Processes and intermediates for preparing JAK inhibitors

Abstract

The present disclosure relates to processes for preparing baricitinib, its salts, and related synthetic intermediate compounds and their salts.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 220,752, filed July 12, 2021, the entire contents of which are incorporated herein.

[0002] The present disclosure relates to processes for preparing baricitinib, its salts, and related synthetic intermediate compounds and their salts. Baricitinib 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]

[0003] Protein kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, including cell proliferation, survival and differentiation, organogenesis and morphogenesis, neovascularization, 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 functions in normal tissues / organs, many protein kinases also play more specialized roles in a host of human diseases, including cancer. A subset of protein kinases, also called oncogenic protein kinases, when dysregulated, can cause tumor formation and proliferation, and can even contribute to tumor maintenance and progression (Blume-Jensen P. et al., Nature 2001, 411(6835):355-365). To date, oncogenic protein kinases are one of the largest and most attractive groups of protein targets for cancer intervention and drug development.

[0004] Protein kinases can be classified into receptor and non-receptor types. Receptor tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion, whereas non-receptor tyrosine kinases are entirely intracellular. The Janus kinase family of protein tyrosine kinases (JAKs) belongs to the non-receptor type of tyrosine kinases 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).

[0005] 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 low molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. In general, cytokine receptors lack intrinsic tyrosine kinase activity and therefore require receptor-associated kinases to propagate phosphorylation cascades. JAKs accomplish this function. Cytokines bind to these receptors, causing receptor dimerization, which allows 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 themselves 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).

[0006] The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. The JAK / STAT pathway, particularly all four members of the JAK family, are believed to play a role in the pathogenesis of asthmatic responses, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower airways. In addition, several cytokines that signal through JAK kinases are associated with inflammatory diseases or conditions of the upper airways, such as those that affect the nose and paranasal sinuses (e.g., rhinitis, sinusitis), whether or not they are classical allergic reactions. The JAK / STAT pathway has also been suggested to play a role in inflammatory diseases / conditions of the eye, including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, and chronic allergic responses. Thus, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.

[0007] Blocking signal transduction at the level of JAK kinases is promising for the development of treatment for human cancer.Inhibition of JAK is also expected to have therapeutic benefits in patients suffering from skin immune disorders, such as atopic dermatitis, alopecia areata, psoriasis, and skin sensitization.Therefore, there is a wide demand for JAK inhibitors.For example, the JAK inhibitor baricitinib, {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, is reported in U.S. Patent No. 8,158,616, filed March 10, 2009, the entirety of which is incorporated herein by reference.

[0008] In view of the increasing demand for compounds for the treatment of disorders associated with JAK inhibitors, new and more efficient routes to baricitinib, its salts, and their related intermediates are needed. The processes and compounds described herein help meet these and other needs. Summary of the Invention

[0009] The present disclosure relates, inter alia, to a process for preparing baricitinib, comprising the step of: [ka] or a salt thereof with a reagent selected from (i) a salt of formula 2a or a salt thereof, and (ii) a compound of formula 2b [ka] In the formula, X - is the counter anion.

[0010] The present disclosure also relates, inter alia, to a process for preparing baricitinib, comprising the step of: [ka] or a salt thereof with a reagent selected from (i) a salt of formula 2a, and (ii) a compound of formula 2b: [ka] In the formula, X - is the counter anion.

[0011] The present disclosure relates to a compound of formula 3 [ka] or a salt thereof.

[0012] The present disclosure also provides a compound of formula 6 [ka] with hydrazine.

[0013] The present disclosure relates to a salt of formula 2c [ka] with a compound of formula 3, [ka] There is further provided a process for preparing baricitinib or a salt thereof, comprising forming baricitinib or a salt thereof.

[0014] In some embodiments, the salt of formula 2c is a salt of formula 2d [ka] with a base to form a salt of formula 2c.

[0015] In some embodiments, the salt of formula 2d is (a) Compound of formula 2P [ka] with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 1aP; [ka] (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; In the formula, P 1 is an amino protecting group.

