, an alcohol, or a combination thereof.

[0034] In some embodiments, the reagent is a salt of Formula 2a: X - is Cl - , Br - , I - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - In some embodiments, X may be selected from - is Cl - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - In some embodiments, X is selected from - is BF4 - In some embodiments, X - PF6 - In some embodiments, X - is AsF6 - In some embodiments, X - is SbF6 - In some embodiments, X - is ClO4 - In some embodiments, X - is Cl - is.

[0035] In some embodiments, the reagent is a compound of Formula 2b. The compound of Formula 2b can be prepared by a method comprising reacting a salt of Formula 2a with a base B1. In some embodiments, the reaction of the salt of Formula 2a with the base B1 is carried out in a solvent component S2 comprising water. In some embodiments, the base B1 is a strong base. In some embodiments, the base B1 is a hydroxide. In some embodiments, the base B1 is an alkali metal hydroxide. In some embodiments, the base B1 is sodium hydroxide. In some embodiments, about 10 to about 15 molar equivalents of the base B1 relative to the salt of Formula 2a or a salt thereof are utilized. In some embodiments, about 12 molar equivalents of the base B1 relative to the salt of Formula 2a or a salt thereof are utilized. In some embodiments, the reaction of the salt of Formula 2a with the base B1 is carried out at a temperature of about -10°C to about 60°C. In some embodiments, the temperature is about 0°C to room temperature. In some embodiments, the temperature is about 40°C to about 60°C. In some embodiments, the temperature is between 0°C and room temperature, and then heated to between about 40°C and about 60°C.

[0036] In some embodiments, the salt of Formula 2a or the compound of Formula 2b is Compounds of Formula 1a: [ka] or its salts can be prepared by a method comprising reacting it with Vilsmeier reagent formed from dimethylformamide.

[0037] In some embodiments, the salt of Formula 2a or the compound of Formula 2b is Compounds of formula 5a: [ka] or its salts can be prepared by a method comprising reacting it with Vilsmeier reagent formed from dimethylformamide.

[0038] In some embodiments, the compound of Formula 5a is a salt, e.g., the compound of Formula 5a is a sodium salt.

[0039] In some embodiments, reaction with Vilsmeier reagent provides a compound of formula 2c: [ka] Generate.

[0040] In some embodiments, after reaction with the Vilsmeier reagent, the compound of formula 2c is + X - wherein M + is the counter cation.

[0041] In some embodiments, the Vilsmeier reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent. In some embodiments, the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride. In some embodiments, the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene. In some embodiments, the chlorinating agent is oxalyl chloride. In some embodiments, the chlorinating agent is phosphorus oxychloride. In some embodiments, the chlorinating agent is triphosgene.

[0042] In some embodiments, about 1 to about 5 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, are utilized. In some embodiments, about 1 to about 4 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, are utilized. In some embodiments, about 1 to about 3 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, are utilized. In some embodiments, about 1 molar equivalent of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, is utilized. In some embodiments, about 2 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, is utilized. In some embodiments, about 3 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, is utilized. In some embodiments, about 4 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, is utilized. In some embodiments, about 5 molar equivalents of chlorinating agent relative to the compound of Formula 1a or 5a, or a salt thereof, is utilized.

[0043] In some embodiments, about 10 to about 25 molar equivalents of dimethylformamide are utilized relative to the compound of Formula 1a or 5a, or a salt thereof. In some embodiments, about 10 to about 20 molar equivalents of dimethylformamide are utilized relative to the compound of Formula 1a or 5a, or a salt thereof. In some embodiments, about 10 to about 15 molar equivalents of dimethylformamide are utilized relative to the compound of Formula 1a or 5a, or a salt thereof. In some embodiments, about 11 to about 14 molar equivalents of dimethylformamide are utilized relative to the compound of Formula 1a or 5a, or a salt thereof. In some embodiments, about 11 to about 13 molar equivalents of dimethylformamide are utilized relative to the compound of Formula 1a.

[0044] In some embodiments, the preparation of the Vilsmeier reagent is carried out in solvent component S3. In some embodiments, solvent component S3 comprises an organic solvent. In some embodiments, solvent component S3 comprises a polar aprotic solvent. In some embodiments, solvent component S3 comprises acetonitrile, dimethylformamide, or a combination thereof.

[0045] In some embodiments, the Vilsmeier reagent is prepared at a temperature of about -10°C to about 60°C. In some embodiments, the Vilsmeier reagent is prepared at a temperature of about -10°C to about 30°C. For example, the Vilsmeier reagent is prepared at a temperature of about -10°C to about room temperature. For example, the temperature is about 0°C to about room temperature. In some embodiments, the Vilsmeier reagent is prepared at a temperature of about room temperature to about 60°C. In some embodiments, the Vilsmeier reagent is prepared at a temperature of about 30°C to about 70°C, about 40°C to about 70°C, about 30°C to about 60°C, or about 40°C to about 60°C. In some embodiments, the Vilsmeier reagent is prepared at a temperature of about 75°C to about 80°C, 80°C to 90°C, or 85°C to 90°C.

[0046] In some embodiments, the reaction of a compound of Formula 1a or 5a, or a salt thereof, with a Vilsmeier reagent is carried out at a temperature of about 40° C. to about 100° C. In some embodiments, the reaction of a compound of Formula 1a or 5a, or a salt thereof, with a Vilsmeier reagent is carried out at a temperature of about 70° C. to about 100° C. In some embodiments, the reaction of a compound of Formula 1a or 5a, or a salt thereof, with a Vilsmeier reagent is carried out at a temperature of about 40° C. to about 60° C.

[0047] In some embodiments, the product of the reaction with the Vilsmeier reagent has formula 2d: [ka] It has.

[0048] In some embodiments, the salt of Formula 2a is Salt of Formula 2c: [ka] Formula M + X - may be formed by a process comprising reacting with a salt of M + is the counter cation, X - is Cl - Counter anions other than

[0049] In some embodiments, M + is an alkali metal countercation. For example, M + Li + , Na + , or K + In some embodiments, M + Na + In some embodiments, X - Br - , I - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - For example, X - is BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - In some embodiments, X is selected from - is BF4 - In some embodiments, X - PF6 - In some embodiments, X - is AsF6 - In some embodiments, X - is SbF6 - In some embodiments, X - is ClO4 - is.

[0050] In some embodiments, the salt of Formula 2c is Salt of formula 2d: [ka] with a base.

[0051] In some embodiments, the compound of Formula 2b is prepared by a method comprising reacting a salt of Formula 2d with a base B2. In some embodiments, (i) the reaction of the salt of Formula 2d with base B2 and (ii) the reaction of the salt of Formula 2d with the compound of Formula 3 are carried out in a single pot. In some embodiments, the reaction of the salt of Formula 2d with base B2 is carried out in a solvent component comprising water. In some embodiments, base B2 is a strong base. In some embodiments, base B2 is a hydroxide base. In some embodiments, base B2 is an alkali metal hydroxide. For example, base B2 is sodium hydroxide. In some embodiments, the reaction of the salt of Formula 2d with base B2 is carried out at a temperature of about −10° C. to about 15° C. In some embodiments, the compound of Formula 1a or a salt thereof is a hydrochloride salt.

[0052] In some embodiments, the compound of formula 1a or salt thereof is Compounds of Formula 1aP: [ka] and deprotecting the compound of formula (I) by a method comprising: In the formula, P 1 is an amino protecting group.

[0053] In some embodiments, P 1 is (R 1 )3Si, wherein R 1 is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. 1 is t-butyldimethylsilyl. In some embodiments, the deprotection is carried out by reacting the compound of Formula 1aP with a base B3. In some embodiments, the base B3 is a hydroxide base. For example, the base B3 is ammonium hydroxide. In some embodiments, the deprotection is carried out in solvent component S4. In some embodiments, the solvent component S4 comprises a polar protic solvent. In some embodiments, the solvent component S4 comprises an alcohol. In some embodiments, the solvent component S4 is a compound of Formula C1-6 For example, the solvent component S4 includes methanol.

[0054] In some embodiments, the compound of formula 1aP is Compound of formula 2P: [ka] with MeMgBr in the presence of a Grignard catalyst, In the formula, P 1 is an amino protecting group.

[0055] In some embodiments, the catalyst is an iron catalyst. In some embodiments, the iron catalyst is iron(III) acetylacetonate. In some embodiments, about 1 to about 2 molar equivalents of MeMgCl relative to the compound of Formula 2P are utilized. In some embodiments, about 1% to about 10% molar equivalents of catalyst relative to the compound of Formula 2P are utilized. In some embodiments, the reaction of the compound of Formula 2P with MeMgCl is carried out in solvent component S5. In some embodiments, solvent component S5 is di-C 1-6 The solvent component S5 may comprise an alkyl ether or a 4- to 10-membered heterocycloalkyl ether. For example, the solvent component S5 may comprise tetrahydrofuran. In some embodiments, the reaction of the compound of Formula 2P with MeMgCl is carried out at a temperature of from about -10°C to about 30°C.

[0056] In some embodiments, the compound of formula 2P is Compound of Formula 12a: [ka] to form a compound of formula 2P.

[0057] In some embodiments, protection is achieved by reacting a compound of Formula 12a with an alkali metal hydride and P 1 -Y, wherein Y is halo. 1 -Y is (R 1)3Si—Y, where Y is halo and R 1 is C 1-6 In some embodiments, P 1 is (R 1 )Si, where R 1 is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. 1 is t-butyldimethylsilyl. In some embodiments, the alkali metal hydride is sodium hydride. In some embodiments, about 1 to about 2 molar equivalents of alkali metal hydride relative to the compound of Formula 12a are utilized. In some embodiments, about 1 to about 2 molar equivalents of P relative to the compound of Formula 12a 1 In some embodiments, a compound of Formula 12a is combined with an alkali metal hydride and P 1 The reaction of -Y with -Y is carried out at a temperature of about -10° C. to about 20° C. In some embodiments, the reaction of the compound of Formula 12a with an alkali metal hydride and P 1 The reaction with -Y is carried out in a solvent component S6, where the solvent component S6 comprises an organic solvent. In some embodiments, the solvent component S6 is 1-6 In some embodiments, the solvent component S6 comprises tetrahydrofuran.

[0058] In some embodiments, the compound of formula 1a or salt thereof is Compound of formula 23P: [ka] may be prepared by a process comprising reducing In the formula, P 2 is an amino protecting group.

[0059] In some embodiments, the reduction of the compound of formula 23P is accomplished by a method comprising reacting the compound of formula 23P with hydrogen gas in the presence of a catalyst. For example, the catalyst may be Pd 0In some embodiments, the amount of catalyst relative to the compound of Formula 23P is about 5% to about 15% by weight. In some embodiments, the reaction of the compound of Formula 23P with hydrogen and the catalyst is carried out at a temperature of about 40° C. to about 70° C. In some embodiments, the reaction of the compound of Formula 23P with hydrogen and the catalyst is carried out at a temperature of about 50° C. to about 60° C. In some embodiments, the reaction of the compound of Formula 23P with hydrogen and the catalyst is carried out at a temperature of about 50° C. to about 55° C. In some embodiments, the reaction of the compound of Formula 23aP with hydrogen and the catalyst is carried out in solvent component S7. In some embodiments, solvent component S7 comprises a polar protic solvent. In some embodiments, solvent component S7 comprises an alcohol. In some embodiments, solvent component S7 comprises a compound of Formula C 1-6 For example, the solvent component S7 includes methanol.

[0060] In some embodiments, the compound of formula 23P is Compound of formula 22P: [ka] with MeMgBr in the presence of a Grignard catalyst, In the formula, P 2 is an amino protecting group.

[0061] In some embodiments, the catalyst is an iron catalyst. For example, the iron catalyst is iron(III) acetylacetonate. In some embodiments, about 1 to about 2 molar equivalents of MeMgCl relative to the compound of Formula 22P are utilized. In some embodiments, about 1% to about 10% molar equivalents of catalyst relative to the compound of Formula 22P are utilized. In some embodiments, the reaction of the compound of Formula 22P with MeMgCl is carried out in solvent component S8. In some embodiments, solvent component S8 is di-C 1-6 The solvent component S8 may comprise a tetrahydrofuran, an alkyl ether, or a 4- to 10-membered heterocycloalkyl ether. In some embodiments, the reaction of the compound of Formula 2P with MeMgCl is carried out at a temperature of about -10°C to about 30°C.

[0062] In some embodiments, the compound of formula 22P is Compound of Formula 22a: [ka] to form a compound of formula 22P.

[0063] In some embodiments, protection is achieved by reacting a compound of Formula 22a with an alkali metal hydride and P 2 -Y, wherein Y is halo. 2 is (R 1 )Si, where R 1 is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. 2 is t-butyldimethylsilyl. In some embodiments, the alkali metal hydride is sodium hydride. In some embodiments, about 1 to about 2 molar equivalents of alkali metal hydride relative to the compound of Formula 22a are utilized. In some embodiments, about 1 to about 2 molar equivalents of P relative to the compound of Formula 22a 2 In some embodiments, a compound of Formula 22a is combined with an alkali metal hydride and P 2 The reaction of the compound of Formula 22a with -Y is carried out at a temperature of about -10° C. to about 20° C. In some embodiments, the reaction of the compound of Formula 22a with an alkali metal hydride and P 2 The reaction with -Y is carried out in a solvent component S9, where the solvent component S9 comprises an organic solvent. In some embodiments, the solvent component S9 is 1-6 For example, the solvent component S9 includes tetrahydrofuran.

[0064] In some embodiments, the compound of formula 1a or salt thereof is Compound of Formula 18a: [ka] with an acid A1 to form a compound of formula 1a.

[0065] In some embodiments, acid A1 is a strong acid. For example, acid A1 is hydrochloric acid. In some embodiments, the reaction of the compound of formula 18a with acid A1 is carried out in solvent component S10, where solvent component S10 comprises a polar protic solvent. In some embodiments, solvent component S10 comprises an alcohol. In some embodiments, solvent component S10 comprises a compound of formula C 1-6 For example, solvent component S10 includes isopropyl alcohol.

[0066] In some embodiments, the compound of Formula 18a or salt thereof is Compound of Formula 17a: [ka] with formamidine acetate and triethyl orthoformate to give a compound of formula 18a The compound may be prepared by a process comprising forming a compound of formula (I).

[0067] In some embodiments, about 10 to about 15 molar equivalents of formamidine acetate are utilized relative to the compound of Formula 17a. In some embodiments, about 10, about 11, about 12, about 13, about 14, or about 15 molar equivalents of formamidine acetate are utilized relative to the compound of Formula 17a. In some embodiments, about 12 molar equivalents of formamidine acetate are utilized relative to the compound of Formula 17a. In some embodiments, about 6 to about 10 molar equivalents of triethyl orthoformate are utilized relative to the compound of Formula 17a. In some embodiments, about 6, about 7, about 8, about 9, or about 10 molar equivalents of triethyl orthoformate are utilized relative to the compound of Formula 17a. For example, about 8 molar equivalents of triethyl orthoformate are utilized relative to the compound of Formula 17a. In some embodiments, the reaction of the compound of Formula 17a with formamidine acetate and triethyl orthoformate is carried out at a temperature of about 100°C to about 150°C. For example, the temperature can be about 110° C. to about 120° C. In some embodiments, the reaction of the compound of Formula 17a with formamidine acetate and triethyl orthoformate is carried out in solvent component S11, where solvent component S11 comprises a polar protic solvent. In some embodiments, solvent component S11 comprises an alcohol. In some embodiments, solvent component S11 comprises a compound of Formula C 1-6 For example, the solvent component S11 includes 1-butanol.

[0068] In some embodiments, the compound of Formula 17a or a salt thereof is Compound of Formula 20a: [ka] to a compound of formula 21a: [ka] to form a compound of formula 17a.

[0069] In some embodiments, about 0.4 to about 1 molar equivalent of the compound of Formula 21a is utilized relative to the compound of Formula 20a. In some embodiments, the reaction of the compound of Formula 20a with the compound of Formula 21a is carried out at room temperature. In some embodiments, the reaction of the compound of Formula 20a with the compound of Formula 21a is carried out in solvent component S12, where solvent component S12 comprises a polar aprotic solvent. For example, solvent component S12 comprises dimethylformamide.

[0070] In some embodiments, the compound of Formula 20a or salt thereof is Compound of Formula 19a: [ka] with bromo-1,1-dimethoxyethane and a base B4 to form a compound of formula 20a.

[0071] In some embodiments, base B4 is an alkali metal carbonate. For example, base B4 is cesium carbonate. In some embodiments, about 1 to about 2 molar equivalents of base B4 are utilized relative to the compound of Formula 19a. In some embodiments, about 1 to about 2 molar equivalents of bromo-1,1-dimethoxyethane are utilized relative to the compound of Formula 19a. In some embodiments, the reaction of the compound of Formula 19a with bromo-1,1-dimethoxyethane is carried out at a temperature of about 70° C. to about 100° C. In some embodiments, the reaction of the compound of Formula 19a with bromo-1,1-dimethoxyethane is carried out in solvent component S13, where solvent component S13 comprises a polar aprotic solvent. In some embodiments, solvent component S13 comprises dimethylformamide.

[0072] In some embodiments, the compound of Formula 17a or a salt thereof is Compound of Formula 16a: [ka] with ethyl acetate and base B5 to form a compound of formula 17a.

[0073] In some embodiments, base B5 is an alkali metal alkoxide. For example, base B5 is potassium tert-butoxide. In some embodiments, about 1 to about 3 molar equivalents of base B5 are utilized relative to the compound of Formula 16a. In some embodiments, about 1 to about 2 molar equivalents of ethyl acetate are utilized relative to the compound of Formula 16a. In some embodiments, about 2 molar equivalents of base B5 are utilized relative to the compound of Formula 16a. In some embodiments, the reaction of the compound of Formula 17a with ethyl acetate and base B5 is carried out at room temperature. In some embodiments, the reaction of the compound of Formula 17a with ethyl acetate and base B5 is carried out in solvent component S14, where solvent component S14 comprises an organic solvent. In some embodiments, solvent component S14 is selected from the group consisting of di-C 1-6 For example, the solvent component S14 includes tetrahydrofuran.

[0074] In some embodiments, the compound of formula 5a or salt thereof is Compound of Formula 27a: [ka] in water in the presence of a base B6.

[0075] In some embodiments, base B6 is an alkali metal hydroxide. For example, base B6 is sodium hydroxide. In some embodiments, about 1 to about 2 molar equivalents of base B6 relative to the compound of Formula 27a are utilized. In some embodiments, about 1.5 molar equivalents of base B6 relative to the compound of Formula 27a are utilized. In some embodiments, the hydrolysis of the compound of Formula 27a is carried out at room temperature. In some embodiments, the hydrolysis of the compound of Formula 27a is carried out in solvent component S15, where solvent component S15 comprises an organic solvent. For example, solvent component S15 comprises tetrahydrofuran, acetone, or a combination thereof.

[0076] In some embodiments, the compound of formula 5a or salt thereof is a sodium salt of the compound of formula 5a. In some embodiments, the compound of formula 5a or salt thereof is a compound of formula 5a.

[0077] In some embodiments, the compound of Formula 5a can be prepared by a method comprising reacting the sodium salt of the compound of Formula 5a with a strong acid A2. For example, the strong acid A2 is hydrochloric acid. In some embodiments, (a) the reaction of the sodium salt of the compound of Formula 5a with the strong acid A2 and (b) the hydrolysis of the sodium salt of the compound of Formula 27a are carried out in a single pot.

[0078] In some embodiments, the compound of Formula 27a is Compound of formula 26P: [ka] with a strong acid A3, wherein P 1 is an amino protecting group.

[0079] In some embodiments, P 1 is p-toluenesulfonyl. For example, A3 is hydrochloric acid. In some embodiments, the reaction of the compound of formula 26P with the strong acid A3 is carried out at room temperature. In some embodiments, the reaction of the compound of formula 26P with the strong acid A3 is carried out in solvent component S16. In some embodiments, the solvent component S16 is a compound of formula C 1-6 In some embodiments, the solvent component S16 comprises ethanol.

[0080] In some embodiments, the compound of formula 26P is Compound of formula 25P: [ka] with an alkali metal alkoxide B8 to form a compound of formula 26P, wherein P 1 is an amino protecting group.

[0081] In some embodiments, about 0.1 molar equivalents of alkali metal alkoxide B8 relative to the compound of Formula 25P are utilized. In some embodiments, the reaction of the compound of Formula 25P with alkali metal alkoxide B8 is carried out at room temperature. In some embodiments, the reaction of the compound of Formula 25P with alkali metal alkoxide B8 is carried out in solvent component S17, where solvent component S17 comprises a polar protic solvent. For example, alkali metal alkoxide B8 is sodium ethoxide. In some embodiments, solvent component S17 comprises an alcohol. In some embodiments, solvent component S17 comprises a compound of Formula C 1-6 For example, the solvent component S17 includes ethanol.

[0082] In some embodiments, the compound of Formula 27a is Compound of formula 25P: [ka] with an alkali metal alkoxide B9 to form a compound of formula 27a.

[0083] In some embodiments, about 1 to about 2 molar equivalents of alkali metal alkoxide B9 relative to the compound of Formula 25P are utilized. In some embodiments, about 1 molar equivalent of alkali metal alkoxide B9 relative to the compound of Formula 25P is utilized. In some embodiments, the reaction of the compound of Formula 25P with alkali metal alkoxide B9 is carried out at a temperature of about 50° C. to about 80° C. In some embodiments, the reaction of the compound of Formula 25P with alkali metal alkoxide B9 is carried out in solvent component S18, wherein solvent component S18 is a compound of Formula C 1-6 For example, the solvent component S18 includes ethanol.

[0084] In some embodiments, the compound of formula 25P is Compound of formula 2P: [ka] with diethyl malonate and a base B10, wherein P 1 is an amino protecting group.

[0085] In some embodiments, the base B10 is an alkali metal carbonate. For example, the base B10 is cesium carbonate. In some embodiments, the reaction of the compound of Formula 2P with the base B10 is carried out at a temperature of about 40° C. to about 70° C. In some embodiments, the reaction of the compound of Formula 2P with the base B10 is carried out in solvent component S19, where solvent component S19 comprises a polar aprotic solvent. For example, solvent component S19 comprises dimethylformamide.

[0086] In some embodiments, a compound of formula 2P can be prepared by a method comprising protecting a compound of formula 12a to form a compound of formula 2P. In some embodiments, the protection comprises protecting a compound of formula 12a with a base B11 and P 1 -Y, where Y is halo. For example, P 1 is p-toluenesulfonyl. In some embodiments, base B11 is an alkali metal hydroxide. For example, base B11 is sodium hydroxide. In some embodiments, protection comprises reacting a compound of Formula 12a with base B11, and is carried out in solvent component S20, where solvent component S20 comprises a polar aprotic solvent. For example, solvent component S20 comprises acetone.

[0087] In some embodiments, the compound of Formula 12a is a compound of Formula 11a: [ka] or its salts can be prepared by a process comprising reacting A4 with a strong acid.

[0088] In some embodiments, the strong acid A4 is hydrochloric acid. In some embodiments, the reaction of the compound of Formula 11a or a salt thereof with the strong acid A4 is carried out in a solvent component S21, wherein the solvent component S21 comprises a polar aprotic solvent. In some embodiments, the solvent component S21 comprises a di-C1-6 The solvent component S21 may comprise an alkyl ether or a 4- to 10-membered heterocycloalkyl ether. For example, the solvent component S21 may comprise tetrahydrofuran. In some embodiments, the reaction of the compound of Formula 11a or a salt thereof with the strong acid A4 is carried out in tetrahydrofuran at reflux temperature.

[0089] In some embodiments, the compound of Formula 11a is a compound of Formula 10a: [ka] or its salt can be prepared by a method comprising reacting with (methoxymethyl)triphenylphosphonium chloride and a base B12.

[0090] In some embodiments, the base B12 is an alkali metal alkoxide. For example, the base B12 is potassium t-butoxide. In some embodiments, the reaction of the compound of Formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and the base B12 is carried out at a temperature of about 10° C. to about 30° C. In some embodiments, the reaction of the compound of Formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and the base B12 is carried out in a solvent component S22, wherein the solvent component S22 comprises a polar aprotic solvent. In some embodiments, the solvent component S22 is a di-C 1-6 For example, the solvent component S22 includes tetrahydrofuran.

[0091] In some embodiments, the compound of Formula 10a or salt thereof is a compound of Formula 9a: [ka] with ammonia.

[0092] In some embodiments, the reaction of the compound of Formula 9a with ammonia is carried out at a temperature of about 40° C. to about 70° C. In some embodiments, the reaction of the compound of Formula 9a with ammonia is carried out in solvent component S23, where solvent component S23 comprises an organic solvent. For example, solvent component S23 comprises toluene.

[0093] In some embodiments, the compound of Formula 9a is a compound of Formula 8a: [ka] can be prepared by a method comprising reacting with Vilsmeier reagent formed from dimethylformamide.

[0094] In some embodiments, the Vilsmeier reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent. In some embodiments, the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride. For example, the chlorinating agent is phosphorus oxychloride. In some embodiments, about 4 to about 6 molar equivalents (e.g., 5 molar equivalents) of the chlorinating agent are utilized relative to the compound of Formula 8a. In some embodiments, about 1 to about 3 molar equivalents (e.g., 2 molar equivalents) of dimethylformamide are utilized relative to the compound of Formula 8a. In some embodiments, the reaction of dimethylformamide with the chlorinating agent is carried out at a temperature of about -10°C to about 20°C (e.g., about 0°C to about 10°C). In some embodiments, the reaction of the compound of Formula 8a with the Vilsmeier reagent is carried out at a temperature of about 80°C to about 130°C (e.g., about 90°C to about 120°C, or about 95°C to about 115°C).

[0095] In some embodiments, the compound of Formula 12a is a compound of Formula 15a: [ka] with a chlorinating agent.

[0096] In some embodiments, the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride. In some embodiments, the chlorinating agent is phosphorus oxychloride. In some embodiments, the reaction of the compound of Formula 15a with the chlorinating agent is carried out at a temperature of about 50° C. to about 100° C. In some embodiments, the reaction of the compound of Formula 15a with ammonia is carried out in solvent component S24, where solvent component S24 comprises an organic solvent. For example, solvent component S24 comprises toluene.

[0097] In some embodiments, the compound of formula 15a is (i) A compound of formula 14a: [ka] with formamidine acetate and an alkali metal hydroxide to produce a compound of formula 14aa: [ka] and (ii) reacting a compound of formula 14aa with a strong acid A4; It can be prepared by a method comprising:

[0098] In some embodiments, the alkali metal hydroxide is sodium ethoxide. In some embodiments, the reaction of the compound of Formula 14a with formamidine acetate and an alkali metal hydroxide is carried out at a temperature of about 50° C. to about 100° C. In some embodiments, the reaction of the compound of Formula 14a with formamidine acetate and an alkali metal hydroxide is carried out in solvent component S25, wherein solvent component S25 comprises a polar protic solvent. In some embodiments, solvent component S25 comprises an alcohol. In some embodiments, solvent component S25 comprises a compound of Formula C 1-6 For example, the solvent component S25 includes ethanol. For example, the strong acid A4 is hydrochloric acid.

[0099] In some embodiments, the compound of Formula 14a is a compound of Formula 13a: [ka] can be prepared by a method comprising reacting with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide.

[0100] In some embodiments, the reaction of the compound of Formula 13a with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide is carried out at a temperature of about 80° C. to about 100° C. In some embodiments, the reaction of the compound of Formula 13a with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide is carried out in solvent component S26, where solvent component S26 comprises a polar aprotic solvent. In some embodiments, solvent component S26 comprises dimethyl sulfoxide.

[0101] In some embodiments, the compound of Formula 3a or salt thereof is the L-tartrate salt of the compound of Formula 3.

[0102] In some embodiments, the L-tartrate salt of Formula 3 is: Compound 7a: [ka] with L-tartaric acid.

[0103] In some embodiments, about 1 molar equivalent of L-tartaric acid is utilized relative to the compound of Formula 7a. In some embodiments, the reaction of the compound of Formula 7a with L-tartaric acid is carried out in solvent component S27. In some embodiments, solvent component S27 comprises water and an organic solvent. In some embodiments, solvent component S27 comprises about 1:1(v) water to organic solvent. In some embodiments, solvent component S27 comprises a polar aprotic solvent. For example, solvent component S27 comprises acetonitrile. In some embodiments, the reaction of the compound of Formula 7a with L-tartaric acid is carried out at a temperature of about 20° C. to about 30° C. In some embodiments, the reaction of the compound of Formula 7a with L-tartaric acid further comprises seeding with a salt of Formula 3a.

[0104] In some embodiments, the compound of Formula 7a is a compound of Formula 6a: [ka] with hydrazine.

[0105] In some embodiments, about 2 to about 3 equivalents of hydrazine are utilized relative to compound 6a. In some embodiments, the hydrazine is hydrazine hydrate. In some embodiments, the reaction of the compound of Formula 6a with hydrazine is carried out at a temperature of about -10°C to about 30°C.

[0106] In some embodiments, the salt of ruxolitinib is ruxolitinib phosphate.

[0107] In some embodiments, ruxolitinib phosphate can be prepared by a method comprising reacting ruxolitinib with phosphoric acid, in which about 1 to about 2 molar equivalents of phosphoric acid relative to ruxolitinib are utilized.

[0108] In some embodiments, the reaction between ruxolitinib and phosphoric acid is carried out at a temperature of about 20° C. to about 50° C. In some embodiments, the phosphoric acid is an aqueous solution of phosphoric acid.

[0109] In some embodiments, ruxolitinib phosphate is (i) adding a first solvent component to ruxolitinib phosphate to form a first solution; (ii) concentrating the first solution to form a second solution; (iii) adding a second solvent component to the second solution to form a third solution; (iv) adding a third solvent component to the third solution to form a fourth solution; (v) concentrating the fourth solution to form a fifth solution; (vi) isolating ruxolitinib phosphate from the fifth solution; and It is purified by a method comprising:

[0110] In some embodiments, the first solvent component is C 1-6 In some embodiments, the first solvent component comprises methanol. In some embodiments, the first solution is heated to a temperature of about 30° C. to about 80° C. In some embodiments, the second solvent component comprises C 1-6 The second solvent component comprises an alkyl-OH. For example, the second solvent component comprises isopropyl alcohol. In some embodiments, the temperature of the second solution is about 30°C to about 80°C. In some embodiments, the third solvent component comprises a non-polar solvent. In some embodiments, the third solvent is C 1-8 The third solvent comprises an alkane. For example, the third solvent comprises n-heptane. In some embodiments, the temperature of the third solution is about 30°C to about 80°C. In some embodiments, the fifth solution is cooled to about 20°C to about 30°C.

[0111] The present disclosure also provides (a) a compound of formula 1a or a salt thereof: [ka] with Vilsmeier reagent formed from dimethylformamide to give a compound of formula 2c: [ka] and (b) converting a compound of formula 2c into a compound of formula 3: [ka] with the L-tartrate salt of (c) reacting ruxolitinib with phosphoric acid to form ruxolitinib phosphate; Also provided is a method for preparing ruxolitinib phosphate, comprising:

[0112] In some embodiments, the compound of formula 1a or salt thereof is (a) a compound of formula 12a: [ka] with t-butyldimethylsilyl chloride to give a compound of formula 12b: [ka] and (b) reacting a compound of formula 12b with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 12c: [ka] and (c) deprotecting the compound of formula 12c to give a compound of formula 1a or a salt thereof; It can be prepared by a method comprising:

[0113] In some embodiments, the compound of formula 1a or salt thereof is (a) A compound of formula 22a: [ka] is reacted with t-butyldimethylsilyl chloride and MeMgBr in the presence of a Grignard catalyst to give a compound of formula 23a: [ka] and (b) reacting a compound of formula 23a with hydrogen and palladium on carbon to form a compound of formula 1a or a salt thereof; It can be prepared by a method comprising:

[0114] In some embodiments, the method for preparing ruxolitinib or a salt thereof comprises reacting ruxolitinib with a salt of Formula 2a: [ka] The compound of formula 3: [ka] with the L-(+)-tartrate salt of formula X to form ruxolitinib or a salt thereof, - is the counter ion.

[0115] In some embodiments, the method for preparing ruxolitinib or a salt thereof comprises providing a salt of Formula 2c: [ka] The compound of formula 3: [ka] with the L-(+)-tartrate salt of to form ruxolitinib or a salt thereof.

[0116] In some embodiments, the method for preparing ruxolitinib or a salt thereof comprises reacting ruxolitinib with a salt of Formula 2a: [ka] The salt of formula 3a: [ka] to form ruxolitinib or a salt thereof, wherein X - is the counter ion.

[0117] In some embodiments, the method for preparing ruxolitinib or a salt thereof comprises providing a salt of Formula 2c: [ka] The salt of formula 3a: [ka] to form ruxolitinib or a salt thereof.

[0118] In some embodiments, the method for preparing ruxolitinib or a salt thereof comprises: (a) Salt of formula 2d: [ka] with a base to form a salt of formula 2c: [ka] and forming (b) converting a salt of formula 2c into a salt of formula 3a: [ka] to form ruxolitinib or a salt thereof; Includes.

[0119] In some embodiments of the above method, the salt of formula 2d is (a) A compound of formula 2P: [ka] with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 1aP: [ka] and forming (b) deprotecting the compound of Formula 1aP to give a compound of Formula 1a: [ka] or a salt thereof; and (c) reacting a compound of formula 1a or a salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form a salt of formula 2d; prepared by a method comprising: In the formula, P 1 is an amino protecting group. 1 is trimethylsilyl.

[0120] In other embodiments, the salt of formula 2d is (a) A compound of formula 22P: [ka] with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 23P: [ka] and forming (b) reducing a compound of formula 23P to give a compound of formula 1a: [ka] or a salt thereof; and (c) reacting a compound of formula 1a or a salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form a salt of formula 2d; prepared by a method comprising: In the formula, P 2 is an amino protecting group. 1 is t-butyldimethylsilyl.

[0121] In some embodiments of the above method, the salt of Formula 3a is (a) A compound of formula 6a: [ka] with hydrazine to give a compound of formula 7a: [ka] and forming Formula (b) 7a with L-tartaric acid to form a salt of formula 3a; It is prepared by a method comprising:

[0122] The present disclosure also provides [ka] Also provided is a compound which is: or a salt thereof.

[0123] In some embodiments, the compound or salt thereof is [ka] is selected from.

[0124] In this specification, [ka] or a salt thereof.

[0125] In this specification, [ka] or a salt thereof.

[0126] In this specification, [ka] or a salt thereof.

[0127] In this specification, [ka] or a salt thereof.

[0128] In this specification, [ka] or a salt thereof.

[0129] As used herein, a salt of formula 2a: [ka] wherein X - is the counter anion, and X - is Cl - In some embodiments, the compound is other than [ka] is selected from.

[0130] In some embodiments, the present disclosure provides a salt of formula 2d: [ka] to provide.

[0131] In some embodiments, the salt of formula 2d can be isolated as a crystalline solid. In some embodiments, the present disclosure provides a crystalline form of the salt of formula 2d. In some embodiments, the crystalline form of the salt of formula 2d is Form I.

[0132] In some embodiments, Form I has an XRPD pattern substantially as shown in Figure 1. Form I may have a DSC thermogram substantially as depicted in Figure 2. In some embodiments, Form I has a TGA thermogram substantially as depicted in Figure 3.

[0133] In some embodiments, Form I has at least one XRPD peak selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees two-theta (±0.2 degrees). In some embodiments, Form I has at least two XRPD peaks selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees two-theta (±0.2 degrees). In some embodiments, Form I has at least three XRPD peaks selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees two-theta (±0.2 degrees). In some embodiments, Form I has at least four XRPD peaks selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees two-theta (±0.2 degrees). In some embodiments, Form I has characteristic XRPD peaks at 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees two-theta (±0.2 degrees).

[0134] In some embodiments, Form I has an endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 56°C and a maximum of 101°C.

[0135] In some embodiments, the crystalline form of the salt of Formula 2d is Form II. In some embodiments, Form II has an XRPD pattern substantially as shown in Figure 4. In some embodiments, Form II has a DSC thermogram substantially as depicted in Figure 5. In some embodiments, Form II has a TGA thermogram substantially as depicted in Figure 6.

[0136] In some embodiments, Form II has at least one XRPD peak selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees two theta (±0.2 degrees). In some embodiments, Form II has at least two XRPD peaks selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees two theta (±0.2 degrees). In some embodiments, Form II has at least three XRPD peaks selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees two theta (±0.2 degrees). In some embodiments, Form II has at least four XRPD peaks selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees two theta (±0.2 degrees). In some embodiments, Form II has characteristic XRPD peaks at 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees two-theta (±0.2 degrees).

[0137] In some embodiments, Form II has an endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 47°C and a maximum of 99°C.

[0138] In some embodiments, provided herein is the hexafluorophosphate salt of Compound 2: [ka] A crystalline form of

[0139] In some embodiments, a crystalline form of a hexafluorophosphate salt of Compound 2 has an XRPD pattern substantially as shown in Figure 7. In some embodiments, a crystalline form of a hexafluorophosphate salt of Compound 2 has a DSC thermogram substantially as shown in Figure 8. In some embodiments, a crystalline form of a hexafluorophosphate salt of Compound 2 has a TGA thermogram substantially as shown in Figure 9.

[0140] In some embodiments, the crystalline form of the hexafluorophosphate salt of Compound 2 has at least one XRPD peak selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees two-theta (±0.2 degrees). In some embodiments, the crystalline form of the hexafluorophosphate salt of Compound 2 has at least two XRPD peaks selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees two-theta (±0.2 degrees). In some embodiments, the crystalline form of the hexafluorophosphate salt of Compound 2 has at least three XRPD peaks selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees two-theta (±0.2 degrees). In some embodiments, the crystalline form of the hexafluorophosphate salt of Compound 2 has at least four XRPD peaks selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees two-theta (±0.2 degrees). In some embodiments, the crystalline form of the hexafluorophosphate salt of Compound 2 has characteristic XRPD peaks at 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees two-theta (±0.2 degrees).

[0141] In some embodiments, the crystalline form of the hexafluorophosphate salt of Compound 2 has a first endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 232°C and a maximum of 233°C, and a second endothermic peak with an onset temperature (±3°C) of 241°C and a maximum of 242°C.

[0142] In some embodiments, the crystalline form of the salt of Formula 3a is characterized by single crystal x-ray diffraction as having a monoclinic P21 space group with a cell formula unit (Z) of 4. In some embodiments, the monoclinic P21 space group has unit cell parameters of a about 7.68 Å, b about 7.60 Å, c about 13.72 Å, and beta about 96.94°.

[0143] In some embodiments, the salt of Formula 3a has a chiral purity of greater than 95%. In some embodiments, the salt of Formula 3a has a chiral purity of greater than 97%. In some embodiments, the salt of Formula 3a has a chiral purity of greater than 99%.

[0144] In some embodiments, provided herein are methods for preparing ruxolitinib and its salts, e.g., phosphate salts. For example, ruxolitinib and its phosphate salts can be prepared according to one or more steps shown in Scheme 1. Scheme 1 [ka]

[0145] The present disclosure further provides ruxolitinib, or a salt thereof, prepared according to the methods provided herein.

[0146] The present disclosure further provides salts of ruxolitinib prepared according to the methods provided herein.

[0147] The present disclosure further provides ruxolitinib prepared according to the methods provided herein.

[0148] The present disclosure further provides ruxolitinib, or a pharmaceutically acceptable salt thereof, prepared according to the methods provided herein.

[0149] The present disclosure further provides pharmaceutically acceptable salts of ruxolitinib prepared according to the methods provided herein.

[0150] The present disclosure further provides ruxolitinib phosphate prepared according to the methods provided herein.

[0151] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is expressly intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0152] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0153] In some embodiments, reagent or solvent components may be referred to by numbers (e.g., solvent component S1 or base B1). These numbers are present merely to facilitate antecedents for subsequent dependent claims and, therefore, may be removed in some embodiments.

[0154] For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, if a structure is described as having two R groups co-occurring on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. In another example, when an optional plurality of substituents is designated in the form: [ka] The substituent R can occur p times on the ring, and it is understood that R can be a different moiety at each occurrence. Each R group can be (CH)n It is understood that any hydrogen atom bonded to a ring atom may be replaced, including one or both of the hydrogen atoms in the Q variable. Furthermore, when the variable Q is defined to include hydrogen, such as when Q is stated to be CH, NH, etc. in the above example, any floating substituent, such as R in the above example, can replace a hydrogen in the Q variable as well as a hydrogen in any other non-variable component of the ring.

[0155] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, or 1 to 6 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and n-octyl. 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.

[0156] As used herein, the terms "halo" and "halogen," employed alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodo.

[0157] As used herein, the term "4- to 10-membered heterocycloalkyl ether" refers to a non-aromatic ring or ring system having at least one oxygen heteroatom ring member and 4 to 10 ring members, optionally containing one or more alkenylene groups as part of the ring structure. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Examples of 4- to 10-membered heterocycloalkyl ethers include tetrahydrofuran, tetrahydropyran, dioxane, and the like.

[0158] The methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, or spectrophotometry (e.g., UV-visible), or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), or other related techniques.

[0159] As used herein, the terms "reacting" and "contacting" are used as known in the art and generally refer to bringing chemical reagents together in a manner that allows their interaction at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reaction involves two reagents, and one or more equivalents of the second reagent relative to the first reagent are used. The reaction steps of the methods described herein can be carried out for times and under conditions suitable to prepare the specified product.

[0160] The compounds of the present invention also include pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salts" refers to salts formed by adding a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the phrase "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint 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 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 similarly known acceptable acids. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., 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.

[0161] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one skilled in the art. The chemical properties of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. The adjustments to the protecting groups described herein and the methods of formation and cleavage may be adjusted as necessary to take into account various substituents.

[0162] The reactions of the methods described herein can be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. A suitable solvent for a particular reaction step can be selected depending on the particular reaction step. In some embodiments, the reaction can be carried out in the absence of a solvent, such as when at least one of the reagents is a liquid or gas.

[0163] 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, mixtures thereof, and the like.

[0164] Suitable solvents may include ether solvents such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, mixtures thereof, and the like.

[0165] Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, mixtures thereof, and the like.

[0166] Suitable aprotic solvents may include, by way of example and without limitation, 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-imidazolidinone (DMI), N-methylpyrrolidinone (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, hexamethylphosphoramide, mixtures thereof, and the like.

[0167] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane (e.g., n-heptane), ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, naphthalene, mixtures thereof, and the like.

[0168] Supercritical carbon dioxide and ionic liquids can also be used as solvents.

[0169] The reactions of the methods described herein can be carried out at any suitable temperature, which can be readily determined by one of ordinary skill in the art. The reaction temperature will depend, for example, on the melting and boiling points of the reagents and solvent (if present), the thermodynamics of the reaction (e.g., a highly exothermic reaction may need to be carried out at a lower temperature), and the kinetics of the reaction (e.g., a high activation energy barrier may require a higher temperature). "High temperature" refers to a temperature above room temperature (about 22°C).

[0170] The reactions of the methods described herein can be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques well known to those skilled in the art.

[0171] In some embodiments, preparation of compounds may involve the addition of acids or bases, for example to affect catalysis of a desired reaction or the formation of salt forms, such as acid addition salts.

[0172] Exemplary 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, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinylacetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0173] Exemplary bases include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, and potassium hydroxide) and alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, and potassium carbonate). Some exemplary strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, where alkoxides include the lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxide, metal amides include sodium amide, potassium amide, and lithium amide, metal hydrides include sodium hydride, potassium hydride, and lithium hydride, and metal dialkylamides include the sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl, and cyclohexyl substituted amides.

[0174] The present invention also includes salt forms of the compounds described herein. Examples of salts (or salt forms) include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali 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 amount or excess of an inorganic or organic acid or base that forms the desired salt in a suitable solvent or various combinations of solvents. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is incorporated herein by reference in its entirety.

[0175] Once the preparation of a compound has been carried out according to the methods described herein, the desired product may be isolated using conventional isolation and purification procedures such as concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography, and the like.

[0176] In some embodiments, the compounds of the present invention and salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched for the compound of the present invention. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present invention or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0177] In some embodiments, ruxolitinib), intermediates for preparing the ruxolitinib reagent, and salts thereof may include both anhydrous forms of the substance and solvated / hydrated forms of the substance. Different forms of the same substance have different bulk properties, for example, with respect to hygroscopicity, solubility, stability, etc. Forms with high melting points often have good thermodynamic stability, which is advantageous for extending the shelf life of drug formulations containing the solid form. Forms with lower melting points often have lower thermodynamic stability, but are advantageous in terms of higher aqueous solubility and therefore higher drug bioavailability. Forms with low hygroscopicity are desirable due to their stability to heat and humidity and resist degradation during long-term storage.

[0178] In some embodiments, solid forms of Compound 1, intermediates for preparing Compound 1, and salts thereof are crystalline. In some embodiments, salts of Compound 1 provided herein (e.g., phosphate salts of Compound 1) are crystalline. As used herein, "crystalline" or "crystalline form" is intended to refer to a particular lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells) due to the different physical properties inherent in each crystalline form. In some cases, different lattice configurations have different water or solvent contents.

[0179] The different solid forms and salt forms thereof can be identified by solid state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, etc. can further help identify the form as well as determine stability and solvent / water content.

[0180] An XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary significantly depending on, among other things, sample preparation techniques, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument employed. In some cases, new peaks may be observed or existing peaks may disappear, depending on the type or settings of the instrument. As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrument variation and other factors may affect 2-theta values. Thus, peak assignments such as those reported herein may vary by plus or minus about 0.2° (2-theta), and the terms "substantially" and "about," as used herein in the context of XRPD, are intended to encompass such variations.

[0181] Similarly, temperature readings associated with DSC, TGA, or other thermal experiments can vary by about ±3° C. depending on the instrument, the particular settings, sample preparation, etc. Thus, it is understood that the crystalline forms reported herein having DSC thermograms "substantially" as shown in any of the figures, or the term "about," take such variations into account.

[0182] Generally, the term "about" means ±10%. In some embodiments, the term "about" means ±5%.

[0183] In some embodiments, the solid and salt forms are substantially isolated. "Substantially isolated" means that the solid form, its salt form, or crystalline form is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched in the solid and salt forms. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the solid and salt forms. Methods for isolating solid and salt forms are conventional in the art.

[0184] In some embodiments, the solid forms and salt forms described herein may be found together with other substances, such as water and solvents (e.g., hydrates and solvates), or may be isolated.

[0185] The phrase "pharmaceutically acceptable" is used herein to refer to salts, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0186] The salt-forming reactions described herein can be carried out at any suitable temperature, which can be readily determined by one skilled in the art. The reaction temperature will depend, for example, on the melting and boiling points of the reagents and solvent (if present), the thermodynamics of the reaction (e.g., a highly exothermic reaction may need to be carried out at a lower temperature), and the kinetics of the reaction (e.g., a high activation energy barrier may require a higher temperature).