[0016] In some embodiments, the salt of formula 2d is (a) Compound of formula 22P [ka] with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 23P; [ka] (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; In the formula, P 2 is an amino protecting group.

[0017] In some embodiments, the compound of formula 3 or salt thereof is Compound of Formula 6 [ka] It is prepared by a process which includes reacting

[0018] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the detailed description below. [Brief description of the drawings]

[0019] [Figure 1] FIG. 2 is an X-ray powder diffraction (XRPD) pattern of compound 2d, Form I. [Diagram 2] 1 is a differential scanning calorimetry (DSC) thermogram of compound 2d, Form I. [Diagram 3] 1 is a thermogravimetric analysis (TGA) thermogram of compound 2d, Form I. [Figure 4] FIG. 1 is an XRPD pattern of compound 2d, Form II. [Diagram 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 compound 2, hexafluorophosphate salt. [Figure 8] 1 is a DSC thermogram of compound 2, hexafluorophosphate salt. [Figure 9] 1 is a TGA thermogram of compound 2, hexafluorophosphate salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present disclosure provides a process for preparing baricitinib, also known as {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, and intermediates used in the process. Baricitinib has the following structure: [ka]

[0021] Baricitinib is also referred to in this disclosure as Compound 1. The compound and various processes for preparing the compound are disclosed in U.S. Patent No. 8,158,616, filed March 10, 2009, which is incorporated herein by reference in its entirety.

[0022] In some embodiments, provided herein is a compound of formula 3: [ka] or a salt thereof with a reagent selected from: (i) a compound of formula 2a or a salt thereof; and (ii) a compound of formula 2b: [ka] In the formula, X - is the counter anion.

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

[0024] In some embodiments, about 1 to about 1.5 molar equivalents of a reagent ((i) a salt of Formula 2a or a salt thereof, or (ii) a compound of Formula 2b) relative to the compound of Formula 3 or a salt thereof is utilized. In some embodiments, about 1.25 molar equivalents of a reagent relative to the compound of Formula 3 or a salt thereof is utilized. In some embodiments, about 1 molar equivalent of a reagent relative to the compound of Formula 3 or a salt thereof is utilized.

[0025] In some embodiments, the reaction of a reagent ((i) a salt of formula 2a or a salt thereof, or (ii) a compound of formula 2b) with a compound of formula 3 or a salt thereof is carried out in a solvent component. The solvent component can include a polar protic solvent or a polar aprotic solvent. In some embodiments, the solvent component includes water. In some embodiments, the solvent component includes an alcohol. In some embodiments, the solvent component includes a compound of formula C 1~6 In some embodiments, the solvent component comprises an alkyl-OH. In some embodiments, the solvent component is ethanol. In some embodiments, the solvent component comprises dimethylformamide. In some embodiments, the solvent component comprises water, an alcohol, or a combination thereof.

[0026] In some embodiments, the reagent is a salt of Formula 2a. In some embodiments, the reagent is a salt of a salt of Formula 2a (e.g., the hydrochloride salt of a salt of Formula 2a). In some embodiments, the reagent is a hydrochloride salt of a salt of Formula 2a. In some embodiments, the hydrochloride salt of a salt of Formula 2a is a salt of Formula 2d. [ka]

[0027] In some embodiments, X - is Cl - , Br - , I - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - In some embodiments, X - is Cl - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - In some embodiments, X - is BF4 - In some embodiments, X - PF6 - In some embodiments, X - AsF6 - In some embodiments, X - is SbF6 - In some embodiments, X - is ClO4 - In some embodiments, X - is Cl - It is.

[0028] In some embodiments, about 1 to about 2 molar equivalents of the reagent that is a salt of formula 2d are utilized relative to the compound of formula 3 or salt thereof. In some embodiments, about 1.5 molar equivalents of the reagent are utilized relative to the compound of formula 3 or salt thereof. In some embodiments, about 1 molar equivalent of the reagent is utilized relative to the compound of formula 3 or salt thereof.