[0187] As used herein, the expressions "ambient temperature" and "room temperature" or "rt" are art-recognized and generally refer to a temperature, e.g., a reaction temperature, i.e., about the temperature of the room at which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0188] Protecting groups as described herein (e.g., P 1 P 2 ) include, but are not limited to, protecting groups for amines depicted in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, pp. 696-887 (and especially pp. 872-887) (2007), which is incorporated herein by reference in its entirety. Examples of protecting groups described herein include CH2OC(=O)C(CH3)3, CHOCH2CH2Si(CH3)3, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dichloroethoxycarbonyl (Dichloroethoxycarbonyl ... Methylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), 2-tetrahydropyranyl (THP), tri(C 1-4 In some embodiments, the protecting group is a tri(C alkyl)silyl (e.g., tri(isopropyl)silyl or t-butyldimethylsilyl), 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl (SEM), N-pivaloyloxymethyl (POM), p-nitrophenylsulfonyl, p-toluenesulfonyl, phenylsulfonyl, methanesulfonyl, and the like. 1-4In some embodiments, the protecting group is t-butyldimethylsilyl. In some embodiments, the protecting group is p-toluenesulfonyl.

[0189] In some embodiments, one or more constituent atoms of the compounds (products or synthetic intermediates) presented herein may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compound contains at least one deuterium atom. For example, in some embodiments, one or more hydrogen atoms in the compounds presented herein may be replaced or substituted with a deuterium atom (e.g., replacing -CH with -CD). 1-6 (One or more hydrogen atoms of the alkyl group may be replaced with a deuterium atom.) In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, or 1 to 8 deuterium atoms.

[0190] In some embodiments, one or more hydrogen atoms of ruxolitinib or a salt thereof are replaced with deuterium atoms. In some embodiments, a CH group on the cyclopentyl ring of ruxolitinib or a salt thereof is replaced with a CD group.

[0191] In some embodiments, one or more hydrogen atoms of the compound of Formula 3 or a salt thereof are replaced with a deuterium atom. In some embodiments, a CH group on the cyclopentyl ring of the compound of Formula 3 or a salt thereof is replaced with a CD group.

[0192] In some embodiments, one or more hydrogen atoms of the salt of Formula 3a are replaced with deuterium atoms. In some embodiments, a CH2 group on the cyclopentyl ring of the salt of Formula 3a is replaced with a CD2 group.

[0193] The present invention will be described in more detail using specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results. [Example]

[0194] (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (compound 1) and its phosphate salt were prepared according to the following scheme. Scheme 2 [ka] When compound 2a is a chloride salt, it can be the chloride of compound 2 (compound 2c) or the chloride hydrochloride of compound 2 (compound 2d): [ka] Note that it can be isolated as

[0195] As described in the following examples, LCMS gave MS data of approximately m / e 244 for compound 2a, which means that compound 2 was detected without the anion.

[0196] Embodiment 1. A method for preparing ruxolitinib or a salt thereof, comprising: Compounds of Formula 3: [ka] or a salt thereof, by reacting a compound of formula 2a or a salt thereof, or a compound of formula 2b: [ka] with a reagent which is In the formula, X - is a counter anion.

[0197] 2. The method of embodiment 1, wherein the compound of formula 3 or the salt thereof is a chiral salt of the compound of formula 3.

[0198] 3. The method of embodiment 2, wherein the chiral salt is prepared by reacting the compound of formula 3 with an optically active form of an acid selected from mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyltartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid, and 2-acrylamido-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid.

[0199] 4. The method of embodiment 2, wherein the chiral salt is the L-(+)-tartrate salt of the compound of formula 3.

[0200] 5. The compound of formula 3 or the salt thereof is represented by formula 3a: [ka] 3. The method of embodiment 2, comprising:

[0201] 6. The method of any one of embodiments 1 to 6, wherein about 1 to about 1.5 molar equivalents of said reagent relative to said compound of formula 3 or salt thereof is utilized.

[0202] 7. The method of any one of embodiments 1 to 6, wherein the reaction of the reagent with the compound of formula 3 or the salt thereof is carried out in solvent component S1.

[0203] 8. The method of embodiment 7, wherein the solvent component S1 comprises water.

[0204] 9. The method of embodiment 7, wherein the solvent component S1 comprises an alcohol.

[0205] 10. The method of embodiment 7, wherein the solvent component S1 comprises ethanol.

[0206] 11. The method of embodiment 7 or 8, wherein the solvent component S1 comprises dimethylformamide.

[0207] 12. The method of embodiment 7 or 8, wherein the solvent component S1 comprises water, an alcohol, or a combination thereof.

[0208] 13. The method of any one of embodiments 1 to 12, wherein the reagent is a salt of formula 2a or a compound of formula 2b.

[0209] 14. The method of any one of embodiments 1 to 13, wherein the reagent is a salt of formula 2a.

[0210] 15.X - But Cl - , Br - , I - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - 14. The method of any one of embodiments 1 to 13, wherein the method is selected from:

[0211] 16.X - But Cl - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - 14. The method of any one of embodiments 1 to 13, wherein the method is selected from:

[0212] 17.X - But BF4 - 14. The method of any one of embodiments 1 to 13, wherein

[0213] 18.X - But PF6 -14. The method of any one of embodiments 1 to 13, wherein

[0214] 19.X - But AsF6 - 14. The method of any one of embodiments 1 to 13, wherein

[0215] 20.X - But SbF6 - 14. The method of any one of embodiments 1 to 13, wherein

[0216] 21.X - But ClO4 - 14. The method of any one of embodiments 1 to 13, wherein

[0217] 22.X - But Cl - 14. The method of any one of embodiments 1 to 13, wherein

[0218] 23. The reagent is the hydrochloride salt of the salt of formula 2a, wherein X - But Cl - 13. The method of any one of embodiments 1 to 12, wherein

[0219] 24. The method of any one of embodiments 1-12, wherein the reagent is a compound of formula 2b.

[0220] 25. The method of any one of embodiments 1-24, wherein the compound of formula 2b is prepared by a process comprising reacting the salt of formula 2a with a base B1.

[0221] 26. The method of embodiment 25, wherein the reaction of the salt of formula 2a with the base B1 is carried out in a solvent component S2 comprising water.

[0222] 27. The method of embodiment 25 or 26, wherein the base B1 is a strong base.

[0223] 28. The method of any one of embodiments 25-27, wherein the base B1 is a hydroxide.

[0224] 29. The method of any one of embodiments 25 to 28, wherein the base B1 is an alkali metal hydroxide.

[0225] 30. The method of any one of embodiments 25-29, wherein the base B1 is sodium hydroxide.

[0226] 31. The method of any one of embodiments 25-30, wherein about 10 to about 15 molar equivalents of base B1 relative to the salt of formula 2a or the salt thereof are utilized.

[0227] 32. The method of any one of embodiments 25-30, wherein about 12 molar equivalents of the base B1 relative to the salt of formula 2a or salt thereof are utilized.

[0228] 33. The method of any one of embodiments 25-32, wherein the reaction of the salt of formula 2a with the base B1 is carried out at a temperature of from about -10°C to about 60°C.

[0229] 34. The salt of formula 2a or the compound of formula 2b is The compound of formula 1a: [ka] 34. The method of any one of embodiments 1-33, wherein the compound is prepared by a process comprising reacting 2-methyl-2-propanol, or a salt thereof, with Vilsmeier reagent formed from dimethylformamide.

[0230] 35. The salt of formula 2a or the compound of formula 2b is The compound of formula 5a: [ka] 34. The method of any one of embodiments 1-33, wherein the compound is prepared by a process comprising reacting 2-methyl-2-propanol, or a salt thereof, with Vilsmeier reagent formed from dimethylformamide.

[0231] 36. The method of embodiment 35, wherein the compound of formula 5a or the salt thereof is a salt.

[0232] 37. The method of embodiment 35 or 36, wherein the compound of formula 5a or the salt thereof is a sodium salt.

[0233] 38. The reaction with the Vilsmeier reagent produces a compound of formula 2c: [ka] 38. The method of any one of embodiments 34 to 37, wherein

[0234] 39. After reaction with Vilsmeier reagent, the compound of formula 2c is converted to the compound of formula M + X - wherein M + 39. The method of embodiment 38, wherein:

[0235] 40. The method of any one of embodiments 34-39, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

[0236] 41. The method of embodiment 40, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

[0237] 42. The method of embodiment 40, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene.

[0238] 43. The method of embodiment 40, wherein the chlorinating agent is oxalyl chloride.

[0239] 44. The method of embodiment 40, wherein the chlorinating agent is phosphorus oxychloride.

[0240] 45. The method of embodiment 40, wherein the chlorinating agent is triphosgene.

[0241] 46. ​​The method of any one of embodiments 40-45, wherein about 1 to about 5 molar equivalents of the chlorinating agent relative to the compound of formula 1a or 5a, or the salt thereof, are utilized.

[0242] 47. The method of any one of embodiments 40-45, wherein about 1 to about 4 molar equivalents of said chlorinating agent relative to said compound of formula 1a or 5a, or said salt thereof, are utilized.

[0243] 48. The method of any one of embodiments 40-45, wherein about 1 to about 3 molar equivalents of the chlorinating agent relative to the compound of formula 1a or 5a, or the salt thereof, is utilized.

[0244] 49. The method of any one of embodiments 34-48, wherein about 10 to about 25 molar equivalents of dimethylformamide relative to the compound of formula 1a or 5a, or the salt thereof, are utilized.

[0245] 50. The method of any one of embodiments 34-48, wherein about 10 to about 20 molar equivalents of dimethylformamide relative to the compound of formula 1a or 5a, or the salt thereof, are utilized.

[0246] 51. The method of any one of embodiments 34-48, wherein about 10 to about 15 molar equivalents of dimethylformamide relative to the compound of formula 1a or 5a, or the salt thereof, are utilized.

[0247] 52. The method of any one of embodiments 34-48, wherein about 11 to about 14 molar equivalents of dimethylformamide relative to the compound of formula 1a or 5a, or the salt thereof, are utilized.

[0248] 53. The method of any one of embodiments 34-48, wherein about 11 to about 13 molar equivalents of dimethylformamide relative to the compound of formula 1a or 5a, or the salt thereof, are utilized.

[0249] 54. The method of any one of embodiments 34-53, wherein the preparation of the Vilsmeier reagent is carried out in solvent component S3.

[0250] 55. The method of embodiment 54, wherein the solvent component S3 comprises an organic solvent.

[0251] 56. The method of embodiment 54 or 55, wherein the solvent component S3 comprises a polar aprotic solvent.

[0252] 57. The method of any one of embodiments 54-56, wherein the solvent component S3 comprises acetonitrile, dimethylformamide, or a combination thereof.

[0253] 58. The method of any one of embodiments 34-57, wherein the Vilsmeier reagent is prepared at a temperature of about -10°C to about 60°C.

[0254] 59. The method of any one of embodiments 34-57, wherein the Vilsmeier reagent is prepared at a temperature of about -10°C to about 30°C.

[0255] 60. The method of any one of embodiments 34-57, wherein the Vilsmeier reagent is prepared at a temperature of about room temperature to about 60°C.

[0256] 61. The method of any one of embodiments 34-60, wherein the reaction of the compound of formula 1a or 5a, or the salt thereof, with the Vilsmeier reagent is carried out at a temperature of from about 40°C to about 100°C.

[0257] 62. The method of any one of embodiments 34-60, wherein the reaction of the compound of formula 1a or 5a, or the salt thereof, with the Vilsmeier reagent is carried out at a temperature of about 70°C to about 100°C.

[0258] 63. The method of any one of embodiments 34-60, wherein the reaction of the compound of formula 1a or 5a, or the salt thereof, with the Vilsmeier reagent is carried out at a temperature of about 40°C to about 60°C.

[0259] 64. The product of the reaction with the Vilsmeier reagent has formula 2d: [ka] 64. The method of any one of embodiments 34 to 63, comprising:

[0260] 65. The salt of formula 2a is The salt of formula 2c: [ka] Formula M + X - with a salt of M + is the counter cation, X - But Cl - is a counter anion other than 65. The method according to any one of embodiments 1 to 64.

[0261] 66.M + 66. The method of embodiment 65, wherein is an alkali metal countercation.

[0262] 67.M + But Li + , Na + , or K + 66. The method of embodiment 65, wherein

[0263] 68.M + But Na + 66. The method of embodiment 65, wherein

[0264] 69.X - But, Br - , I - , BF4 - , PF6 -, AsF6 - , SbF6 - , and ClO4 - 69. The method of any one of embodiments 65 to 68, wherein the method is selected from:

[0265] 70. The salt of formula 2c is Salt of formula 2d: [ka] 70. The method of any one of embodiments 38-69, wherein the compound is produced by a process comprising reacting

[0266] 71. The method of any one of embodiments 1-14, 24, and 70, wherein said compound of formula 2b is prepared by a process comprising reacting a salt of formula 2d with a base B2.

[0267] 72. The method of embodiment 71, wherein (i) the reaction of the salt of formula 2d with base B2, and (ii) the reaction of the salt of formula 2a with the compound of formula 3 are carried out in a single pot.

[0268] 73. The method of embodiment 71 or 72, wherein the reaction of the salt of formula 2d with base B2 is carried out in a solvent component comprising water.

[0269] 74. The method of any one of embodiments 71-73, wherein the base B2 is a strong base.

[0270] 75. The method of any one of embodiments 71-74, wherein the base B2 is a hydroxide base.

[0271] 76. The method of any one of embodiments 71-75, wherein the base B2 is an alkali metal hydroxide.

[0272] 77. The method of any one of embodiments 71-76, wherein the base B2 is sodium hydroxide.

[0273] 78. The method of any one of embodiments 71-77, wherein the reaction of the salt of formula 2d with base B2 is carried out at a temperature of from about -10°C to about 15°C.

[0274] 79. The method of embodiment 34, wherein the compound of formula 1a or the salt thereof is the hydrochloride salt.

[0275] 80. The compound of formula 1a or the salt thereof is Compounds of Formula 1aP: [ka] and deprotecting the compound of formula (I) In the formula, P 1 80. The method of embodiment 34 or 79, wherein is an amino protecting group.

[0276] 81.P 1 However, (R 1 )3Si, wherein R 1 But C 1-6 81. The method of embodiment 80, wherein the alkyl is alkyl.

[0277] 82.R 1 82. The method of embodiment 81, wherein is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

[0278] 83.P 1 The method of any one of embodiments 80-82, wherein is t-butyldimethylsilyl.

[0279] 84. The method of any one of embodiments 80-83, wherein said deprotection is carried out by reacting said compound of formula 1aP with a base B3.

[0280] 85. The method of embodiment 84, wherein the base B3 is a hydroxide base.

[0281] 86. The method of embodiment 84 or 85, wherein the base B3 is ammonium hydroxide.

[0282] 87. The method of any one of embodiments 80-86, wherein the deprotection is carried out in solvent component S4.

[0283] 88. The method of embodiment 87, wherein the solvent component S4 comprises a polar protic solvent.

[0284] 89. The method of embodiment 87 or 88, wherein the solvent component S4 comprises an alcohol.

[0285] 90. The solvent component S4 is a compound represented by the formula C 1-6 90. The method of any one of embodiments 87-89, comprising alkyl-OH.

[0286] 91. The method of any one of embodiments 87-90, wherein the solvent component S4 comprises methanol.

[0287] 92. The compound of formula 1aP is Compound of formula 2P: [ka] with MeMgBr in the presence of a Grignard catalyst, In the formula, P 1 92. The method of any one of embodiments 80-91, wherein is an amino protecting group.

[0288] 93. The method of embodiment 92, wherein the catalyst is an iron catalyst.

[0289] 94. The method of embodiment 92 or 93, wherein the iron catalyst is iron(III) acetylacetonate.

[0290] 95. The method of any one of embodiments 92-94, wherein about 1 to about 2 molar equivalents of MeMgCl relative to said compound of formula 2P is utilized.

[0291] 96. The method of any one of embodiments 92-95, wherein about 1% to about 10% molar equivalents of said catalyst relative to said compound of formula 2P are utilized.

[0292] 97. The method of any one of embodiments 92-96, wherein the reaction of the compound of formula 2P with MeMgCl is carried out in solvent component S5.

[0293] 98. The solvent component S5 is di-C 1-6 98. The method of embodiment 97, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0294] 99. The method of embodiment 97 or 98, wherein the solvent component S5 comprises tetrahydrofuran.

[0295] 100. The method of any one of embodiments 92-99, wherein said reacting said compound of formula 2P with MeMgCl is carried out at a temperature of from about -10°C to about 30°C.

[0296] 101. The compound of formula 2P is Compound of Formula 12a: [ka] to form said compound of formula 2P.

[0297] 102. The protection step comprises reacting the compound of formula 12a with an alkali metal hydride and P 1 102. The method of embodiment 101, comprising reacting -Y with -Y, wherein Y is halo.

[0298] 103.P 1 -Y is (R 1 )3Si—Y, where Y is halo and R 1 But C 1-6 103. The method of embodiment 102, wherein the alkyl is alkyl.

[0299] 104.P1 However, (R 1 )Si, where R 1 But C 1-6 The method of embodiment 103, wherein the alkyl is alkyl.

[0300] 105.R 1 The method of embodiments 102 and 103, wherein is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

[0301] 106.P 1 The method of any one of embodiments 102 to 105, wherein is t-butyldimethylsilyl.

[0302] 107. The method of any one of embodiments 102-106, wherein the alkali metal hydride is sodium hydride.

[0303] 108. The method of any one of embodiments 102-107, wherein about 1 to about 2 molar equivalents of said alkali metal hydride relative to said compound of Formula 12a are utilized.

[0304] 109. About 1 to about 2 molar equivalents of P relative to the compound of formula 12a 1 The method of any one of embodiments 102 to 108, wherein -Y is utilized.

[0305] 110. The compound of formula 12a and the alkali metal hydride and P 1 109. The method of any one of embodiments 102-109, wherein said reacting with -Y is carried out at a temperature of from about -10°C to about 20°C.

[0306] 111. The compound of formula 12a and the alkali metal hydride and P 1 111. The method of any one of embodiments 102 to 110, wherein the reaction with -Y is carried out in solvent component S6, wherein solvent component S6 comprises an organic solvent.

[0307] 112. The solvent component S6 is di-C 1-6112. The method of embodiment 111, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0308] 113. The method of embodiment 111 or 112, wherein the solvent component S6 comprises tetrahydrofuran.

[0309] 114. The compound of formula 1a or the salt thereof is Compound of formula 23P: [ka] and preparing the compound by a process comprising reducing In the formula, P 2 The method of any one of embodiments 34 and 79-113, wherein is an amino protecting group.

[0310] 115. The method of embodiment 114, wherein said reduction of said compound of formula 23P is accomplished by a process comprising reacting said compound of formula 23P with hydrogen gas in the presence of a catalyst.

[0311] 116. The catalyst is Pd 0 116. The method of embodiment 115, wherein the carbon is carbon.

[0312] 117. The method of embodiment 115 or 116, wherein the amount of the catalyst relative to the compound of formula 23P is from about 5% to about 15% by weight.

[0313] 118. The method of any one of embodiments 115-117, wherein the reacting of the compound of Formula 23P with hydrogen and the catalyst is carried out at a temperature of from about 40°C to about 70°C.

[0314] 119. The method of any one of embodiments 115-118, wherein the reacting of the compound of Formula 23aP with hydrogen and the catalyst is carried out in solvent component S7.

[0315] 120. The method of embodiment 119, wherein the solvent component S7 comprises a polar protic solvent.

[0316] 121. The method of embodiment 119 or 120, wherein the solvent component S7 comprises an alcohol.

[0317] 122. The solvent component S7 is a compound represented by the formula C 1-6 122. The method of any one of embodiments 119-121, comprising alkyl-OH.

[0318] 123. The method of any one of embodiments 119-122, wherein the solvent component S7 comprises methanol.

[0319] 124. The compound of formula 23P is Compound of formula 22P: [ka] with MeMgBr in the presence of a Grignard catalyst, In the formula, P 2 The method of any one of embodiments 114-123, wherein is an amino protecting group.

[0320] 125. The method of embodiment 124, wherein the catalyst is an iron catalyst.

[0321] 126. The method of embodiment 125, wherein the iron catalyst is iron(III) acetylacetonate.

[0322] 127. The method of any one of embodiments 124-126, wherein about 1 to about 2 molar equivalents of MeMgCl relative to said compound of formula 22P is utilized.

[0323] 128. The method of any one of embodiments 124-127, wherein about 1% to about 10% molar equivalents of said catalyst relative to said compound of formula 22P are utilized.

[0324] 129. The method of any one of embodiments 124-128, wherein the reaction of the compound of formula 22P with MeMgCl is carried out in solvent component S8.

[0325] 130. The solvent component S8 is di-C 1-6 130. The method of embodiment 129, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0326] 131. The method of embodiment 129 or 130, wherein the solvent component S8 comprises tetrahydrofuran.

[0327] 132. The method of any one of embodiments 124-131, wherein said reacting said compound of formula 2P with MeMgCl is carried out at a temperature of from about -10°C to about 30°C.

[0328] 133. The compound of formula 22P is Compound of Formula 22a: [ka] to form said compound of formula 22P.

[0329] 134. The protection step comprises reacting the compound of formula 22a with an alkali metal hydride and P 2 134. The method of embodiment 133, comprising reacting with -Y, wherein Y is halo.

[0330] 135.P 2 However, (R 1 )Si, where R 1 But C 1-6 The method of embodiment 134, wherein the alkyl is alkyl.

[0331] 136.R 1 136. The method of embodiment 135, wherein is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

[0332] 137.P 2 The method of any one of embodiments 134-136, wherein is t-butyldimethylsilyl.

[0333] 138. The method of any one of embodiments 134-137, wherein the alkali metal hydride is sodium hydride.

[0334] 139. The method of any one of embodiments 134-138, wherein about 1 to about 2 molar equivalents of said alkali metal hydride relative to said compound of Formula 22a are utilized.

[0335] 140. About 1 to about 2 molar equivalents of P relative to the compound of formula 22a 2 The method of any one of embodiments 134 to 139, wherein -Y is utilized.

[0336] 141. The compound of formula 22a and the alkali metal hydride and P 2 141. The method of any one of embodiments 134-140, wherein said reacting with -Y is carried out at a temperature of from about -10°C to about 20°C.

[0337] 142. The compound of formula 22a and the alkali metal hydride and P 2 142. The method of any one of embodiments 134-141, wherein the reaction with -Y is carried out in solvent component S9, wherein solvent component S9 comprises an organic solvent.

[0338] 143. The solvent component S9 is di-C 1-6 143. The method of embodiment 142, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0339] 144. The method of embodiment 142 or 143, wherein the solvent component S9 comprises tetrahydrofuran.

[0340] 145. The compound of formula 1a or a salt thereof, Compound of Formula 18a: [ka] The method of any one of embodiments 34 and 79-113, wherein the compound is prepared by a process comprising reacting

[0341] 146. The method of embodiment 145, wherein the acid A1 is a strong acid.

[0342] 147. The method of embodiment 145 or 146, wherein the acid A1 is hydrochloric acid.

[0343] 148. The method of any one of embodiments 145-147, wherein the reaction of the compound of formula 18a with the acid A1 is carried out in solvent component S10, and solvent component S10 comprises a polar protic solvent.

[0344] 149. The method of embodiment 148, wherein the solvent component S10 comprises an alcohol.

[0345] 150. The solvent component S10 is a compound represented by the formula C 1-6 150. The method of embodiment 148 or 149, comprising alkyl-OH.

[0346] 151. The method of any one of embodiments 148-150, wherein the solvent component S10 comprises isopropyl alcohol.

[0347] 152. The compound of formula 18a or a salt thereof is Compound of Formula 17a: [ka] with formamidine acetate and triethyl orthoformate to obtain a compound of the formula 18a 152. The method of any one of embodiments 148-151, wherein the compound is prepared by a process comprising forming a compound of formula:

[0348] 153. The method of embodiment 152, wherein about 10 to about 15 molar equivalents of formamidine acetate are utilized relative to about 10 to about 15 of the compound of formula 17a.

[0349] 154. The method of embodiment 152 or 153, wherein about 6 to about 10 molar equivalents of triethyl orthoformate relative to said compound of formula 17a are utilized.

[0350] 155. The method of any one of embodiments 152-154, wherein said reacting said compound of Formula 17a with formamidine acetate and triethyl orthoformate is carried out at a temperature of about 100°C to about 150°C.

[0351] 156. The method of any one of embodiments 152-155, wherein the reaction of the compound of formula 17a with formamidine acetate and triethyl orthoformate is carried out in solvent component S11, wherein solvent component S11 comprises a polar protic solvent.

[0352] 157. The method of embodiment 156, wherein the solvent component S11 comprises an alcohol.

[0353] 158. The solvent component S11 is a compound represented by the formula C 1-6 158. The method of embodiment 156 or 157, comprising alkyl-OH.

[0354] 159. The method of any one of embodiments 156-158, wherein the solvent component S11 comprises 1-butanol.

[0355] 160. The compound of formula 17a or a salt thereof is Compound of Formula 20a: [ka] to a compound of formula 21a: [ka] to form said compound of formula 17a.

[0356] 161. The method of embodiment 160, wherein about 0.4 to about 1 molar equivalent of the compound of formula 21a relative to the compound of formula 20a is utilized.

[0357] 162. The method of embodiment 160 or 161, wherein said reacting said compound of formula 20a with said compound of formula 21a is carried out at room temperature.

[0358] 163. The method of any one of embodiments 160-162, wherein the reaction of the compound of Formula 20a with the compound of Formula 21a is carried out in solvent component S12, and the solvent component S12 comprises a polar aprotic solvent.

[0359] 164. The method of embodiment 163, wherein the solvent component S12 comprises dimethylformamide.

[0360] 165. The compound of formula 20a or a salt thereof is Compound of Formula 19a: [ka] with bromo-1,1-dimethoxyethane and a base B4 to form a compound of formula 20a.

[0361] 166. The method of embodiment 165, wherein the base B4 is an alkali metal carbonate.

[0362] 167. The method of embodiment 165 or 166, wherein the base B4 is cesium carbonate.

[0363] 168. The method of any one of embodiments 165-167, wherein about 1 to about 2 molar equivalents of said base B4 relative to said compound of Formula 19a are utilized.

[0364] 169. The method of any one of embodiments 165-168, wherein about 1 to about 2 molar equivalents of bromo-1,1-dimethoxyethane relative to said compound of formula 19a are utilized.

[0365] 170. The method of any one of embodiments 165-169, wherein said reacting said compound of Formula 19a with bromo-1,1-dimethoxyethane is carried out at a temperature of from about 70°C to about 100°C.

[0366] 171. The method of any one of embodiments 165-170, wherein the reaction of the compound of formula 19a with bromo-1,1-dimethoxyethane is carried out in solvent component S13, and solvent component S13 comprises a polar aprotic solvent.

[0367] 172. The method of embodiment 171, wherein the solvent component S13 is dimethylformamide.

[0368] 173. The compound of formula 17a or a salt thereof, Compound of Formula 16a: [ka] with ethyl acetate and a base B5 to form a compound of formula 17a.

[0369] 174. The method of embodiment 173, wherein the base B5 is an alkali metal alkoxide.

[0370] 175. The method of embodiment 173 or 174, wherein the base B5 is potassium tert-butoxide.

[0371] 176. The method of any one of embodiments 173-175, wherein about 1 to about 3 molar equivalents of said base B5 relative to said compound of Formula 16a are utilized.

[0372] 177. The method of any one of embodiments 173-176, wherein about 1 to about 2 molar equivalents of ethyl acetate relative to said compound of formula 16a is utilized.

[0373] 178. The method of any one of embodiments 172-177, wherein said reacting said compound of Formula 17a with ethyl acetate and base B5 is carried out at room temperature.

[0374] 179. The method of any one of embodiments 172-178, wherein the reaction of the compound of Formula 17a with ethyl acetate and base B5 is carried out in solvent component S14, wherein solvent component S14 comprises an organic solvent.

[0375] 180. The solvent component S14 is di-C 1-6 180. The method of embodiment 179, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0376] 181. The method of embodiment 179 or 180, wherein the solvent component S14 comprises tetrahydrofuran.

[0377] 182. The compound of formula 5a or a salt thereof is Compound of Formula 27a: [ka] in water in the presence of a base B6.

[0378] 183. The method of embodiment 182, wherein the base B6 is an alkali metal hydroxide.

[0379] 184. The method of embodiment 182 or 183, wherein the base B6 is sodium hydroxide.

[0380] 185. The method of any one of embodiments 182-184, wherein about 1 to about 2 molar equivalents of said base B6 relative to said compound of Formula 27a are utilized.

[0381] 186. The method of any one of embodiments 182-185, wherein said hydrolysis of said compound of formula 27a is carried out at room temperature.

[0382] 187. The method of any one of embodiments 182-186, wherein said hydrolysis of said compound of Formula 27a is carried out in solvent component S15, said solvent component S15 comprising an organic solvent.

[0383] 188. The method of embodiment 187, wherein the solvent component S15 comprises tetrahydrofuran, acetone, or a combination thereof.

[0384] 189. The method of any one of embodiments 182-188, wherein said compound of formula 5a or said salt thereof is the sodium salt of said compound of formula 5a.

[0385] 190. The method of any one of embodiments 182-188, wherein said compound of formula 5a or said salt thereof is a compound of formula 5a.

[0386] 191. The method of embodiment 190, wherein said compound of formula 5a is prepared by a process comprising reacting the sodium salt of said compound of formula 5a with a strong acid A2.

[0387] 192. The method of embodiment 191, wherein the strong acid A2 is hydrochloric acid.

[0388] 193. The method of embodiment 191 or 192, wherein (a) the reaction of the sodium salt of the compound of formula 5a with a strong acid A2, and (b) the hydrolysis of the sodium salt of the compound of formula 27a are carried out in a single pot.

[0389] 194. The compound of formula 27a is Compound of formula 26P: [ka] with a strong acid A3, wherein P 1 The method of any one of embodiments 182-193, wherein is an amino protecting group.

[0390] 195.P 1 195. The method of embodiment 194, wherein is p-toluenesulfonyl.

[0391] 196. The method of embodiment 194 or 195, wherein A3 is hydrochloric acid.

[0392] 197. The method of any one of embodiments 194-196, wherein said reacting said compound of formula 26P with a strong acid A3 is carried out at room temperature.

[0393] 198. The method of any one of embodiments 194-197, wherein the reaction of the compound of formula 26P with a strong acid A3 is carried out in solvent component S16.

[0394] 199. The solvent component S16 is a compound represented by the formula C 1-6 199. The method of any one of embodiments 194-198, comprising alkyl-OH.

[0395] 200. The method of embodiment 199, wherein the solvent component S16 comprises ethanol.

[0396] 201. The compound of formula 26P is Compound of formula 25P: [ka] with an alkali metal alkoxide B8 to form a compound of formula 26P, wherein P 1 The method of any one of embodiments 194-200, wherein is an amino protecting group.

[0397] 202. The method of embodiment 201, wherein about 0.1 molar equivalents of alkali metal alkoxide B8 relative to the compound of formula 25P is utilized.

[0398] 203. The method of embodiment 201 or 202, wherein the reaction of the compound of formula 25P with an alkali metal alkoxide B8 is carried out at room temperature.

[0399] 204. The method of any one of embodiments 201-202, wherein the reaction of the compound of formula 25P with alkali metal alkoxide B8 is carried out in solvent component S17, and solvent component S17 comprises a polar protic solvent.

[0400] 205. The method of any one of embodiments 201-202, wherein the alkali metal alkoxide B8 is sodium ethoxide.

[0401] 206. The method of embodiment 204 or 205, wherein the solvent component S17 comprises an alcohol.

[0402] 207. The solvent component S17 is a compound represented by the formula C 1-6 207. The method of any one of embodiments 204 to 206, comprising alkyl-OH.

[0403] 208. The method of any one of embodiments 204-207, wherein the solvent component S17 comprises ethanol.

[0404] 209. The compound of formula 27a is Compound of formula 25P: [ka] with an alkali metal alkoxide B9 to form said compound of formula 27a.

[0405] 210. The method of embodiment 209, wherein about 1 to about 2 molar equivalents of alkali metal alkoxide B9 relative to the compound of formula 25P is utilized.

[0406] 211. The method of embodiment 209, wherein about 1 molar equivalent of alkali metal alkoxide B9 relative to said compound of formula 25P is utilized.

[0407] 212. The method of any one of embodiments 209-211, wherein the reacting of the compound of Formula 25P with an alkali metal alkoxide B9 is carried out at a temperature of from about 50°C to about 80°C.

[0408] 213. The reaction of the compound of formula 25P with alkali metal alkoxide B9 is carried out in solvent component S18, and the solvent component S18 is a compound of formula C 1-6 213. The method of any one of embodiments 209-212, comprising alkyl-OH.

[0409] 214. The method of embodiment 213, wherein the solvent component S18 comprises ethanol.

[0410] 215. The compound of formula 25P is Compound of formula 2P: [ka] with diethyl malonate and a base B10, wherein P 1 The method of any one of embodiments 201-214, wherein is an amino protecting group.

[0411] 216. The method of embodiment 215, wherein the base B10 is an alkali metal carbonate.

[0412] 217. The method of embodiment 215 or 216, wherein the base B10 is cesium carbonate.

[0413] 218. The method of any one of embodiments 215-217, wherein said reacting said compound of formula 2P with base B10 is carried out at a temperature of from about 40°C to about 70°C.

[0414] 219. The method of any one of embodiments 215-218, wherein the reaction of the compound of formula 2P with base B10 is carried out in solvent component S19, and solvent component S19 comprises a polar aprotic solvent.

[0415] 220. The method of embodiment 219, wherein the solvent component S19 comprises dimethylformamide.

[0416] 221. The method of any one of embodiments 215-220, wherein said compound of formula 2P is prepared by a process comprising protecting a compound of formula 12a to form said compound of formula 2P.

[0417] 222. The protection step comprises reacting the compound of formula 12a with a base B11 and P 1 222. The method of embodiment 221, comprising reacting with -Y, wherein Y is halo.

[0418] 223.P 1 223. The method of embodiment 222, wherein is p-toluenesulfonyl.

[0419] 224. The method of embodiment 222 or 223, wherein the base B11 is an alkali metal hydroxide.

[0420] 225. The method of any one of embodiments 222-224, wherein the base B11 is sodium hydroxide.

[0421] 226. The method of any one of embodiments 222-225, wherein the protection comprises reacting the compound of formula 12a with a base B11, and is carried out in solvent component S20, wherein solvent component S20 comprises a polar aprotic solvent.

[0422] 227. The method of embodiment 226, wherein the solvent component S20 comprises acetone.

[0423] 228. The compound of formula 12a is Compound of formula 11a: [ka] The method of any one of embodiments 101-113 and 221-227, wherein the compound is prepared by a process comprising reacting A4, or a salt thereof, with a strong acid A4.

[0424] 229. The method of embodiment 228, wherein the strong acid A4 is hydrochloric acid.

[0425] 230. The method of embodiment 228 or 229, wherein the reaction of the compound of formula 11a or salt thereof with a strong acid A4 is carried out in solvent component S21, and solvent component S21 comprises a polar aprotic solvent.

[0426] 231. The solvent component S21 is di-C 1-6 231. The method of embodiment 230, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0427] 232. The method of embodiment 230 or 231, wherein the solvent component S21 comprises tetrahydrofuran.

[0428] 233. The method of any one of embodiments 228-232, wherein the reaction of the compound of formula 11a or salt thereof with a strong acid A4 is carried out in tetrahydrofuran at reflux temperature.

[0429] 234. The compound of formula 11a or a salt thereof is Compound of Formula 10a: [ka] 234. The method of any one of embodiments 228-233, wherein the compound is prepared by a process comprising reacting C14, or a salt thereof, with (methoxymethyl)triphenylphosphonium chloride and a base B12.

[0430] 235. The method of embodiment 234, wherein the base B12 is an alkali metal alkoxide.

[0431] 236. The method of embodiment 234 or 235, wherein the base B12 is potassium t-butoxide.

[0432] 237. The method of any one of embodiments 234-236, wherein the reaction of the compound of formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and base B12 is carried out at a temperature of from about 10°C to about 30°C.

[0433] 238. The method of any one of embodiments 234-237, wherein the reaction of the compound of formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and base B12 is carried out in solvent component S22, wherein solvent component S22 comprises a polar aprotic solvent.

[0434] 239. The solvent component S22 is di-C 1-6 239. The method of embodiment 238, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0435] 240. The method of embodiment 238 or 239, wherein the solvent component S22 comprises tetrahydrofuran.

[0436] 241. The compound of formula 10a or a salt thereof is Compound of Formula 9a: [ka] 241. The method of any one of embodiments 238-240, wherein the compound is prepared by a process comprising reacting

[0437] 242. The method of embodiment 241, wherein the reacting of the compound of Formula 9a with ammonia is carried out at a temperature of about 40°C to about 70°C.

[0438] 243. The method of embodiment 241 or 242, wherein the reaction of the compound of formula 9a with ammonia is carried out in solvent component S23, and solvent component S23 comprises an organic solvent.

[0439] 244. The method of embodiment 243, wherein the solvent component S23 comprises toluene.

[0440] 245. The compound of formula 9a is Compound of Formula 8a: [ka] 245. The method of any one of embodiments 241 to 244, wherein the compound is prepared by a process comprising reacting

[0441] 246. The method of embodiment 245, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

[0442] 247. The method of embodiment 246, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

[0443] 248. The method of embodiment 246 or 247, wherein the chlorinating agent is phosphorus oxychloride.

[0444] 249. The compound of formula 12a is Compound of Formula 15a: [ka] The method of any one of embodiments 101-113 and 221-237, wherein the compound is prepared by a process comprising reacting

[0445] 250. The method of embodiment 249, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

[0446] 251. The method of embodiment 249 or 250, wherein the chlorinating agent is phosphorus oxychloride.

[0447] 252. The method of any one of embodiments 249-251, wherein said reacting said compound of Formula 15a with a chlorinating agent is carried out at a temperature of from about 50°C to about 100°C.

[0448] 253. The method of any one of embodiments 249-252, wherein the reaction of the compound of Formula 15a with ammonia is carried out in solvent component S24, and solvent component S24 comprises an organic solvent.

[0449] 254. The method of embodiment 253, wherein the solvent component S24 comprises toluene.

[0450] 255. The compound of formula 15a is (i) A compound of formula 14a: [ka] with formamidine acetate and an alkali metal hydroxide to produce a compound of formula 14aa: [ka] and (ii) reacting said compound of formula 14aa with a strong acid A4; 255. The method of any one of embodiments 249 to 254, wherein the compound is prepared by a method comprising:

[0451] 256. The method of embodiment 255, wherein the alkali metal hydroxide is sodium ethoxide.

[0452] 257. The method of embodiment 255 or 256, wherein said reacting said compound of Formula 14a with formamidine acetate and an alkali metal hydroxide is carried out at a temperature of about 50°C to about 100°C.

[0453] 258. The method of any one of embodiments 255-257, wherein the reaction of the compound of formula 14a with formamidine acetate and an alkali metal hydroxide is carried out in solvent component S25, and solvent component S25 comprises a polar protic solvent.

[0454] 259. The method of embodiment 258, wherein the solvent component S25 comprises an alcohol.

[0455] 260. The solvent component S25 is a compound represented by the formula C 1-6 260. The method of embodiment 258 or 259, comprising alkyl-OH.

[0456] 261. The method of any one of embodiments 258-260, wherein the solvent component S25 comprises ethanol.

[0457] 262. The method of any one of embodiments 258-261, wherein the strong acid A4 is hydrochloric acid.

[0458] 263. The compound of formula 14a is Compound of Formula 13a: [ka] 263. The method of any one of embodiments 258-262, wherein the compound is prepared by a process comprising reacting with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide.

[0459] 264. The method of embodiment 263, wherein the reacting of the compound of Formula 13a with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide is carried out at a temperature of about 80°C to about 100°C.

[0460] 265. The process of embodiment 263 or 264, wherein the reaction of the compound of formula 13a with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide is carried out in solvent component S26, and solvent component S26 comprises a polar aprotic solvent.

[0461] 266. The method of embodiment 265, wherein the solvent component S26 comprises dimethyl sulfoxide.

[0462] 267. The method of any one of embodiments 1-266, wherein said compound of formula 3a or said salt thereof is the L-tartrate salt of said compound of formula 3.

[0463] 268. The L-tartrate salt of formula 3 is Compound 7a: [ka] 268. The method of embodiment 267, wherein the compound is prepared by a process comprising reacting

[0464] 269. The method of embodiment 268, wherein about 1 molar equivalent of L-tartaric acid is utilized relative to said compound of formula 7a.

[0465] 270. The method of embodiment 268 or 269, wherein the reaction of the compound of formula 7a with L-tartaric acid is carried out in solvent component S27.

[0466] 271. The method of embodiment 270, wherein the solvent component S27 comprises water and an organic solvent.

[0467] 272. The method of embodiment 270 or 271, wherein said solvent component S27 comprises about 1:1(v) water to organic solvent.

[0468] 273. The method of any one of embodiments 270-272, wherein the solvent component S27 comprises a polar aprotic solvent.

[0469] 274. The method of any one of embodiments 270-273, wherein the solvent component S27 comprises acetonitrile.

[0470] 275. The method of any one of embodiments 268-274, wherein said reacting said compound of formula 7a with L-tartaric acid is carried out at a temperature of about 20°C to about 30°C.

[0471] 276. The method of any one of embodiments 268-275, wherein said reacting said compound of formula 7a and L-tartaric acid further comprises seeding said salt of formula 3a.

[0472] 277. The compound of formula 7a is The compound of formula 6a: [ka] 277. The method of any one of embodiments 268-276, wherein the compound is prepared by a process comprising reacting

[0473] 278. The method of embodiment 277, wherein about 2 to about 3 equivalents of hydrazine relative to compound 6a are utilized.

[0474] 279. The method of embodiment 278, wherein the hydrazine is hydrazine hydrate.

[0475] 280. The method of embodiment 278 or 279, wherein said reacting said compound of formula 6a with hydrazine is carried out at a temperature of from about -10°C to about 30°C.

[0476] 281. The method of any one of embodiments 1-280, wherein the salt of ruxolitinib is ruxolitinib phosphate.

[0477] 282. The method according to embodiment 281, wherein the ruxolitinib phosphate is prepared by a process comprising reacting ruxolitinib with phosphoric acid.

[0478] 283. The method of embodiment 282, wherein about 1 to about 2 molar equivalents of phosphoric acid relative to ruxolitinib are utilized.

[0479] 284. The method of embodiment 282 or 283, wherein said reaction of ruxolitinib with phosphoric acid is carried out at a temperature of about 20°C to about 50°C.

[0480] 285. The method of any one of embodiments 282-284, wherein the phosphoric acid is an aqueous solution of phosphoric acid.

[0481] 286. Ruxolitinib phosphate (i) adding a first solvent component to ruxolitinib phosphate to form a first solution; (ii) concentrating the first solution to form a second solution; (iii) adding a second solvent component to the second solution to form a third solution; (iv) adding a third solvent to the third solution to form a fourth solution; (v) concentrating the fourth solution to form a fifth solution; (vi) isolating ruxolitinib phosphate from the fifth solution; and 286. The method of any one of embodiments 281 to 285, wherein the purified product is purified by a method comprising:

[0482] 287. The first solvent component is C 1-6 287. The method of embodiment 286, comprising alkyl-OH.

[0483] 288. The method of embodiment 286 or 287, wherein the first solvent component comprises methanol.

[0484] 289. The method of any one of embodiments 286-288, wherein the first solution is heated to a temperature of about 30°C to about 80°C.

[0485] 290. The second solvent component is C 1-6 289. The method of any one of embodiments 286-289, comprising alkyl-OH.

[0486] 291. The method of any one of embodiments 286-290, wherein the second solvent component comprises isopropyl alcohol.

[0487] 292. The method of any one of embodiments 286-291, wherein the temperature of the second solution is from about 30°C to about 80°C.

[0488] 293. The method of any one of embodiments 286-292, wherein the third solvent component comprises a non-polar solvent.

[0489] 294. The third solvent component is C 1-8 294. The method of any one of embodiments 286 to 293, comprising an alkane.

[0490] 295. The method of any one of embodiments 286-294, wherein the third solvent comprises n-heptane.

[0491] 296. The method of any one of embodiments 286-295, wherein the temperature of the third solution is from about 30°C to about 80°C.

[0492] 297. The method of any one of embodiments 286-296, wherein the fifth solution is cooled to about 20°C to about 30°C.

[0493] 298. A method for preparing ruxolitinib phosphate, comprising: (a) a compound of formula 1a or a salt thereof: [ka] with Vilsmeier reagent formed from dimethylformamide to give a compound of formula 2c: [ka] and (b) reacting the compound of formula 2c with a compound of formula 3: [ka] with the L-tartrate salt of (c) reacting ruxolitinib with phosphoric acid to form ruxolitinib phosphate; The method comprising:

[0494] 299. The compound of formula 1a or a salt thereof is (a) a compound of formula 12a: [ka] with t-butyldimethylsilyl chloride to give a compound of formula 12b: [ka] and (b) reacting the compound of formula 12b with MeMgBr in the presence of a Grignard catalyst to produce a compound of formula 12c: [ka] and (c) deprotecting the compound of formula 12c to yield a compound of formula 1a or a salt thereof; 300. The method of embodiment 298, wherein the compound is prepared by a method comprising:

[0495] 300. The compound of formula 1a or a salt thereof is (a) A compound of formula 22a: [ka] is reacted with t-butyldimethylsilyl chloride and MeMgBr in the presence of a Grignard catalyst to give a compound of formula 23a: [ka] and (b) reacting said compound of formula 23a with hydrogen and palladium on carbon to produce a compound of formula 1a or a salt thereof; 300. The method of embodiment 298, wherein the compound is prepared by a method comprising:

[0496] 301. [ka] or a salt thereof.

[0497] 302. The compound or a salt thereof, [ka] The compound of embodiment 301, selected from:

[0498] 303. A compound which is: [ka] Or its salt.

[0499] 304. A compound which is: [ka] Or its salt.

[0500] 305. A compound which is: [ka] Or its salt.

[0501] 306. A compound which is: [ka] Or its salt.

[0502] 307. A compound which is: [ka] Or its salt.

[0503] 308. Salt of formula 2a: [ka] and In the formula, X - But Cl -A compound in which the counter anion is other than

[0504] 309. The compound, [ka] The compound of embodiment 308, selected from:

[0505] 310. Salt of formula 2d: [ka] Crystalline form of.

[0506] 311. The crystalline form according to embodiment 310, having form I.

[0507] 312. The crystalline form of embodiment 311, having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1.

[0508] 313. The crystalline form of embodiment 311 or 312, having a differential scanning calorimetry (DSC) thermogram substantially as depicted in FIG. 2.