[0029] In some embodiments, the reaction of a reagent ((i) a salt of formula 2a or a salt thereof, or (ii) a compound of formula 2b) with a compound of formula 3 or a salt thereof is carried out in a solvent component. The solvent component can include a polar protic solvent or a polar aprotic solvent. In some embodiments, the solvent component includes water. In some embodiments, the solvent component includes an alcohol. In some embodiments, the solvent component includes a compound of formula C 1~6 In some embodiments, the solvent component comprises an alkyl-OH compound. In some embodiments, the solvent component is ethanol. In some embodiments, the solvent component comprises dimethylformamide. In some embodiments, the solvent component comprises water, an alcohol, or a combination thereof.

[0030] In some embodiments, the reagent is a compound of formula 2b. In some embodiments, the compound of formula 2b is prepared by a process comprising reacting a salt of formula 2a or a salt of formula 2c, or a salt thereof, with a base. In some embodiments, the reaction of the salt of formula 2a or a salt of formula 2c, or a salt thereof with a base is carried out in a solvent component comprising water. In some embodiments, the base present for the reaction of the salt of formula 2a or a salt of formula 2c, or a salt thereof is a strong base. In some embodiments, the base present for the reaction of the salt of formula 2a or a salt of formula 2c, or a salt thereof is a hydroxide. In some embodiments, the base present for the reaction of the salt of formula 2a or a salt of formula 2c, or a salt thereof is an alkali metal hydroxide. In some embodiments, the base present for the reaction of the salt of formula 2a or a salt of formula 2c, or a salt thereof is sodium hydroxide. In some embodiments, about 10 to about 15 molar equivalents of base are utilized relative to the salt of formula 2a or a salt of formula 2c, or a salt thereof. In some embodiments, about 12 molar equivalents of base are utilized relative to the salt of Formula 2a or the salt of Formula 2c, or salts thereof. In some embodiments, the reaction of the salt of Formula 2a or the salt of Formula 2c, or salts thereof with the base is carried out at a temperature of about -10°C to 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 0°C to room temperature and then heated to about 40°C to about 60°C. In some embodiments, the salt of formula 2a or a salt thereof, or the compound of formula 2b is Compound of Formula 1a [ka] or its salts with Vilsmeier reagent formed from dimethylformamide.

[0031] In some embodiments, the salt of formula 2a or a salt thereof, or the compound of formula 2b is Compound of Formula 5a [ka] or its salts with Vilsmeier reagent formed from dimethylformamide.

[0032] In some embodiments, the compound of formula 5a is a salt. In some embodiments, the compound of formula 5a is a sodium salt.

[0033] In some embodiments, the product of the reaction of a salt of Formula 2a or a salt thereof (or a compound of Formula 5a or a salt thereof) with a Vilsmeier reagent is a salt of Formula 2d. [ka]

[0034] In some embodiments, the salt of Formula 2d is crystalline. In some embodiments, the crystalline form of the salt of Formula 2d is Form I.

[0035] In some embodiments, Form I has an XRPD pattern substantially as shown in Figure 1. Form I may have a DSC thermogram substantially as shown in Figure 2. In some embodiments, Form I has a TGA thermogram substantially as shown in Figure 3.

[0036] 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).

[0037] In some embodiments, Form I has an endothermic peak with an onset temperature (±3° C.) of 56° C. and a maximum of 101° C. in a DSC thermogram.

[0038] 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 shown in Figure 5. In some embodiments, Form II has a TGA thermogram substantially as shown in Figure 6.

[0039] 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).

[0040] In some embodiments, Form II has an endothermic peak with an onset temperature (±3° C.) of 47° C. and a maximum of 99° C. in a DSC thermogram.