[0509] 314. The crystalline form of any one of embodiments 311-313, having a thermogravimetric analysis (TGA) thermogram substantially as depicted in FIG.

[0510] The crystalline form of any one of embodiments 311-314, having at least one XRPD peak selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees at 315.2 theta (±0.2 degrees).

[0511] The crystalline form of any one of embodiments 311-314, having at least two XRPD peaks selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees at 316.2 theta (±0.2 degrees).

[0512] The crystalline form of any one of embodiments 311-314, having at least three XRPD peaks selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees at 317.2 theta (±0.2 degrees).

[0513] The crystalline form of any one of embodiments 311-314, having at least four XRPD peaks selected from 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees at 318.2 theta (±0.2 degrees).

[0514] The crystalline form of any one of embodiments 311-314, having characteristic XRPD peaks at 7.4, 12.5, 13.1, 14.1, 14.6, 15.0, 15.9, 17.7, 18.5, 19.0, 20.5, 20.8, 22.2, 23.0, 24.3, 26.3, and 27.9 degrees at 319.2 theta (±0.2 degrees).

[0515] 320. The crystalline form of any one of embodiments 311-319, having an endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 56°C and a maximum of 101°C.

[0516] 321. The crystalline form according to embodiment 310, having form II.

[0517] 322. The crystalline form of embodiment 321, having an XRPD pattern substantially as shown in Figure 4.

[0518] 323. The crystalline form of embodiment 321 or 322, having a DSC thermogram substantially as depicted in FIG. 5.

[0519] 324. The crystalline form of any one of embodiments 321-323, having a TGA thermogram substantially as depicted in FIG. 6.

[0520] The crystalline form of any one of embodiments 321-324, having at least one XRPD peak selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees at 325.2 theta (±0.2 degrees).

[0521] The crystalline form of any one of embodiments 321-324, having at least two XRPD peaks selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees at 326.2 theta (±0.2 degrees).

[0522] The crystalline form of any one of embodiments 321-324, having at least three XRPD peaks selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees at 327.2 theta (±0.2 degrees).

[0523] The crystalline form of any one of embodiments 321-324, having at least four XRPD peaks selected from 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees at 328.2 theta (±0.2 degrees).

[0524] The crystalline form of any one of embodiments 321-324, having characteristic XRPD peaks at 7.3, 11.5, 11.9, 13.3, 15.5, 15.8, 16.1, 17.4, 19.1, 19.4, 19.6, 21.4, 22.0, 22.6, 23.2, 24.9, 25.5, 26.7, and 29.1 degrees at 329.2 theta (±0.2 degrees).

[0525] 330. The crystalline form of any one of embodiments 321-329, having an endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 47°C and a maximum of 99°C.

[0526] 331. Hexafluorophosphate salt of compound 2: [ka] Crystalline form of.

[0527] 332. The crystalline form of embodiment 331, having an XRPD pattern substantially as shown in Figure 7.

[0528] 333. The crystalline form of embodiment 331 or 332, having a DSC thermogram substantially as depicted in FIG. 8.

[0529] 334. The crystalline form of any one of embodiments 331-333, having a TGA thermogram substantially as depicted in FIG. 9.

[0530] The crystalline form of any one of embodiments 331-334, having at least one XRPD peak selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees at 335.2 theta (±0.2 degrees).

[0531] The crystalline form of any one of embodiments 331-334, having at least two XRPD peaks selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees at 336.2 theta (±0.2 degrees).

[0532] The crystalline form of any one of embodiments 331-334, having at least three XRPD peaks selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees at 337.2 theta (±0.2 degrees).

[0533] The crystalline form of any one of embodiments 331-334, having at least four XRPD peaks selected from 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees at 338.2 theta (±0.2 degrees).

[0534] The crystalline form of any one of embodiments 331-334, having characteristic XRPD peaks at 10.8, 12.0, 13.9, 14.3, 15.2, 16.6, 17.0, 17.6, 18.1, 20.1, 20.4, 21.3, 21.5, 22.1, 24.2, 24.7, 25.0, and 26.3 degrees at 339.2 theta (±0.2 degrees).

[0535] 340. The crystalline form of any one of embodiments 331-339, having a first endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 232°C and a maximum of 233°C, and a second endothermic peak with an onset temperature (±3°C) of 241°C and a maximum of 242°C.

[0536] 341.Compound 3a: [ka] Crystalline form of.

[0537] 342. The crystalline form of embodiment 341, having an XRPD pattern substantially as shown in Figure 11.

[0538] 343. The crystalline form of embodiment 341 or 342, having a DSC thermogram substantially as depicted in FIG. 12.

[0539] 344. The crystalline form of any one of embodiments 341-343, having a TGA thermogram substantially as depicted in FIG. 13.

[0540] The crystalline form of any one of embodiments 341-344, having at least one XRPD peak selected from 6.4, 12.8, 13.8, 16.3, 17.3, 18.0, 18.2, 19.3, 22.5, 25.9, 26.4, 27.2, and 29.6 degrees at 345.2 theta (±0.2 degrees).

[0541] The crystalline form of any one of embodiments 341-344, having at least two XRPD peaks selected from 6.4, 12.8, 13.8, 16.3, 17.3, 18.0, 18.2, 19.3, 22.5, 25.9, 26.4, 27.2, and 29.6 degrees at 346.2 theta (±0.2 degrees).

[0542] The crystalline form of any one of embodiments 341-344, having at least three XRPD peaks selected from 6.4, 12.8, 13.8, 16.3, 17.3, 18.0, 18.2, 19.3, 22.5, 25.9, 26.4, 27.2, and 29.6 degrees at 347.2 theta (±0.2 degrees).

[0543] The crystalline form of any one of embodiments 341-344, having at least four XRPD peaks selected from 6.4, 12.8, 13.8, 16.3, 17.3, 18.0, 18.2, 19.3, 22.5, 25.9, 26.4, 27.2, and 29.6 degrees at 348.2 theta (±0.2 degrees).

[0544] The crystalline form of any one of embodiments 341-344, having characteristic XRPD peaks at 6.4, 12.8, 13.8, 16.3, 17.3, 18.0, 18.2, 19.3, 22.5, 25.9, 26.4, 27.2, and 29.6 degrees at 349.2 theta (±0.2 degrees).

[0545] 350. The crystalline form of any one of embodiments 341-349, having a first endothermic peak in a DSC thermogram with an onset temperature (±3°C) of 55°C and a maximum of 79°C, and a second endothermic peak with an onset temperature (±3°C) of 121°C and a maximum of 124°C.

[0546] 351. The crystalline form of embodiment 341, characterized by single crystal x-ray diffraction as having a monoclinic P21 space group and a number of compositional units in the cell (Z) of 4.

[0547] 352. The crystalline form of embodiment 351, wherein the space group has unit cell parameters of a about 7.68 Å, b about 7.60 Å, c about 13.72 Å, and beta about 96.94°.

[0548] 353. The crystalline form of any one of embodiments 341-352, wherein compound 3a has a chiral purity of greater than 99%.

[0549] Example 1. Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (chloride hydrochloride of compound 2) [ka] A solution of oxalyl chloride (21.88 g, 15.1 mL, 169 mmol, 2.25 equiv.) in anhydrous acetonitrile (65 mL) was cooled to 0–5°C in an ice bath. Anhydrous DMF (70.8 g, 75.0 mL, 969 mmol, 12.9 equiv.) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled below 10°C during the DMF addition. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature over 40 min. Methyl-7H-pyrrolo[2,3-d]pyrimidine (1a, 10.0 g, 75.1 mmol) was charged in one portion as a solid into the in situ generated Vilsmeier reagent at ambient temperature. The resulting slurry was stirred at ambient temperature for 5–10 min to ensure complete mixing, and then warmed to 85–90°C. The reaction mixture was stirred at 85-90°C for 1 hour and then slowly cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 100 mL) was charged and the resulting slurry was stirred at ambient temperature for 2 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration, washed with a 1:1 mixture of THF and MTBE (2 x 100 mL), and dried under vacuum to constant weight to give the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (2d, 24.38 g, 23.72 g (theoretical yield), 98.9% by HPLC area %, 90.2% by NMR weight %, 92.6% yield) as a yellow to brown crystalline solid (Form I) containing 6-7% DMF and acetonitrile and 1-2% water, which was used in subsequent reactions without further purification. For compound 2d: 1H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19 Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0550] Crystalline Form I of compound 2d was characterized by XRPD, DSC, and TGA.

[0551] X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) data were obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: start angle 3 degrees, stop angle 30 degrees, sampling 0.015 degrees, and a scan rate of 2 degrees / min.

[0552] Form I of compound 2d was confirmed to be a crystalline solid by XRPD analysis. The XRPD pattern of compound 2d, crystalline Form I, is shown in Figure 1, and the peak data is provided in Table 1. [Table 1]

[0553] Differential Scanning Calorimetry (DSC): DSC was obtained from a TA Instruments Differential Scanning Calorimeter, Discovery DSC2500, equipped with an autosampler. DSC instrument conditions were as follows: 20-300 °C at 10 °C / min, Tzero aluminum sample pan and lid, and a nitrogen gas flow rate of 50 mL / min. DSC analysis of compound 2d, crystalline form I, revealed a single endothermic peak with an onset temperature of 55.6 °C and a maximum of 100.6 °C. The DSC thermogram of compound 2d, crystalline form I, is provided in Figure 2.

[0554] Thermogravimetric Analysis (TGA): TGA was obtained from a TA Instruments Thermogravimetric Analyzer, Discovery TGA5500, equipped with an autosampler. General experimental conditions for TGA were as follows: 25°C to 300°C ramp at 10°C / min, nitrogen purge gas flow rate of 25 mL / min, platinum sample holder. TGA analysis of compound 2d, crystalline form I, revealed an 8.0% weight loss below 100°C and a significant weight loss above 175°C due to decomposition. The TGA thermogram of compound 2d, crystalline form I, is provided in Figure 3.

[0555] Example 2: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (compound 2d) A solution of oxalyl chloride (43.76 g, 30.2 mL, 338 mmol, 2.25 equiv.) in anhydrous acetonitrile (130 mL) was cooled to 0–5°C in an ice bath. Anhydrous DMF (141.6 g, 140.0 mL, 1938 mmol, 12.9 equiv.) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled below 10°C during the DMF addition. The ice bath was removed, and the reaction mixture was gradually warmed to ambient temperature over 40 min. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (25.44 g, 150 mmol of the hydrochloride salt of compound 1a) was added as a solid in one portion at ambient temperature to the in situ generated Vilsmeier reagent. The resulting slurry was stirred at ambient temperature for 5–10 min to ensure complete mixing, and then warmed to 85–90°C. The reaction mixture was stirred at 85-90°C for 1 hour and then slowly cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 200 mL) was charged and the resulting slurry was stirred at ambient temperature for 48 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration, washed with a 1:1 mixture of THF and MTBE (2 x 200 mL), and dried under vacuum to a constant weight to give the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (Compound 2d), 46.17 g, 47.43 g (theoretical yield), 99.5% by HPLC area %, 95.2% by NMR weight %, 92.7% yield) as a yellow to brown crystalline solid (Form II) containing 2.3% DMF and acetonitrile and 0.8% water, which was used in subsequent reactions without further purification. For Compound 2d: 1 H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0556] Crystalline Form II of compound 2d was characterized by XRPD, DSC, and TGA.

[0557] X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) data were obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: start angle 3 degrees, stop angle 30 degrees, sampling 0.015 degrees, and a scan rate of 2 degrees / min.

[0558] Crystalline Form II of compound 2d was confirmed to be a crystalline solid by XRPD analysis. The XRPD pattern of compound 2d, crystalline Form II, is shown in Figure 4, and the peak data is provided in Table 2. [Table 2]

[0559] Differential Scanning Calorimetry (DSC): DSC was obtained from a TA Instruments Differential Scanning Calorimeter, Discovery DSC2500, equipped with an autosampler. DSC instrument conditions were as follows: 20-300 °C at 10 °C / min, Tzero aluminum sample pan and lid, and a nitrogen gas flow rate of 50 mL / min. DSC analysis of compound 2d, crystalline form II, revealed a single endothermic peak with an onset temperature of 46.6 °C and a maximum of 99.2 °C. The DSC thermogram of compound 2d, crystalline form II, is provided in Figure 5.

[0560] Thermogravimetric Analysis (TGA): TGA was obtained from a TA Instruments Thermogravimetric Analyzer, Discovery TGA5500, equipped with an autosampler. General experimental conditions for TGA were as follows: 25°C to 300°C ramp at 10°C / min, nitrogen purge gas flow rate of 25 mL / min, platinum sample holder. TGA analysis of compound 2d, crystalline form II, revealed a 4.7% weight loss below 150°C and a significant weight loss above 175°C due to decomposition. The TGA thermogram of compound 2d, crystalline form II, is provided in Figure 6.

[0561] Example 3: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (2d) [ka] A solution of phosphorus oxochloride (POCl3, 17.25 g, 10.5 mL, 112.5 mmol, 1.5 equiv.) in anhydrous acetonitrile (65 mL) was cooled to 0–5 °C in an ice bath. Anhydrous DMF (70.8 g, 70.0 mL, 968 mmol, 12.9 equiv.) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled below 10 °C during the DMF addition. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (the hydrochloride salt of compound 1a, 12.72 g, 75.0 mmol) was charged in one portion as a solid into the in situ generated Vilsmeier reagent at ambient temperature. The resulting slurry was stirred at ambient temperature for 5–10 min to ensure complete mixing, and then warmed to 75–80 °C. The reaction mixture was stirred at 75-80°C for 1 hour and then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 100 mL) was charged, and the resulting slurry was stirred at ambient temperature for 2 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration and washed with a 1:1 mixture of THF and MTBE (2 x 100 mL) to afford the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (Compound 2d, 27.83 g, 23.72 g (theoretical yield), 96.1% by HPLC area %, 69.0% by NMR weight %, 81.0% yield), as a yellow to brown crystalline (Form I) solid containing 11.49% DMF and acetonitrile and 1.38% water, which was used in subsequent reactions without further purification. Regarding compound 2d: 1 H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0562] Example 4: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Compound 1) A solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (compound 2d, 20.0 g, 55.8 mmol) in water (22.7 mL) was treated with 50% aqueous NaOH at 0-5 °C until the pH reached 7-8. Charcoal (3.6 g) was added to the resulting aqueous solution, and the mixture was stirred at ambient temperature for 2-4 h. The charcoal was removed by filtration through a bed of Celite, and the wet charcoal cake was washed with water (20 mL). The resulting aqueous solution containing (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (Compound 2c) was then treated with ethanol (160 mL) and (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (Compound 3a, 18.91 g, 55.8 mmol, 1.0 equiv.) at ambient temperature. The resulting mixture was then stirred at ambient temperature for 12–24 h. Upon completion of the reaction, the reaction mixture was filtered to remove the solid (L-tartaric acid). The cake was washed with ethanol (2 × 25 mL). The filtrate and washings were combined, and the combined solution was concentrated under reduced pressure at 40–50 °C to remove most of the ethanol. To the residue was then added HO (70 mL) and dichloromethane (DCM, 200 mL). The two layers were separated, and the aqueous layer was extracted with DCM (80 mL). The combined organic extracts were washed with aqueous sodium bicarbonate (4% aqueous NaHCO3, 112 mL) and water (2 x 100 mL). The resulting solution containing the desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Compound 1), was concentrated under reduced pressure, and the residue (18.7 g, 17.1 g (theoretical yield)) was used in the subsequent phosphate salt formation reaction without further purification. The free base of Compound 1 obtained by the current synthetic method is identical in all comparable aspects to the compound obtained by the previously reported synthetic method (US Pat. No. 8,410,265 B2). Regarding Compound 1: 1H NMR(DMSO-d6,400MHz)δ12.10(br.s,1H),8.78(s,1H),8.67(s,1H),8.36(s,1H),7.58(dd,1H,J=2.3,3.4Hz),6.97(dd,1H,J=1.5,3.6Hz), C 17 H 18 N6(MW,306.37),LCMS(EI)m / e 307(M + +H).

[0563] Example 5: Alternative preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Compound 1) [ka] This is a general procedure for the preparation of compound 1 using any one of the salts of compound 2a (e.g., the perchlorate salt of compound 2, the tetrafluoroborate salt of compound 2, the hexafluorophosphate salt of compound 2, the hexafluoroarsenate salt of compound 2, or the hexafluoroantimonate salt of compound 2) as the starting material, where scales, molarity, and volumes may be adjusted proportionally as appropriate. The preparation of compound 1 using the perchlorate salt of compound 2 as the starting material is included herein as an illustrative example.

[0564] To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (the perchlorate salt of compound 2, 200.0 mg, 0.582 mmol) in ethanol (EtOH, 2.0 mL) was added (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a, 217.2 mg, 0.64 mmol, 1.1 equiv.) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours. Upon completion of the reaction, the reaction mixture was filtered to remove the solid (L-tartaric acid). The cake was washed with ethanol (2.0 mL). The filtrate and washings were combined, and the combined solution was concentrated under reduced pressure at 40-50 °C to remove most of the ethanol. To the residue was then added HO (4.0 mL) and dichloromethane (DCM, 5.0 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 × 4.0 mL). The combined organic extracts were washed with brine (4.0 mL) and water (4.0 mL), dried over NaSO, and concentrated under reduced pressure to give the crude desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (compound 1, 174 mg, 178.3 mg (theoretical yield), 97.6%), as a yellow oil, which was identical in all comparable respects to the compound obtained in Example 4 and by a previously reported synthetic method (US Pat. No. 8,410,265 B2), and was used in the subsequent phosphate-forming reaction without further purification.

[0565] Example 6: Alternative preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Compound 1). [ka] To a slurry of (E)-3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde (compound 2b, 5.0 g, 26.4 mmol) in DMF (70.4 mL) was added (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a, 9.4 g, 27.7 mmol, 1.05 equiv.). The resulting reaction mixture was stirred at ambient temperature for 22 hours. Upon completion of the reaction, water (80 mL) and sodium bicarbonate (NaHCO3, 5.0 g, 59.5 mmol, 2.25 equiv.) were added, and the resulting mixture was stirred at ambient temperature for 30 minutes. The mixture was extracted with dichloromethane (DCM, 3 × 40 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (20 mL) and water (2 × 20 mL). The resulting solution in DCM containing the crude desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (Compound 1), was concentrated under reduced pressure, and the residue (7.88 g, 8.09 g (theoretical yield)) was used in the subsequent phosphate salt formation reaction without further purification. The free base of Compound 1 obtained by the current synthetic method is identical in all comparable aspects to the product obtained by the procedures listed under Examples 4-5 and the previously reported synthetic method (US Pat. No. 8,410,265 B2). For Compound 1: 1 H NMR(DMSO-d6,400MHz)δ12.10(br.s,1H),8.78(s,1H),8.67(s,1H),8.36(s,1H),7.58(dd,1H,J=2.3,3.4Hz),6.97(dd,1H,J=1.5,3.6Hz), C 17 H 18 N6(MW,306.37),LCMS(EI)m / e 307(M + +H).

[0566] Example 7 Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (chloride of compound 2) using POCl [ka] A solution of phosphorus oxochloride (POCl3, 23.0 g, 14.0 mL, 150 mmol, 2.0 equiv.) in anhydrous acetonitrile (65 mL) was cooled to 0–5 °C in an ice bath. Anhydrous DMF (70.8 g, 70.0 mL, 968 mmol, 12.9 equiv.) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled below 10 °C during the DMF addition. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (the hydrochloride salt of compound 1a, 12.72 g, 75.0 mmol) was charged in one portion as a solid into the in situ generated Vilsmeier reagent at ambient temperature. The resulting slurry was stirred at ambient temperature for 5–10 min to ensure complete mixing, and then warmed to 75–80 °C. The reaction mixture was stirred at 75–80°C for 1 hour and then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (100 mL) was charged, and the resulting slurry was stirred at ambient temperature for 2 hours, followed by 2 hours at 0–5°C. The solid was collected by filtration and washed with a 1:1 mixture of THF and MTBE (2 × 100 mL) to give the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (Compound 2d), as a yellow to brown wet cake. The wet cake was then dissolved in water (120 mL), and the pH of the resulting aqueous solution was adjusted to 7–8 by treatment with 50% aqueous sodium hydroxide (NaOH, 19.06 g) at 0–5°C. The neutralized solution was treated with charcoal (5.5 g) and stirred at ambient temperature for 12 hours. The charcoal was removed by filtration through a Celite bed, and the Celite bed was washed with water (50 mL). The resulting aqueous solution containing the desired product, (£)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (Compound 2c, 99.0% ultrapure by HPLC area %), was used in the subsequent reaction without further treatment.

[0567] Example 8: Synthesis of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (compound 2c) using triphosgene [ka] A solution of triphosgene ((CClO)CO, 37.4 g, 126 mmol, 1.5 equiv.) in anhydrous acetonitrile (73 mL) was cooled to 0–5 °C in an ice bath. Anhydrous DMF (79.0 g, 84 mL, 1083 mmol, 12.9 equiv.) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled below 10 °C during the addition of DMF. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature over 40 min. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (the hydrochloride salt of compound 1a, 14.25 g, 84.0 mmol) was charged in one portion as a solid into the in situ generated Vilsmeier reagent at ambient temperature. The resulting slurry was stirred at ambient temperature for 5–10 min to ensure complete mixing, and then warmed to 80–90 °C. The reaction mixture was stirred at 80-90 °C for 1 h and then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 112 mL) was charged, and the resulting slurry was stirred at ambient temperature for 12 h, followed by 2 h at 0-5 °C. The solid was collected by filtration, washed with a 1:1 mixture of THF and MTBE (2 × 200 mL), and dried under vacuum to constant weight to afford the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (Compound 2c), 28.3 g, 23.5 g (theoretical yield), 98.8% by HPLC area %, 64.9% by HPLC weight %, 78.2% yield, as a yellow to brown amorphous solid containing 19.7% DMF and 0.8% water, which was used in the subsequent reaction without further purification. Regarding compound 2c: 1H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19 Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0568] Example 9: Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium salt [ka] (E)—N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (perchlorate salt of compound 2): To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL), sodium perchlorate (NaClO, 1.933 g, 15.79 mmol, 1.50 equiv.) was added at ambient temperature. After stirring at 20-25 °C for 12 h, the slurry was cooled in an ice bath for 2 h. The solid was filtered, washed with cold HO (3 × 2 mL), and dried under vacuum to give the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (the perchlorate salt of compound 2), as a white solid, which was used in the subsequent reaction without further purification. 1H NMR(400MHz,DMSO-d6)δ12.50-12.17(s,1H),8.94-8.73(s,1H),8.08-7.87(s,2H),7.77-7.57(dd C 13 H 18 ClNO (MW 343.77 for the perchlorate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0569] (E)—N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium tetrafluoroborate (tetrafluoroborate salt of compound 2): To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL) was added sodium tetrafluoroborate (NaBF, 1.733 g, 15.79 mmol, 1.50 equiv.) at ambient temperature. After stirring at 20-25 °C for 12 h, the slurry was cooled in an ice bath for 2 h. The solid was filtered, washed with cold HO (3 × 2 mL), and dried under vacuum to give the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium tetrafluoroborate (the tetrafluoroborate salt of compound 2, 1.80 g, 3.49 g (theoretical), 51.6% yield) as a white solid, which was used in the subsequent reaction without further purification. 1H NMR(400MHz,DMSO-d6)δ12.39-12.34(s,1H),8.85-8.80(s,1H),7.99-7.94(s,2H),7.71-7.65(d d,J=3.4,2.2Hz,1H),6.52-6.46(dd,J=3.5,1.7Hz,1H),3.34-3.29(s,6H),2.38-2.33(s,6H)ppm; 11 B NMR(DMSO-d6,128MHz)δ-1.27ppm; 19 F NMR (DMSO-d6, 376.5 MHz) δ -148.23 and -148.28 ppm; C 13 H 18 BF4N5 (MW, 331.13 for the tetrafluoroborate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0570] (E)—N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluorophosphate (hexafluorophosphate salt of compound 2): To a solution of crude (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (compound 2d, 25.61 g, 91.6 mmol), produced from 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.19 g, 91.6 mmol) via the corresponding Vilsmeier reaction described in Example 1, in water (80 mL) was added aqueous sodium hydroxide (NaOH) at 0-5 °C to adjust the pH of the solution to 7-8. Charcoal (7.69 g) was added to the resulting aqueous solution, and the mixture was stirred at ambient temperature for 2-4 h. The charcoal was removed by filtration through a celite bed, and the wet charcoal cake was washed with water (15 mL). Sodium hexafluorophosphate (NaPF, 20.08 g, 120 mmol, 1.31 equiv.) was then added to the combined aqueous solution at ambient temperature. After stirring at 20–25 °C for 1 h, the slurry was cooled in an ice bath for 30 min. The solid was filtered, washed with cold HO (2 × 25 mL), and dried under vacuum to give the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluorophosphate (hexafluorophosphate salt of compound 2, 24.30 g, 35.81 g (theoretical yield), 67.9% yield, 98.7% by HPLC area %), as a white crystalline solid, which was used in the subsequent reaction without further purification. The crude hexafluorophosphate salt of compound 2 can be purified by recrystallization from water to give the pure product as a white crystalline solid. For the hexafluorophosphate salt of compound 2: 1 H NMR(500MHz,DMSO-d6)δ12.36(s,1H),8.83(s,1H),7.97(br s,2H),7.68(dd,J=3.2,2.6Hz,1H),6.48(dd,J=3.4,1.8Hz,1H),3.32(s,6H),2.36(br s,6H)ppm; 13 C NMR(125MHz,DMSO-d6)δ163.7,152.9,151.4,151.0,128.9,120.7,101.5,99.8,48.9,40.0ppm; 19F NMR(DMSO-d6,470.6MHz)δ-70.2(d, 1 J(PF) = 711.1Hz) ppm; 31 P NMR(DMSO-d6,162MHz)δ-144.19(septet, 1 J(PF)=711Hz)ppm.C 13 H 18 F6N5P (MW, 389.29 for the hexafluorophosphate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak). The crystallinity of the hexafluorophosphate salt of compound 2 was characterized by XRPD, DSC, and TGA.

[0571] X-ray Powder Diffraction (XRPD): X-ray powder diffraction (XRPD) data were obtained using a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: start angle 3 degrees, stop angle 30 degrees, sampling 0.015 degrees, and scan rate 2 degrees / min. The hexafluorophosphate salt of compound 2 was confirmed to be a crystalline solid by XRPD analysis. The XRPD pattern of the hexafluorophosphate salt of compound 2 is shown in Figure 7, and the peak data are provided in Table 3. [Table 3]

[0572] Differential Scanning Calorimetry (DSC): DSC data were obtained from a TA Instruments Differential Scanning Calorimeter, Discovery DSC2500, equipped with an autosampler. DSC instrument conditions were as follows: 20-300 °C at 10 °C / min, Tzero aluminum sample pan and lid, and a nitrogen gas flow rate of 50 mL / min. DSC analysis of a crystalline sample of the hexafluorophosphate salt of compound 2 revealed one endothermic peak with an onset of 231.7 °C and a maximum of 232.7 °C, attributed to the melting point, and a second endothermic peak with an onset of 241.1 °C and a maximum of 242.1 °C, attributed to decomposition. The DSC thermogram of the hexafluorophosphate salt of compound 2 is provided in Figure 8.

[0573] Thermogravimetric Analysis (TGA): TGA was obtained from a TA Instruments Thermogravimetric Analyzer, Discovery TGA5500, equipped with an autosampler. Typical experimental conditions for TGA were as follows: ramp from 25°C to 300°C at 10°C / min, nitrogen purge gas flow rate of 25 mL / min, platinum sample holder. TGA analysis of a crystalline sample of the hexafluorophosphate salt of compound 2 revealed significant weight loss above 250°C, due to decomposition. The TGA thermogram of the hexafluorophosphate salt of compound 2 is provided in Figure 9.

[0574] (E)—N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluoroarsenate (hexafluoroarsenate salt of compound 2): To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL) was added sodium hexafluoroarsenate (NaAsF, 3.35 g, 15.79 mmol, 1.50 equiv.) at ambient temperature. After stirring at 20-25 °C for 12 h, the slurry was cooled in an ice bath for 2 h. The solid was filtered, washed with cold HO (3 x 2 mL), and dried under vacuum to give the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluoroarsenate (hexafluoroarsenate salt of compound 2, 4.51 g, 4.56 g (theoretical yield), 99% yield) as a white solid, which was used in the subsequent reaction without further purification. For the hexafluoroarsenate salt of compound 2: 1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.83(s,1H),7.97(s,2H),7.76-7.57(t, J=2.9Hz,1H),6.59-6.36(dd,J=3.2,1.8Hz,1H),3.32(s,6H),2.35(s,6H)ppm; 19 F NMR(DMSO-d6,376.5MHz)δ-62.16(quartet, 1 J(AsF)=937.5Hz)ppm;C 13 H 18 F6N5As (MW, 433.23 for the hexafluoroarsenate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0575] (E)—N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluoroantimonate (hexafluoroantimonate salt of compound 2): To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL) was added sodium hexafluoroantimonate (NaSbF, 4.08 g, 15.79 mmol, 1.50 equiv.) at ambient temperature. After stirring at 20-25 °C for 12 h, the slurry was cooled in an ice bath for 2 h. The solid was filtered, washed with cold HO (3 x 2 mL), and dried under vacuum to give the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluoroantimonate (hexafluoroantimonate salt of compound 2, 2.61 g, 5.05 g (theoretical yield), 51.7% yield) as a white solid, which was used in subsequent reactions without further purification. For hexafluoroantimonate salt of compound 2: 1 H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.83(s,1H),7.98(s,2H),7.68(s,1H),6.49(s,1H),3.32(s,6H),2.35(s,6H)ppm; 19 F NMR(DMSO-d6,376.5MHz)δ-166.86ppm;C 13 H 18 F6N5Sb (MW, 480.07 for compound 2 hexafluoroantimonate and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0576] Example 10: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (perchlorate salt of compound 2) Method 1 [ka] Oxalyl chloride (20.0 mL, 228 mmol, 3.04 equiv.) was slowly charged to DMF (107 mL, 1378 mmol, 18.4 equiv.) over 15 minutes, maintaining the internal temperature below 50°C. After the addition, the resulting slurry was cooled to ambient temperature and stirred at ambient temperature for 2 hours. 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1a, 10.0 g, 75 mmol) was added to the slurry at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 16 hours and then at 50°C for 5.5 hours. The reaction mixture was cooled to ambient temperature and quenched with ice (60 g). The quenched reaction mixture was concentrated in vacuo to a residue, which was then dissolved in water (50 mL). Sodium perchlorate (NaClO4, 20.23 g, 165 mmol, 2.2 equiv.) was then added to the aqueous solution at ambient temperature. The resulting mixture was cooled in an ice bath, and then sodium hydroxide (NaOH, 7.5 g, 188 mmol, 2.5 equiv.) was slowly added. The solid was collected by filtration, washed with water (30 mL), and dried under vacuum to give the crude desired product, (£)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (the perchlorate salt of compound 2, 18.7 g, 25.78 g (theoretical yield), 72.5% yield), as a gray solid, which was used in the subsequent reaction without further purification. 1 H NMR(400MHz,DMSO-d6)δ12.50-12.17(s,1H),8.94-8.73(s,1H),8.08-7.87(s,2H),7.77-7.57(dd C 13 H 18 ClNO (MW 343.77 for the perchlorate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0577] Method 2 [ka] To a solution of 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetic acid (compound 5a, 354 mg, 2.0 mmol) in anhydrous DMF (2.92 g, 3.1 mL, 40 mmol, 20 equiv.) was added phosphorus oxychloride (POCl3, 920 mg, 0.56 mL, 6.0 mmol, 3.0 equiv.) at ambient temperature. The resulting reaction mixture was then warmed to 80-90 °C and stirred at 80-90 °C for 30 min. Upon completion of the reaction, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was quenched by pouring it into ice (10 g). The solution was then concentrated under reduced pressure, and the resulting residue was treated with water (3 mL). The aqueous solution was neutralized to pH 7-8 with aqueous NaOH and then treated with activated carbon (50 mg). The mixture was stirred at ambient temperature for 30 min and then filtered through a celite bed. The celite bed was washed with water (2 mL). The combined filtrate and washings were then treated with solid sodium perchlorate (NaClO4, 367 mg, 3.0 mmol, 1.5 equiv.) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour, followed by 1 hour at 0-5 °C. The solid was then collected by filtration, washed with water (2 × 2 mL), and dried under vacuum to give the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (the perchlorate salt of compound 2), 330 mg, 688 mg (theoretical yield, 48%), as a gray solid, which was used in the subsequent reaction without further purification. For the perchlorate salt of compound 2: 1 H NMR(400MHz,DMSO-d6)δ12.50-12.17(s,1H),8.94-8.73(s,1H),8.08-7.87(s,2H),7.77-7.57(dd C 13 H 18 ClNO (MW 343.77 for the perchlorate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0578] Method 3 [ka] To a solution of sodium 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 5b, 1.70 g, 8.54 mmol) in anhydrous DMF (12.48 g, 13.2 mL, 171 mmol, 20 equiv.) was added phosphorus oxychloride (POCl3, 3.93 g, 2.4 mL, 25.6 mmol, 3.0 equiv.) at ambient temperature. The resulting reaction mixture was then warmed to 80-90 °C and stirred at 80-90 °C for 30 min. Upon completion of the reaction, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was quenched by pouring it into ice (40 g). The solution was then concentrated under reduced pressure, and the resulting residue was treated with water (10 mL). The aqueous solution was neutralized to pH 7-8 with aqueous NaOH and then treated with activated carbon (200 mg). The mixture was stirred at ambient temperature for 30 min and then filtered through a bed of Celite. The Celite bed was washed with water (5 mL). The combined filtrate and washings were then treated with solid sodium perchlorate (NaClO4, 1.57 g, 12.8 mmol, 1.5 equiv.) at ambient temperature. The mixture was stirred at ambient temperature for 1 h, followed by 1 h at 0–5 °C. The solid was then collected by filtration, washed with water (2 × 5 mL), and dried under vacuum to give the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium perchlorate (the perchlorate salt of compound 2, 1.3 g, 2.94 g (theoretical yield), 44.3% yield), as an off-white solid, which was used in the subsequent reaction without further purification. 1 H NMR(400MHz,DMSO-d6)δ12.50-12.17(s,1H),8.94-8.73(s,1H),8.08-7.87(s,2H),7.77-7.57(dd C 13 H 18ClNO (MW 343.77 for the perchlorate salt of compound 2 and 244.32 for compound 2 without the anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0579] Example 11: Preparation of 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonaldehyde ((E)-3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde (Compound 2b) [ka] Oxalyl chloride (12.00 ml, 137 mmol, 3.64 equiv.) was added dropwise to DMF (50 mL, 646 mmol, 17.18 equiv.) while maintaining the internal temperature below 50°C. The resulting mixture was stirred at ambient temperature for 30 minutes. 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1a, 5.00 g, 37.6 mmol) was added as a solid in one portion, and the resulting reaction mixture was stirred at room temperature for 3 days and at 50°C for 4 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature and quenched with ice (30 g). Sodium hydroxide (NaOH, 16.1 g, 403 mmol, 10.72 equiv.) was added to the quenched reaction mixture, and the mixture was stirred at room temperature for 26 hours. Additional sodium hydroxide (NaOH, 2.2 g, 55.0 mmol, 1.46 equiv.) was added, and the mixture was stirred at 40 °C for 4 h. Once the hydrolysis reaction was complete, the mixture was cooled to 0-5 °C in a batch of ice, and then concentrated HCl solution was added to adjust the pH to 5-6. The mixture was gradually warmed to ambient temperature and stirred at ambient temperature for 2 h. The solid was collected by filtration, washed with cold water, and dried under vacuum to afford the crude desired product, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonaldehyde ((E)-3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde (compound 2b, 6.33 g, 7.113 g (theoretical yield), 89%), as a gray powder, which was used directly in the subsequent reaction without further purification. For compound 2b: 1H NMR(400MHz,DMSO-d6)δ13.74(br s,2H),9.52(s,2H),8.73(s,1H),7.53(dd,J=3.4,2.3Hz,1H),7.46(dd,J=3.5,1.7Hz,1H)ppm;C9H7N3O2(MW,189.17)LCMS(EI)m / e 190.1(M + , base peak).

[0580] Example 12. Preparation of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (Compound 3a) [ka] Step 1: 3-Cyclopentyl-3-hydrazinylpropanenitrile (Compound 7a): A 20 L reaction vessel was charged with (E)-3-cyclopentylacrylonitrile (compound 6a, 1040 g, 8.582 mol, 1.0 equiv.) and cooled in an ice bath under a nitrogen atmosphere. Hydrazine hydrate (902 g, 18.0 mol, 2.1 equiv.) was slowly added to the reaction vessel over 40 minutes while controlling the reaction temperature between 0 and 5°C. The reaction mixture was then stirred at ambient temperature between 18 and 22°C for 24 to 30 hours. Upon completion of the reaction, the reaction mixture was diluted with DCM (2080 mL) and brine (1040 mL). The resulting biphasic mixture was stirred for 10 minutes to ensure mixing. The organic layer was then separated and collected. The aqueous layer was extracted once more with DCM (1040 mL). The combined organic layers were evaporated under vacuum. The crude desired product, 3-cyclopentyl-3-hydrazinylpropanenitrile (compound 7a), was obtained as a pale yellow gel, which was used directly in the next step without further purification. 1 H NMR(DMSO-d6,400MHz)δ3.45(br,3H),2.79(dd,J=16.8,4.6Hz,1H),2.56(dd,J=16.8,4.6Hz,1H),2.4 9(dt,J=8.9,4.5Hz,1H),1.94-1.65(m,3H),1.62-1.44(m,4H),1.21(dtt,J=20.6,8.3,4.6Hz,2H)ppm; 13C NMR(DMSO-d6,101MHz)δ119.90,64.03,42.22,29.71(29.75,29.67),25.36(25.43,25.29),20.04ppm;C8H 15 N3(MW,153.23),LCMS(EI)m / e 154.2(M + +H).

[0581] Step 2. (R)-3-Cyclopentyl-3-hydrazinylpropanenitrile (2R,3R)-2,3-dihydroxysuccinate dihydrate (compound 3a): A solution of crude 3-cyclopentyl-3-hydrazinylpropanenitrile (compound 7a, 1315 g, 8.582 mol, 1.0 equiv.) in a 1:1 (volume to volume) mixture of water and acetonitrile (3.29 L) was slowly added to a solution of L-tartaric acid (1417 g, 9.44 mol, 1.1 equiv.) in a 1:1 (volume to volume) mixture of water and acetonitrile (9.86 L) over 1 to 1.5 h. The reaction mixture was protected under nitrogen while the reaction temperature was controlled below 25 °C using a water bath. When 42–43% of the solution of 3-cyclopentyl-3-hydrazinylpropanenitrile (compound 7a) had been added, the reaction mixture was seeded with the desired (R)-3-cyclopentyl-3-hydrazinylpropanenitrile (2R,3R)-2,3-dihydroxysuccinate dihydrate (compound 3a, 0.03–0.05 wt%) solid. After seeding, the reaction mixture was stirred for 10 minutes to ensure the seeds were not dissolved. The remaining portion of the solution of 3-cyclopentyl-3-hydrazinylpropanenitrile (compound 7a) was then slowly added to the reaction mixture within 0.5–1 hour. The resulting reaction mixture was stirred at ambient temperature for 2 hours and then slowly cooled to -2°C–2°C over a 2-hour period. After stirring at -2°C–2°C for an additional 2 hours, the solid was isolated. The wet solid cake was washed three times with a mixture of 5% v / v water in acetonitrile (2 L each time). After drying the solid by passing air through it for 24 hours, the desired product, (R)-3-cyclopentyl-3-hydrazinylpropanenitrile (2R,3R)-2,3-dihydroxysuccinate dihydrate (compound 3a), was obtained as a white crystalline solid (1177 g, 40.4% over two steps). 1 H NMR(D2O,400MHz)δ4.79(br,11H),4.54(s,2H),3.26(dt,J=9.1,4.5Hz,1H),3.11-2.87(m ,2H),2.12(h,J=9.2Hz,1H),1.92-1.88(m,2H),1.71-1.62(m,4H),1.38-1.25(m,2H)ppm; 13C NMR(D2O,101MHz)δ176.36,118.37,72.82,60.15,41.01,29.06(29.11,29.01),24.69(24.85,24.53),19.31ppm;C 12 H 25 N3O8(MW,339.35),C8H 15 N3 (153.23, MW for free base), LCMS (EI) m / e 154.2 (M + +H); Chiral purity (er, R:S) = 99.71:0.29; KF = 9.98; Salt ratio = 1 (acid:base = 1:1).

[0582] Optional reslurry purification of compound 3a to improve chiral purity: To a reaction vessel was added (R)-3-cyclopentyl-3-hydrazinylpropanenitrile (2R,3R)-2,3-dihydroxysuccinate dihydrate (Compound 3a, 20 g, 1.0 equivalent) and 10% aqueous acetonitrile (water to acetonitrile = 1:9 by volume, 200 mL). The reaction mixture was stirred at ambient temperature. After 16 hours, the reaction mixture was filtered and the solid collected. The wet solid cake was washed twice with 5% aqueous acetonitrile (water to acetonitrile = 5:95 by volume, 40 mL each time). The solid was dried by passing air through it for 24 hours to obtain the purified product, (R)-3-cyclopentyl-3-hydrazinylpropanenitrile (2R,3R)-2,3-dihydroxysuccinate dihydrate (Compound 3a), as a white crystalline solid. The structure and absolute stereochemistry of compound 3a were also confirmed by single crystal x-ray crystallography (FIGS. 10A and 10B).

[0583] Single crystal x-ray data: C6 H12.50 N1.50 O4, derived from water, colorless rectangular plate, approximately 0.240 x 0.180 x 0.020 mm, monoclinic, P21, a = 7.6791(5) Å, b = 7.5988(5) Å, c = 13.7174(8) Å, beta = 96.941(2)°, volume = 794.57(9) Å 3 , Z=4, T=-173.℃, formula weight=169.67, density=1.418g / cm 3 , μ(Cu)=1.02mm-1 .

[0584] Single crystal x-ray data collection: Photon II detector, Bruker D8 Venture with Cu microsource, wavelength = 1.5418, anode power = 50.0 kV x 1.1 mA, crystal-to-plate distance = 2.7 cm, 768 x 1024 pixels / frame, beam center = (381.11, 510.89), total frames = 5679, oscillation / frame = 0.00°, exposure / frame = variable, SAINT integral, hkl min / max = (-9, 9, -9, 8, -16, 16), data input to shelx = 19514, unique data = 3003, 2-theta range = 6.49 to 144.58°, completeness for 2-theta 144.58 = 99.80%, R(int-xl) = 0.0416, SADABS correction applied.

[0585] Elucidation and refinement: The structure was solved using XS (Shelxtl) and refined using the shelxtl software package. 2 Full matrix least squares refinement for, scattering factors from Tables 4.2.6.8 and 6.1.1.4 in Int.Tab.Vol C, number of data = 3003, number of suppressions = 1, number of parameters = 308, data / parameter ratio = 9.75, F 2 Goodness of fit for = 1.06, R-index [I > 4 sigma (I)] R1 = 0.0245, wR2 = 0.0586, R-index (all data) R1 = 0.0256, wR2 = 0.0592, maximum difference between peaks and holes = 0.250 and -0.137 e / Å 3 , refined Flack parameter = 0.08 (5), all of the hydrogen atoms are idealized using the riding model.

[0586] Single-crystal x-ray studies determined that the asymmetric unit contains one C8N3H16 molecule [+1], one L-tartaric acid [-1], and two water molecules, as shown in Figures 10A and 10B, along with thermal ellipsoids plotted at the 50% probability level. The predicted structure is confirmed. The enantiomer assignment was based on the chirality of the L-tartrate salt and a refined Flack parameter of 0.08 (5). This study determined the absolute configuration of the chiral center C1=R.

[0587] The crystallinity of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (Compound 3a) was characterized by XRPD, DSC, and TGA. X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) data were obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: a start angle of 3 degrees, a stop angle of 30 degrees, a sampling angle of 0.015 degrees, and a scan rate of 2 degrees / min.

[0588] The (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (Compound 3a) obtained by the above method was confirmed to be a crystalline solid by XRPD analysis. The XRPD pattern of the crystalline sample of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (Compound 3a) is shown in Figure 11, and the peak data are provided in Table 4. [Table 4]

[0589] Differential Scanning Calorimetry (DSC): DSC data were obtained from a TA Instruments Differential Scanning Calorimeter, Discovery DSC2500, equipped with an autosampler. DSC instrument conditions were as follows: 20-300 °C at 10 °C / min, Tzero aluminum sample pan and lid, and a nitrogen gas flow rate of 50 mL / min. DSC analysis of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a) revealed one endothermic peak with an onset temperature of 55.3 °C and a maximum of 79.1 °C, due to dehydration, and a second exothermic peak with an onset temperature of 121.0 °C and a maximum of 123.5 °C. A DSC thermogram of a crystalline sample of compound 3a is provided in Figure 12.

[0590] Thermogravimetric analysis (TGA): TGA was obtained from a TA Instruments thermogravimetric analyzer, Discovery TGA5500, equipped with an autosampler. General experimental conditions for TGA were as follows: ramp from 25 to 300 °C at 10 °C / min, nitrogen purge gas flow rate of 25 mL / min, platinum sample holder. TGA analysis of a crystalline sample of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dehydrate (compound 3a) revealed a weight loss of 10.3% below 100 °C, attributed to dehydration decomposition above 120 °C. The TGA thermogram of a crystalline sample of compound 3a is provided in Figure 13.

[0591] Example 13: Preparation of the phosphate salt of Compound 1 Crude (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate (crude phosphate salt of compound 1): [ka] A solution of crude (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile (compound 1 free base, 18.7 g, 17.1 g (theoretical yield), 55.8 mmol) produced from the previous process step in dichloromethane (DCM, 294 mL) and isopropanol (IPA, 12.8 mL) was heated to 36 °C, and then a solution of phosphoric acid (85% aqueous HPO, 7.40 g, 64.2 mmol, 1.15 equiv.) in isopropanol (IPA, 12.7 mL) was added at 36 °C. A precipitate formed almost immediately. The resulting mixture was then heated at 36 °C for 1 hour, then gradually cooled to ambient temperature, and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with DCM (2 x 50.8 mL) and n-heptane (22.6 mL), and dried to constant weight in a vacuum oven at 40-45 °C to afford (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate (crude phosphate salt of Compound 1, 23.04 g, 22.56 g (theoretical yield), 102% yield) as a white to off-white crystalline powder containing some residual phosphoric acid, which was purified in a subsequent step by recrystallization in a mixture of methanol (MeOH), isopropanol (IPA), and n-heptane. For the phosphate salt of Compound 1: 1 H NMR(DMSO-d6,500MHz)d ppm 12.10(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); 13C NMR(DMSO-d6,125MHz)d ppm 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 for free base) LCMS (EI) m / e 307 (M + +H, base peak), 329.1 (M + +Na).

[0592] Purification of crude Compound 1 phosphate: [ka] (3R)-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate (phosphate salt of compound 1) A suspension of crude compound 1 phosphate salt (40.0 g, 100 mmol) in methanol (MeOH, 520 mL) is heated to 50-60 °C to produce a homogeneous solution. The solution is polish filtered at 50-60 °C. Methanol (287 mL) is partially distilled at 60-70 °C at atmospheric pressure, and then IPA (320 mL) is added to the mixture at the same temperature to initiate crystallization of the final product (compound 1 phosphate salt). n-Heptane (1000 mL) is then added to the mixture at 60-70 °C, and distillation is continued at 60-70 °C at atmospheric pressure. Once distillation is complete, the mixture is stirred at 60-70 °C for 10-60 minutes, then gradually cooled to room temperature and stirred at room temperature for 3-6 hours. The solid is collected by filtration, washed successively with a mixture of IPA and n-heptane, and n-heptane, and dried under vacuum at 40-50°C to obtain the final product (compound 1 phosphate salt, 39.4 g, 98.5%) as a white crystalline powder. For compound 1 phosphate salt: mp. 197.6°C; 1H NMR(DMSO-d6,500MHz)δ ppm 12.10(s,1H),8.78(s,1H),8.68(s,1H),8.36(s1H),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),3.16(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)δ ppm 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 for free base) LCMS (EI) m / e 307 (M + +H, base peak), 329.1 (M + +Na).

[0593] Example 14: Preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Compound 12a) [ka] Step 1. 4,6-Dichloropyrimidine-5-carbaldehyde (compound 9a): In a 5 L four-neck flask equipped with a mechanical stirrer, addition funnel, condenser, thermocouple, and a N2 sweep through the aqueous NaOH scrubbing solution, phosphorus oxychloride (POCl3, 1 L, 10.572 mol, 4.82 equiv.) was charged and cooled in an ice / salt bath. N,N-dimethylformamide (DMF, 320 mL, 4.138 mol, 1.85 equiv.) was then added dropwise to the flask at 0 ± 2 °C. After approximately 100 mL of DMF was added over approximately 0.5 h, crystallization occurred and the reaction temperature increased from 0 to 10 °C. The addition was stopped, and the mixture was allowed to cool again to approximately 2 °C. The remaining DMF was added over 2.5 h at below 8 °C. The suspension became very thick and difficult to stir. When the DMF addition was complete, the mixture was stirred at 3–5 °C for 0.5 h. 4,6-Dihydroxypyrimidine (compound 8a, 250 g, 2.232 mol) was added portionwise as a solid. After approximately one-third of the 4,6-dihydroxypyrimidine was added, the reaction mixture became more fluid, and a slow exotherm occurred, increasing the reaction temperature to approximately 12 °C over 0.5 h. The remaining 4,6-dihydroxypyrimidine was added portionwise over 0.25 h, increasing the reaction temperature from 12 °C to 27 °C. The reaction temperature was maintained at 25–27 °C with intermittent cooling, during which time the yellow suspension became thinner and then thicker again. After the exotherm subsided in approximately 1 h, the reaction mixture was slowly heated. At approximately 55 °C, the reaction mixture became very thick and a second mild exotherm occurred. The heating mantle was removed, but the reaction temperature continued to increase to approximately 63 °C, where it remained for several minutes before decreasing. Heating of the mixture resumed, eventually achieving a gentle reflux (approximately 100 °C). At approximately 95°C, a steady and fairly rapid evolution of HCl gas began, and the reaction mixture gradually became thinner and darker. After approximately 0.5 h, a clear brown solution developed, and the reflux temperature slowly increased to 115°C over 1.25 h. After a total of 2.5 h at reflux, the reaction mixture was cooled to ambient temperature and stirred at ambient temperature overnight. The excess POCl3 (as much as possible) was removed under reduced pressure (bath temperature 45-50°C).The remaining thick brown oil was very slowly poured into cold HO (5 L) in a 20 L separatory funnel, adding ice as needed to maintain the aqueous mixture near room temperature. The aqueous mixture was extracted with EtOAc (2 × 3 L, followed by 1 × 2 L). The combined EtOAc extracts were washed with HO (2 × 2.5 L), saturated aqueous NaHCO (1 L), brine (1 L), dried over NaSO, filtered, and concentrated under reduced pressure (35 °C bath temperature) to give crude 4,6-dichloropyrimidine-5-carbaldehyde (compound 9a, 270 g, 395 g (theoretical yield), 68.4%) as a yellow-orange solid. A 20 g portion of this crude material was purified by Kugelrohr distillation (90-100 °C oven temperature, 225 mTorr) to give 15.3 g of pure 4,6-dichloropyrimidine-5-carbaldehyde (compound 9a) as a white solid that turned yellow on standing at room temperature. 1 H NMR(300MHz,CDCl3)δ10.46(s,1H),8.89(s,1H)ppm.

[0594] Step 2. 4-Amino-6-chloropyrimidine-5-carbaldehyde (compound 10a): A solution of 7 M NH in MeOH (265 mL, 1.855 mol, 2.0 equiv.) was added to a solution of 4,6-dichloropyrimidine-5-carbaldehyde (compound 9a, 163.7 g, 0.9301 mol) in toluene (3 L) at ambient temperature over 1.25 h. The reaction temperature slowly increased from 20 to 26 °C, and a yellow suspension formed. Gentle cooling was applied to maintain the reaction temperature below 26 °C. The suspension was stirred at ambient temperature for 3.5 h, and then the solid was collected by filtration. The solid was washed with EtOAc (1 L). The filtrate was concentrated under reduced pressure, and the solid was triturated with toluene and n-heptane (2:1 v / v, 600 mL), filtered, and dried to give 71.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde as a yellow solid. The original solid filtered from the reaction mixture contained an additional amount of 4-amino-6-chloropyrimidine-5-carbaldehyde. The product was extracted from the filtered solid by stirring in EtOAc (1.25 L) for 1.5 hours, filtering, and then stirring in THF (750 mL) for 1 hour and filtering. Both the EtOAc and THF filtrates were concentrated under reduced pressure, and the resulting solid was triturated with toluene and n-heptane (2:1 v / v, 450 mL), filtered, and dried to give an additional 44.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde as a yellow solid. The combined yield of 4-amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 146.5 g (theoretical yield)) was 78.6%. For 4-amino-6-chloropyrimidine-5-carbaldehyde: 1 HNMR(300MHz,DMSO-d6)δ10.23(s,1H),8.71(bs,1H),8.55(bs,1H),8.39(s,1H)ppm;C5H4ClN3O(MW,157.56),LCMS(EI)m / e 158(M + +H).

[0595] Step 3. 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (compound 11a): A suspension of (methoxymethyl)triphenylphosphonium chloride (276.0 g, 0.807 mol, 1.1 equiv.) in THF (1.5 L) was cooled to −2 °C in an ice / salt bath and 1 M potassium tert-butoxide (KO) in THF (807 mL, 0.807 mol, 1.1 equiv.) was added. tBu) was added over 1.5 h at −2 to −3 °C. The deep reddish-orange mixture was stirred at −2 to −3 °C for 1 h. 4-Amino-6-chloropyrimidine-5-carbaldehyde (Compound 10a, 115.2 g, 0.7338 mol, 1.0 equiv.) was then added portionwise to the reaction mixture as a solid using THF (200 mL) to rinse the vessel and funnel. During the addition, the reaction temperature increased from −3 to 13 °C, and a brown color developed. When the reaction temperature dropped to 10 °C, the cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 42 h. The reaction mixture was cooled to −2 °C and then quenched by the slow addition of saturated aqueous NH₄Cl (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and HO (1 L). The organic phase was filtered to remove insoluble material at the interface and then extracted with 2 N HCl (4 × 250 mL) followed by 3 N HCl (2 × 250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) and then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice / brine bath, adjusted to pH 8 with 6 N aqueous NaOH, and extracted with EtOAc (3 × 1 L). The combined EtOAc extracts were washed with brine (1 L), dried over NaSO, and stirred with charcoal (10 g) and silica gel (10 g) for 1 h. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, and the residual EtOAc was co-evaporated with n-heptane (500 mL). The resulting brown solid was pumped under high vacuum for 2 hours to give crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (Compound 11a, 72.3 g, 136.2 g (theoretical yield), 53.1%). The crude desired product Compound 11a was used in the subsequent reaction without further purification. A sample of crude product Compound 11a (2.3 g) was purified by silica gel column chromatography, eluting with 0% to 35% EtOAc / n-heptane, to give 1.7 g of pure 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (Compound 11a) as a white solid, which was found to be a 1:2 mixture of E / Z isomers.For 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine: 1 H NMR (300 MHz, DMSO-d) for E isomer: δ 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J = 13.1), 5.35 (d, 1H, J = 13.0 Hz), 3.68 (s, 3H) ppm and for Z isomer: δ 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J = 6.8 Hz), 5.02 (d, 1H, J = 6.7 Hz), 3.69 (s, 3H) ppm; C7H8ClNO3 (MW, 185.61), LCMS (EI) m / e 186 / 188 (M + +H).

[0596] Step 4. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a): Concentrated aqueous hydrochloric acid (HCl, 5 mL) was added to a solution of crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (Compound 11a, 70.0 g, 0.3784 mol) in THF (700 mL), and the resulting reaction mixture was heated to reflux for 7.5 hours. Upon warming, a light suspension formed, which gradually redissolved. When the reaction was deemed complete as monitored by HPLC, the reaction mixture was cooled to ambient temperature and stirred at ambient temperature overnight. Solid NaHCO3 (15 g) was added to the reaction mixture, and the resulting mixture was stirred at ambient temperature for 1 hour. Charcoal (7 g), silica gel (7 g), and Na2SO4 (20 g) were added, and the mixture was heated to 40 °C for 1 hour. The mixture was then cooled to ambient temperature and filtered through Celite, washing the Celite pad with THF (1 L). The filtrate was concentrated under reduced pressure, and the resulting solid was dried under reduced pressure to give crude 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 58.1 g, 58.1 g (theoretical yield), 100%) as a tan solid. The crude desired product, compound 12, was dissolved in EtOAc (1.0 L) at 50-55 °C and treated with activated charcoal (3 g). The mixture was filtered warm through Celite, and the Celite pad was washed with warm EtOAc (250 mL). The filtrate was concentrated to approximately 500 mL, and the suspension was allowed to stand overnight at ambient temperature. The suspension was then cooled to 0-5 °C for 2 h, and the solid was collected by filtration. The solid was dried to give pure 4-chloro-7H-[pyrrolo[2,3-d]pyrimidine (compound 12a, 54.5 g, 58.1 g (theoretical yield), 94%) as tan crystals. Regarding compound 12a: 1 H NMR(400MHz,DMSO-d6)δ12.58(bs,1H),8.58(s,1H),7.69(d,1H,J=3.5Hz),6.59(d,1H,J=3.5Hz)ppm;LCMS(EI)m / e 154 / 156(M + +H).

[0597] Example 15: Alternative preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) [ka] Step 1. Ethyl 2-cyano-4,4-diethoxybutanoate (compound 14a): To a mixture of ethyl cyanoacetate (compound 13a, 182 kg, 1609 mol) and DMSO (325 kg) was added sodium tert-amyloxide ( t AmONa (158.8 kg) was added in small portions at 5°C. The mixture was then warmed to 70-75°C, and ethyl cyanoacetate (191 kg, 1689 moles, total 3298 moles, 5.0 equivalents) was charged. The mixture was stirred at 70-75°C for 30 minutes, after which bromoacetaldehyde diethyl acetal (130.4 kg, 665.2 moles) was added. The resulting reaction mixture was then heated to 90°C and stirred at 90°C until the reaction was complete. The reaction mixture was cooled to 5°C, and 16% aqueous ammonium chloride (NH4Cl) solution was added. The mixture was stirred for 30 minutes, and then ethyl acetate (490 kg) was charged. The organic phase was separated and washed with water (695 kg). The aqueous phase was extracted with ethyl acetate (455 kg). The combined organic phase was washed with 17% aqueous sodium chloride (NaCl, 318 kg) and brine (325 kg). The organic solution was dried over sodium sulfate (NaSO) and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in petroleum ether (390 kg) and treated with charcoal at 60°C. The mixture was filtered, and the filtrate was concentrated to dryness to give crude ethyl 2-cyano-4,4-diethoxybutanoate (compound 14a, 146.6 kg, 152.5 kg (theoretical yield), 96.1%) as a yellow to brown oil, which was used directly in the subsequent reaction without further purification.

[0598] Step 2. 7H-Pyrrolo[2,3-d]pyrimidin-4-ol (compound 15a): A reactor was charged with 1558 kg of an 18% solution of sodium ethoxide (EtONa) in ethanol and formamidine acetate (153.5 kg, 1474.4 mol). The mixture was stirred at ambient temperature for 1 hour, and then ethyl 2-cyano-4,4-diethoxybutanoate (14a, 269.8 kg, 1176.7 mol, 1.25 equivalents) was charged. The reaction mixture was heated to 75 °C and stirred at 75 °C until no unreacted ethyl 2-cyano-4,4-diethoxybutanoate (14) was detected. The mixture was cooled to 0 °C and charged with 21% aqueous ammonium chloride solution (NH4Cl, 783 kg). The resulting mixture was stirred at 0 °C for 30 minutes and concentrated under reduced pressure. The remaining solution was cooled to 20-30 °C and filtered. The cake was reslurried with water (493 kg) and filtered. The solid was suspended in water (474 ​​kg) and concentrated hydrochloric acid (HCl, 89.2 kg) was added. The mixture was stirred at 20°C for 1 hour and then warmed to 30°C until the cyclization reaction was complete. The mixture was then cooled to 5°C and an aqueous solution of ammonium hydroxide (NHOH, 72 kg) was added. After the addition, the mixture was stirred at 5°C for 1 hour and then filtered. The wet cake was washed with water and dried in a vacuum oven to give 7H-pyrrolo[2,3-d]pyrimidin-4-ol (compound 15a, 99.6 kg, 159 kg (theoretical yield), 62.6%) as an off-white to yellow solid, which was used in the subsequent reaction without further purification.

[0599] Step 3. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a): 7H-Pyrrolo[2,3-d]pyrimidin-4-ol (compound 15a, 99.6 kg, 737 mol) was added to a solution of DIEA (128.4 kg, 99.53 mol, 1.35 eq) in toluene (500 kg) at ambient temperature, and the resulting mixture was cooled to 0 °C. POCl (338 kg, 2202 mol, 3.0 eq) was then added to the mixture at 0 °C, and the resulting reaction mixture was heated to 70 °C and stirred at 70 °C until the reaction was complete. The reaction mixture was cooled to 30 °C, and water (3500 kg), sodium carbonate (NaCO, 700 kg), and 2-methyltetrahydrofuran (MeTHF, 1200 kg) were added. The resulting mixture was then filtered. The organic phase of the filtrate was separated, washed with brine (424 kg), dried over sodium sulfate (NaSO), and filtered. The filtrate was concentrated to remove approximately 1000 kg of MeTHF. The remaining solution was treated with charcoal (28 kg) at 60° C. for 1 hour and filtered. The filtrate was concentrated to a thick slurry, cooled to 0° C., and filtered. The cake was dried under reduced pressure to give pure 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 71.9 kg, 113.2 kg (theoretical yield), 63.5%) as yellow to brown crystals. The 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) produced by this synthetic method is identical in all comparable respects to the compound obtained by Example 14. 1 H NMR(400MHz,DMSO-d6)δ12.58(bs,1H),8.58(s,1H),7.69(d,1H,J=3.5Hz),6.59(d,1H,J=3.5Hz)ppm;LCMS(EI)m / e 154 / 156(M + +H).

[0600] Example 16. Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1a) [ka] A suspension of sodium hydride (NaH, 60% suspension in mineral oil, 309, 7726 mmol, 1.211 equiv.) in THF (4.0 L) was cooled to 0-5 °C in an ice bath before 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Compound 12a, 980.0 g, 6381 mmol) was added. The mixture was stirred at 0-15 °C for 30 min, and then a solution of TBDMS-Cl (1165 g, 7728 mmol, 1.211 equiv.) in THF was added at 0-15 °C. The resulting mixture was stirred at 0-15 °C for 1-2 h. The mixture was cooled to -10 °C and iron(III) acetylacetonate (Fe(acac)3, 113 g, 319 mmol, 0.05 equiv.) was added. A solution of methylmagnesium bromide in THF (3260 mL, 9780 mmol, 1.53 equiv.) was slowly charged to the mixture, controlling the internal temperature below 15 °C. The resulting reaction mixture was stirred at 15–30 °C for 2 h. Upon completion of the coupling reaction, the reaction mixture was quenched by charging an aqueous solution of ammonium chloride (NH4Cl, 8.0 L), controlling the internal temperature below 10 °C during the quenching. Methyl tert-butyl ether (MTBE, 5.0 L) was charged to the quenched reaction mixture, and the resulting mixture was filtered through a Celite bed. The Celite bed was washed with MTBE (2 × 500 mL). The two phases of the combined filtrate and washings were separated, and the aqueous phase was extracted with MTBE (2 × 5.0 L). The combined organic extracts were concentrated under reduced pressure, and the residue was dissolved in methanol (MeOH, 5.0 L). The solution was then treated with 26-28% aqueous ammonium hydroxide (NHOH, 1.0 L), and the resulting mixture was stirred at 15-40 °C for 16 h. Upon completion of the N-TBDMS deprotection reaction, the reaction mixture was concentrated under reduced pressure and charged with n-heptane (2 × 4.0 L) to remove water under azeotropic conditions. The residue was then treated with n-heptane (8.0 L), and the resulting mixture was stirred at ambient temperature for at least 1 h. The solid was collected by filtration and washed with n-heptane (2 × 1.0 L) to afford the crude desired product, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1a, 840 g, 849.6 g (theoretical yield), 98.9%), as a brown powder, which was purified by recrystallization in a mixture of ethyl acetate and n-heptane.

[0601] A solution of crude methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 1640 g) in methanol (MeOH, 8.0 L) was treated with charcoal (2.0 kg), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was filtered through a Celite bed, and the Celite bed was washed with MeOH (2 x 8.0 L). The combined methanol solution was concentrated under reduced pressure, and ethyl acetate (8.0 L) was added to the residue. The resulting solution was concentrated under reduced pressure to remove most of the ethyl acetate (approximately 6.0 L), and then n-heptane (8.0 L) was introduced. The resulting mixture was stirred at ambient temperature for 14 hours. The solid was collected by filtration, washed with a mixture of ethyl acetate and n-heptane, followed by n-heptane, and dried to a constant weight to give purified methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 1325 g, 1640 g (theoretical yield), 80.8% purified by recrystallization and 80% overall) as a yellow to light brown crystalline powder. For compound 1a: 1 H NMR (DMSO-d6,500MHz)δ12.10(br s,1H),8.61(s,1H),7.47(dd,J=3.3,2.5Hz,1H),6.62(s,dd,J=3.5,1.7Hz,1H),2.64(s,3H)ppm; 13 C NMR(DMSO-d6,125MHz)δ158.7,151.3,151.2,126.5,117.6,99.6,21.3ppm;C7H7N3(MW,133.15)LCMS(EI)m / e 134.1(M + +H, base peak).

[0602] Example 17. Alternative Preparation of 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1a) [ka] Step 1. 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a): A cloudy mixture of potassium tert-butoxide (18.31 g, 163 mmol, 2.12 equiv.) in THF (100 mL) was cooled in an ice bath, and then a solution of 4,4-dimethoxybutanenitrile (Compound 16a, 10.00 g, 77 mmol) and ethyl acetate (7.46 g, 85 mmol, 1.1 equiv.) in THF (20 mL) was added over 15 min. The mixture was allowed to warm to room temperature and stirred at ambient temperature for 3 h. The in situ generated 2-acetyl-4,4-dimethoxybutanenitrile was then treated with formamidine acetate (65.0 g, 624 mmol, 8.1 equiv.), 1-butanol (80 mL), and triethyl orthoformate (56.2 mL, 337 mmol, 4.38 equiv.) at ambient temperature. The resulting mixture was heated to 110-120°C and stirred at 110-120°C for 1 hour. Additional triethyl orthoformate (26.5 mL, 159 mmol, 2.06 equiv.) was added. The mixture was stirred at 110°C for an additional 16 hours. Additional formamidine acetate (31.38 g, 302 mmol, 3.92 equiv.) and triethyl orthoformate (56.5 mL, 115 mmol, 1.5 equiv.) were added in three portions over 24 hours. The mixture was heated for an additional 24 hours and concentrated to a residue under reduced pressure. The residue was treated with water (150 mL) and MeTHF (210 mL). The resulting mixture was passed through a bed of Celite (12 g). The two phases of the filtrate were separated, and the aqueous phase was extracted with MeTHF (175 mL x 2). The combined organic extracts were concentrated under reduced pressure, and the resulting residue was treated with a solution of HCl in IPA (5.5 M, 50.8 g), water (31 mL), and concentrated HCl (12 M, 15.6 g). The mixture was stirred at room temperature for 3 days. Concentrated aqueous NH4OH (38.6 g, 28-30%) was added, and the mixture was concentrated to a residue that was triturated with THF (170 mL, 2 x 150 mL).The filtrates were combined and concentrated to a residue, which was dissolved in DCM (30 mL) and purified by column chromatography on silica gel (SiO, 120 g) eluting with 0% to 100% EtOAc in DCM to give the desired product, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 5.1 g, 10.25 g (theoretical yield), 49.8% over three steps), as an off-white crystalline solid, which is identical in all comparable aspects to the compound obtained by Example 16.

[0603] Step 2. 2-Acetyl-4,4-dimethoxybutanamide (compound 20a): A solution of 3-oxobutanamide (compound 19a, 5.0 g, 49.5 mmol) in DMF (15 mL) was treated with cesium carbonate (CsCO, 16.11 g, 49.5 mmol, 1.0 equiv.) at ambient temperature. The resulting mixture was stirred at ambient temperature. 2-Bromo-1,1-dimethoxyethane (8.36 g, 49.5 mmol, 1.0 equiv.) was then added to the mixture, and the resulting reaction mixture was heated to 80 °C for 5–8 h. The reaction mixture was cooled to ambient temperature and then quenched with water (20 mL). The quenched reaction mixture was then extracted with ethyl acetate (3 × 20 mL), and the combined organic extracts were washed with water (2 × 10 mL), dried over anhydrous sodium sulfate (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel (SiO) column chromatography to give 2-acetyl-4,4-dimethoxybutanamide (compound 20a, 5.8 g, 9.37 g (theoretical yield), 61.9%) as a thick oil containing some residual DMF. For 2-acetyl-4,4-dimethoxybutanamide: 1 C8H 15 NO4(MW,189.21),LCMS(EI)m / e 190.2(M + +H).

[0604] Step 3. 2-Acetyl-4,4-dimethoxybutanenitrile (Compound 17a): A solution of 2-acetyl-4,4-dimethoxybutanamide (compound 20a, 1.0 g, 4.23 mmol) in DMF (4 mL) was treated with cyanuric chloride (compound 21a, 0.39 g, 2.11 mmol, 0.5 equivalents). The resulting reaction mixture was stirred at ambient temperature for 1 hour. Once the reaction was complete, the reaction mixture was quenched with water (10 mL), and the quenched reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with water (2 × 10 mL), dried over anhydrous sodium sulfate (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel (SiO) column chromatography to afford 2-acetyl-4,4-dimethoxybutanenitrile (compound 17a, 280 mg, 724 mg (theoretical yield), 38.7%) as a thick oil. For 2-acetyl-4,4-dimethoxybutanenitrile: 1 H NMR (DMSO-d6, 400 MHz, mixture of ketone and enol forms obtained) δ 10.7 (br.s, 1 / 2H for the enol -OH), 4.38 (m, 1H), 3.25 (m, 6H for the two OMe and 1 / 2H for the ketone -CH-), 2.25-2.50 (m, 2H), 2.15 and 2.25 (s, 3H); CH 13 NO3(MW,171.196),LCMS(EI)m / e 172.2(M + +H). The 2-acetyl-4,4-dimethoxybutanenitrile (compound 17a) produced by this method is reacted with formamidine acetate followed by treatment with HCl to give 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a) according to Example 16 above.

[0605] Example 18. Preparation of 4-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) hydrochloride (hydrochloride salt of compound 1a) [ka] A reactor under nitrogen was charged with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (Compound 22a, 200 g, 1.064 mol) and THF (1.2 L). The contents of the reactor were cooled to below −5°C, and then 60% NaH in mineral oil (51 g, 1.28 mol, 1.2 equiv.) was added in small portions. The internal temperature was maintained between −5 and 5°C during the NaH addition. Stirring was continued for 30 min after the addition, and then a solution of TBDMS-Cl (193 g, 1.28 mol, 1.2 equiv.) in THF (200 mL) was added slowly, maintaining the internal temperature between −5 and 5°C. Stirring of the reaction mixture was continued for 30 min, and then Fe(acac)3 (18.8 g, 53.2 mmol, 0.05 equiv.) was added, followed by the addition of 3.0 M MeMgCl solution in THF (532 mL, 1.596 mol, 1.5 equiv.) at -5 to 5 °C. The reaction mixture was maintained for an additional 1 h, by which time IPC by HPLC indicated the coupling reaction was complete. The reaction mixture was then poured into a solution of EDTA disodium salt dihydrate (200 g) in water (2.0 L) while controlling the internal temperature below 15 °C. The biphasic mixture was diluted with methyl tert-butyl ether (MTBE, 2.0 L), treated with Celite (150 g), and filtered by centrifugation. The solid cake was washed with MTBE, and the filtrate was phase-separated. The aqueous phase was separated and extracted with MTBE (1.0 L). The organic phases were combined and washed successively with 3% aqueous citric acid (2 × 400 mL) and brine (600 mL). After drying over NaSO, the organic phase was filtered and concentrated to dryness. The residue was taken up in petroleum ether (2.0 L), and any insoluble material was removed by filtration through a thin layer of silica gel. The filtrate was concentrated to give the crude desired product, 7-(tert-butyldimethylsilyl)-2-chloro-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 22a, 300 g), as an oily residue, which was used directly in the subsequent reaction without further purification.

[0606] A mixture of crude 7-(tert-butyldimethylsilyl)-2-chloro-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 22a, 300 g, 1.064 mol) and 5% palladium on carbon (Pd / C, 30 g) in methanol (1.8 L) was vigorously stirred under 1 atmosphere of hydrogen at 50-55°C for 3 hours. After completion of the reaction as determined by IPC by HPLC, the reaction mixture was cooled to 20-25°C and filtered. The filter cake was washed with methanol, and the filtrate was concentrated to dryness. The residue was suspended in ethyl acetate (EtOAc, 225 mL) and stirred at 10-15°C for 1 hour. The solid was collected by filtration, washed with ethyl acetate, and dried under vacuum at 40-45 °C to give 4-methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (the hydrochloride salt of compound 1a, 151.5 g, 180.5 g (theoretical yield), 84% yield over two steps) as a pale yellow crystalline powder. 1 H NMR(DMSO-d6,500MHz)δppm 13.54(br s,1H),9.04(s,1H),7.95(dd,J=3.4,2.4Hz,1H),7.13(s,dd,J=3.4,1.5Hz,1H),2.97(s,3H); 13 C NMR (DMSO-d, 125 MHz) δ ppm 154.0, 151.0, 144.0, 131.6, 117.2, 103.1, 17.6; C7H8ClN3 (MW, 169.61; for free base, C7H7N3, MW 133.15); LCMS (EI) m / e 134.1 (M + +H, base peak).

[0607] Example 19. Preparation of sodium 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (5b) and 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetic acid (compound 5a) [ka] Step 1. 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (compound 24a): To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Compound 12a, 18.0 g, 117 mmol) in acetone (180 mL) was added 50% aqueous sodium hydroxide (NaOH, 14.07 g, 176 mmol, 1.5 equivalents) at ambient temperature. The resulting mixture was then stirred at ambient temperature until a clear solution was formed. p-Toluenesulfonyl chloride (pTsCl, 25.7 g, 135 mmol, 1.15 equivalents) was added to the solution at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 1 hour. Upon completion of the reaction, the reaction mixture was filtered, and the solid was washed with acetone and discarded. The filtrate was then concentrated under reduced pressure, and the residue was treated with methyl tert-butyl ether (MTBE, 180 mL) and n-heptane (180 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with n-heptane (180 mL), and dried to constant weight in a vacuum oven to give the desired product, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (compound 24a, 32.1 g, 36.0 g (theoretical yield), 89.2% yield) as an off-white powder, which was used in subsequent reactions without further purification. For 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine: 1 H NMR(DMSO-d6,400MHz)δ8.78(s,1H),8.10(d,2H),7.79(d,1H),7.34(d,2H),6.72(d,1H),2.41(s,3H)ppm; 13 H 10 ClN3O2S(MW,307.75),LCMS(EI)m / e 308.1(M + +H).

[0608] Step 2. Diethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonate (compound 25a): A solution of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (compound 24a, 7.0 g, 22.75 mmol) and diethyl malonate (5.46 g, 34.1 mmol, 1.5 equiv.) in anhydrous DMF (30 mL) was treated with solid cesium carbonate (CsCO, 18.53 g, 56.9 mmol, 2.5 equiv.) at ambient temperature. The resulting reaction mixture was then warmed to 50-60 °C and stirred at 50-60 °C for 2-3 h. Upon completion of the reaction, the reaction mixture was cooled to ambient temperature and then treated with water (HO, 80 mL). The quenched reaction mixture was then stirred at ambient temperature for 1 h, followed by 1 h at 0-5 °C. The solid was collected by filtration, washed with water (50 mL), followed by n-heptane (50 mL), and dried to constant weight in a vacuum oven at 40° C. to give the desired product, diethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonate (compound 25a, 6.2 g, 9.81 g (theoretical yield), 63.2% yield), as an off-white powder, which was used in subsequent reactions without further purification. For diethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonate: 1 C 20 H 21 N3O6S(MW,431.46),LCMS(EI)m / e 432.3(M + +H).

[0609] Step 3. Ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 26a): A solution of diethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonate (Compound 25a, 4.0 g, 9.27 mmol) in ethanol (EtOH, 20 mL) was treated with a solution of 21% sodium ethoxide in ethanol (NaOEt, 21 wt%, 0.30 g, 0.927 mmol, 0.10 equiv.) at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was quenched with 0.1 N aqueous hydrochloric acid (10 mL), and the resulting mixture was concentrated under reduced pressure. The residue was then purified by silica gel (SiO2) column chromatography to obtain the desired product, ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 26a, 2.08 g, 3.33 g (theoretical yield), 62.6% yield) as an off-white powder, which was used in the subsequent reaction without further purification. For ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate: 1 C 17 H 17 N3O4S(MW,359.40),LCMS(EI)m / e 360.2(M + +H).

[0610] Step 4. Ethyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 27a): A solution of diethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)malonate (compound 25a, 4.0 g, 9.27 mmol) in ethanol (EtOH, 20 mL) was treated with a solution of 21% sodium ethoxide in ethanol (NaOEt, 21 wt%, 3.0 g, 9.27 mmol, 1.0 equiv.) at ambient temperature. The resulting reaction mixture was heated to 65-75 °C and stirred at 65-75 °C for 12 h. The reaction mixture was quenched with 1.0 N aqueous hydrochloric acid, and the resulting mixture was concentrated under reduced pressure. The residue was then purified by silica gel (SiO2) column chromatography to obtain the desired product, ethyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 27a, 1.3 g, 1.9 g (theoretical yield), 68.3% yield) as an off-white powder, which was used in the subsequent reaction without further purification. For ethyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate: 1 C 10 H 11 N3O2(MW,205.22),LCMS(EI)m / e 206.2(M + +H).

[0611] Step 5. Sodium 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (Compound 5b): A solution of ethyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (Compound 27a, 1.2 g, 5.85 mmol) in acetone (10 mL) and THF (10 mL) was treated with an aqueous solution of 6 N sodium hydroxide (6 N NaOH, 1.462 mL, 8.77 mmol, 1.5 equiv.) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours. The solid was collected by filtration, and the isolated solid was suspended in methanol (MeOH, 4.0 mL). Acetone (15 mL) was then added to the resulting suspension, and the mixture was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with acetone (2 x 5 mL), and dried under vacuum to give the desired product, sodium 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 5b, 1.1 g, 1.164 g (theoretical yield), 94.5% yield) as an off-white powder, which was used in subsequent reactions without further purification. For sodium 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate: 1 H NMR (DMSO-d6, 400 MHz) δ 8.36 (s, 1H), 7.37 (d, 1H), 6.40 (d, 1H), 3.61 (s, 2H) ppm; C8H6N3NaO2 (MW, 199.15; for the corresponding acid, C8H7N3O2, MW 177.16); LCMS (EI) m / e 178.1 (M + +H).

[0612] Step 6. 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)acetic acid (compound 5a): A solution of ethyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (Compound 27a, 1.2 g, 5.85 mmol) in acetone (10 mL) and THF (10 mL) was treated with a 6 N aqueous solution of sodium hydroxide (6 N NaOH, 1.462 mL, 8.77 mmol, 1.5 equiv.) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then treated with a 1 N aqueous solution of hydrochloric acid (1 N HCl, 9.0 mL) and then concentrated under reduced pressure. The residue was then purified by silica gel (SiO2) column chromatography to give the desired product, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetic acid (Compound 5a, 0.83 g, 1.04 g (theoretical yield), 79.8%), as an off-white solid, which was used in the subsequent reaction without further purification. About 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetic acid: 1 H NMR(DMSO-d6,400MHz)δ12.01(br s,1H),8.56(s,1H),7.36(d,1H),6.57(d,1H),3.66(s,2H)ppm;C8H7N3O2(MW,177.16),LCMS(EI)m / e 178.1(M + +H).

[0613] Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety. The present application also includes the following aspects. [Aspect 1] 1. A method for preparing ruxolitinib or a salt thereof, comprising: Compounds of Formula 3: [ka] or a salt thereof, by reacting a compound of formula 2a or a salt thereof, or a compound of formula 2b: [ka] with a reagent which is In the formula, X - is a counter anion. [Aspect 2] The method for preparing ruxolitinib or a salt thereof comprises: Compounds of Formula 3:

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Claims

1. 1. A method for preparing ruxolitinib or a salt thereof, comprising: Compound of Formula 3: 【Chemistry 1】 or a salt thereof, by reacting a compound of formula 2a or a salt thereof, or a compound of formula 2b: 【Chemistry 2】 with a reagent which is In the formula, X － is a counter anion.

2. The method for preparing ruxolitinib or a salt thereof comprises: Compound of Formula 3: 【Transformation 3】 or a salt thereof, by reacting a salt of formula 2a or a compound of formula 2b: 【Chemistry 4】 with a reagent which is In the formula, X － The method of claim 1 , wherein is the counter anion.

3. 3. The method of claim 2, wherein the compound of formula 3 or the salt thereof is a chiral salt of the compound of formula 3.

4. 4. The method of claim 3, wherein the chiral salt is prepared by reacting the compound of Formula 3 with an optically active form of an acid selected from mandelic acid, 2-chloromandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, dibenzoyltartaric acid, di-p-toluoyltartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid, and 2-acrylamido-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid.

5. 4. The method of claim 3, wherein the chiral salt is the L-(+)-tartrate salt of the compound of formula 3.

6. The compound of formula 3 or the salt thereof is represented by formula 3a: 【Transformation 5】 4. The method of claim 3, comprising:

7. The L-tartrate salt of formula 3 is Compound 7a: 【Transformation 6】 7. The method according to claim 5, wherein the compound is prepared by a process comprising reacting

8. The compound of formula 7a is The compound of formula 6a: 【Transformation 7】 8. The method of claim 7, wherein the compound is prepared by a process comprising reacting

9. X － But Cl － , B.F. ４ － , P.F. ６ － , AsF ６ － , SbF ６ － , and ClO ４ － The method according to any one of claims 2 to 8, wherein the compound is selected from the group consisting of:

10. X － But Cl － The method according to any one of claims 2 to 8, wherein

11. The method of any one of claims 2 to 10, wherein the reagent is a salt of formula 2a.

12. The method of any one of claims 2 to 8, wherein the reagent is a compound of formula 2b.

13. wherein the salt of formula 2a or the compound of formula 2b is The compound of formula 1a: 【Transformation 8】 13. The method of any one of claims 2 to 12, wherein the compound is prepared by a process comprising reacting 2-(2-methyl-2-propanol)-4-one or a salt thereof with Vilsmeier reagent formed from dimethylformamide.

14. 14. The method of claim 13, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

15. 15. The method of claim 14, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene.

16. 16. The method of claim 14 or 15, wherein the chlorinating agent is oxalyl chloride.

17. The product of the reaction with the Vilsmeier reagent is a compound of formula 2d: 【Chemistry 9】 The method according to any one of claims 13 to 16, comprising:

18. Salts of formula 2d: 【Chemistry 10】 with a base to form a salt of formula 2c: 【Chemistry 11】 20. The method of claim 17, further comprising forming:

19. The reaction with the Vilsmeier reagent produces a salt of formula 2c: 【Chemistry 12】 The method according to any one of claims 13 to 16, wherein

20. The salt of formula 2c: 【Chemistry 13】 Formula M ＋ X － to form said salt of formula 2a, wherein M ＋ is the counter cation, X － But Cl － is a counter anion other than The method according to any one of claims 18 to 19.

21. 21. The method of any one of claims 18 to 20, wherein the compound of formula 2b is prepared by a process comprising reacting the salt of formula 2a or the salt of formula 2c with a base to form the compound of formula 2b.

22. The compound of formula 1a or the salt thereof is Compounds of Formula 1aP: 【Chemistry 14】 and deprotecting the compound of formula (I) In the formula, P １ The method of any one of claims 13 to 21, wherein is an amino protecting group.

23. P １ However, (R １ ) ３ Si, where R １ But C １－６ 23. The method of claim 22, wherein the alkyl is alkyl.

24. R １ 24. The method of claim 23, wherein is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

25. The compound of formula 1aP is Compound of Formula 2P: 【Chemistry 15】 with MeMgBr in the presence of a Grignard catalyst, In the formula, P １ is an amino protecting group; The method according to any one of claims 22 to 24.

26. The compound of formula 2P is Compound of Formula 12a: 【Chemistry 16】 to form said compound of formula 2P.

27. The protection may be achieved by reacting the compound of formula 12a with an alkali metal hydride and P １ 27. The method of claim 26, comprising reacting with -Y, wherein Y is halo.

28. P １ -Y is (R １ ) ３ Si—Y, where Y is halo, and R １ But C １－６ 28. The method of claim 27, wherein the alkyl is alkyl.

29. The compound of formula 12a is Compound of formula 11a: 【Chemistry 17】 29. The method of any one of claims 26 to 28, wherein the compound is prepared by a process comprising reacting the compound or a salt thereof with a strong acid.

30. The compound of formula 11a or a salt thereof is Compound of Formula 10a: [Chemistry 18] 30. The method of claim 29, wherein the compound is prepared by a process comprising reacting methyltriphenylphosphonium chloride or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and a base.

31. The compound of formula 10a or a salt thereof is Compound of Formula 9a: 【Chemistry 19】 31. The method of claim 30, wherein the compound is prepared by a process comprising reacting

32. The compound of formula 9a is Compound of Formula 8a: 【Chemistry 20】 32. The method of claim 31 , wherein the compound is prepared by a process comprising reacting a compound represented by the formula (I) with a Vilsmeier reagent formed from dimethylformamide.

33. 33. The method of claim 32, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

34. The compound of formula 12a is Compound of formula 15a: 【Chemistry 21】 29. The method of any one of claims 26 to 28, wherein the compound is prepared by a process comprising reacting

35. The compound of formula 15a is (i) A compound of formula 14a: 【Chemistry 22】 with formamidine acetate and an alkali metal hydroxide to give a compound of formula 14aa: 【Chemistry 23】 and (ii) reacting said compound of formula 14aa with a strong acid; 35. The method of claim 34, wherein the compound is prepared by a method comprising:

36. The compound of formula 14a is Compound of formula 13a: 【Chemistry 24】 36. The method of claim 35, wherein the compound is prepared by a process comprising reacting with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide.

37. The compound of formula 1a or the salt thereof is Compound of Formula 23P: 【Chemistry 25】 and preparing the compound by a process comprising reducing In the formula, P ２ The method of any one of claims 13 to 21, wherein is an amino protecting group.

38. 38. The method of claim 37, wherein said reduction of said compound of formula 23P is accomplished by a process comprising reacting said compound of formula 23P with hydrogen gas in the presence of a catalyst.

39. The compound of formula 23P is Compound of Formula 22P: 【Chemistry 26】 with MeMgBr in the presence of a Grignard catalyst, In the formula, P ２ The method of any one of claims 37 to 38, wherein is an amino protecting group.

40. The compound of formula 22P is Compound of Formula 22a: 【Chemistry 27】 to form said compound of formula 22P.

41. The protection may be achieved by reacting the compound of formula 22a with an alkali metal hydride and P ２ 41. The method of claim 40, comprising reacting with -Y, wherein Y is halo.

42. P ２ However, (R １ ) ３ Si, where R １ But C １－６ 42. The method of claim 41, wherein the alkyl is alkyl.

43. The compound of formula 1a or the salt thereof is Compound of formula 18a: 【Chemistry 28】 with an acid to form said compound of formula 1a.

44. The compound of formula 18a or a salt thereof is Compound of formula 17a: 【Chemistry 29】 with formamidine acetate and triethyl orthoformate to form the compound of formula 18a.

45. The compound of formula 17a or a salt thereof is Compound of Formula 20a: 【Transformation 30】 with a compound of formula 21a: 【Chemistry 31】 to form said compound of formula 17a.

46. The compound of formula 20a or a salt thereof is Compound of formula 19a: 【Chemistry 32】 with bromo-1,1-dimethoxyethane and a base to form the compound of formula 20a.

47. 47. The method of claim 46, wherein the base is an alkali metal carbonate.

48. The compound of formula 17a or a salt thereof is Compound of formula 16a: 【Transformation 33】 with ethyl acetate and a base to form said compound of formula 17a.

49. 49. The method of claim 48, wherein the base is an alkali metal alkoxide.

50. wherein the salt of formula 2a or the compound of formula 2b is Compound of formula 5a: 【Transformation 34】 13. The method of any one of claims 2 to 12, wherein the compound is prepared by a process comprising reacting 2-(2-methyl-2-propanol)-4-one or a salt thereof with Vilsmeier reagent formed from dimethylformamide.

51. 51. The method of claim 50, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

52. 52. The method of claim 51 , wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene.

53. 52. The method of claim 51 , wherein the chlorinating agent is oxalyl chloride.

54. The product of the reaction with the Vilsmeier reagent is a compound of formula 2d: 【Chemistry 35】 54. The method of any one of claims 50 to 53, comprising:

55. The salt of formula 2d: 【Transformation 36】 with a base to form a salt of formula 2c: 【Chemistry 37】 55. The method of claim 54, further comprising forming:

56. The reaction with the Vilsmeier reagent produces a salt of formula 2c: 【Transformation 38】 The method of any one of claims 50 to 53, wherein

57. The salt of formula 2c: 【Chemistry 39】 Formula M ＋ X － to form said salt of formula 2a, wherein M ＋ is the counter cation, X － But Cl － is a counter anion other than 57. The method according to any one of claims 55 to 56.

58. 58. The method of any one of claims 55 to 57, wherein the compound of formula 2b is prepared by a process comprising reacting the salt of formula 2a or the salt of formula 2c with a base to form the compound of formula 2b.

59. The compound of formula 5a or the salt thereof is Compound of Formula 27a: 【Chemistry 40】 59. The method of any one of claims 50 to 58, wherein the compound is prepared by a process comprising hydrolyzing in water in the presence of a base.

60. 60. The method of claim 59, wherein the base present for the hydrolysis of the compound of formula 27a is sodium hydroxide, and the compound of formula 5a or the salt thereof is the sodium salt of the compound of formula 5a.

61. 61. The method of claim 60, further comprising reacting the sodium salt of the compound of formula 5a with a strong acid.

62. The compound of formula 27a is Compound of Formula 26P: 【Chemistry 41】 with a strong acid, wherein P １ The method of any one of claims 59 to 61, wherein is an amino protecting group.

63. P １ 63. The method of claim 62, wherein is p-toluenesulfonyl.

64. The compound of formula 26P is Compound of Formula 25P: 【Chemistry 42】 with an alkali metal alkoxide to form a compound of formula 26P, １ The method of any one of claims 62 to 63, wherein is an amino protecting group.

65. The compound of formula 25P is Compound of Formula 2P: 【Chemistry 43】 with diethyl malonate and a base, wherein P １ 65. The method of claim 64, wherein is an amino protecting group.

66. The method of any one of claims 1 to 65, wherein the ruxolitinib or the salt thereof is ruxolitinib phosphate.

67. 67. The method of claim 66, wherein the ruxolitinib phosphate is prepared by a process comprising reacting the ruxolitinib with phosphoric acid.

68. A method for preparing ruxolitinib or a salt thereof, comprising administering to a subject a compound of formula 2c: 【Chemistry 44】 to a compound of formula 3: 【Chemistry 45】 with the L-(+)-tartrate salt of the compound to form ruxolitinib or a salt thereof.

69. The L-(+)-tartrate salt of the compound of formula 3 is a salt of formula 3a: 【Chemistry 46】 69. The method of claim 68, wherein:

70. The salt of formula 2c is a salt of formula 2d: 【Chemistry 47】 with a base to form the salt of formula 2c.

71. wherein the salt of formula 2d is (a) A compound of formula 2P: 【Chemistry 48】 is reacted with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 1aP: 【Chemistry 49】 and forming (b) deprotecting the compound of formula 1aP to give a compound of formula 1a: [Transformation 50] or a salt thereof; and (c) reacting the compound of formula 1a or the salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form the salt of formula 2d; prepared by a method comprising: In the formula, P １ 71. The method of claim 70, wherein is an amino protecting group.

72. wherein the salt of formula 2d is (a) A compound of formula 22P: 【Chemistry 51】 is reacted with MeMgBr in the presence of a Grignard catalyst to give a compound of formula 23P: 【Chemistry 52】 and forming (b) reducing the compound of formula 23P to give a compound of formula 1a: 【Chemistry 53】 or a salt thereof; and (c) reacting the compound of formula 1a or the salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form the salt of formula 2d; prepared by a method comprising: In the formula, P ２ 71. The method of claim 70, wherein is an amino protecting group.

73. The salt of formula 3a is (a) A compound of formula 6a: 【Chemistry 54】 with hydrazine to give a compound of formula 7a: 【Transformation 55】 and forming (b) reacting the compound of formula 7a with L-tartaric acid to form the salt of formula 3a; 73. The method of any one of claims 69 to 72, wherein the composition is prepared by a process comprising:

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