[0041] In some embodiments, the process of making a salt of Formula 2a further comprises reacting a salt of Formula 2d with a base to form a salt of Formula 2c. [ka]

[0042] In some embodiments, the product of the reaction of a salt of formula 2a or a salt thereof (or a compound of formula 5a or a salt thereof) with a Vilsmeier reagent is a salt of formula 2c (wherein X- is Cl). - (which is a salt of formula 2a). [ka]

[0043] In some embodiments, the process for making the salt of formula 2a comprises reacting a salt of formula 2c with M + X - with a salt of formula 2a to form a salt of formula 2b, M + is the counter cation, X - But Cl - The counter anion is other than

[0044] In some embodiments, M + is an alkali metal countercation. In some embodiments, M + Li + , Na + , or K + In some embodiments, M + is Na + In some embodiments, X - Br - , I - , BF4 - , PF6 - , AsF6 - , SbF6 -, and ClO4 - In some embodiments, X - is BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - In some embodiments, X - is BF4 - In some embodiments, X - PF6 - In some embodiments, X - AsF6 - In some embodiments, X - is SbF6 - In some embodiments, X - is ClO4 - It is.

[0045] In some embodiments, the Vilsmeier reagent used in any of the reactions described herein is prepared by a process 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.

[0046] In some embodiments, about 1 to about 5 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a or salt thereof. In some embodiments, about 1 to about 4 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a or salt thereof. In some embodiments, about 1 to about 3 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a or salt thereof. In some embodiments, about 1 molar equivalent of chlorinating agent present for reaction with dimethylformamide is utilized relative to the compound of formula 1a or 5a or salt thereof. In some embodiments, about 2 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a or salt thereof. In some embodiments, about 3 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a or salt thereof. In some embodiments, about 4 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a, or salt thereof. In some embodiments, about 5 molar equivalents of chlorinating agent present for reaction with dimethylformamide are utilized relative to the compound of formula 1a or 5a, or salt thereof.

[0047] In some embodiments, about 10 to about 25 molar equivalents of dimethylformamide present for reaction with the chlorinating agent 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 present for reaction with the chlorinating agent 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 present for reaction with the chlorinating agent 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 present for reaction with the chlorinating agent 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 present for reaction with the chlorinating agent are utilized relative to the compound of formula 1a, or a salt thereof.

[0048] In some embodiments, the preparation of the Vilsmeier reagent is carried out in a solvent component. In some embodiments, the solvent component present for the preparation of the Vilsmeier reagent comprises an organic solvent. In some embodiments, the solvent component present for the preparation of the Vilsmeier reagent comprises a polar aprotic solvent. In some embodiments, the solvent component present for the preparation of the Vilsmeier reagent comprises acetonitrile, dimethyformamide, or a combination thereof.

[0049] 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. In some embodiments, the Vilsmeier reagent is prepared at a temperature of about -10°C to about room temperature. In some embodiments, 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, about 80°C to about 90°C, or about 85°C to about 90°C.

[0050] In some embodiments, the reaction of the compound of Formula 1a or 5a, or a salt thereof, with the Vilsmeier reagent is carried out at a temperature of about 40° C. to about 100° C. In some embodiments, the reaction of the compound of Formula 1a or 5a, or a salt thereof, with the Vilsmeier reagent is carried out at a temperature of about 70° C. to about 100° C. In some embodiments, the reaction of the compound of Formula 1a or 5a, or a salt thereof, with the Vilsmeier reagent is carried out at a temperature of about 40° C. to about 60° C.

[0051] In some embodiments, the compound of formula 1a or salt thereof is a hydrochloride salt.

[0052] In some embodiments, the compound of formula 1a or a salt thereof is and deprotecting a compound of formula 1aP, [ka] 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 1~6In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. 1 is t-butyldimethylsilyl. In some embodiments, P 1 is trimethylsilyl. In some embodiments, the deprotection is carried out by reacting the compound of formula 1aP with a base. In some embodiments, the base present to deprotect the compound of formula 1aP is a hydroxide base. In some embodiments, the base present to deprotect the compound of formula 1aP is ammonium hydroxide. In some embodiments, the deprotection is carried out in a solvent component. In some embodiments, the solvent component present to deprotect the compound of formula 1aP comprises a polar protic solvent. In some embodiments, the solvent component present to deprotect the compound of formula 1aP comprises an alcohol. In some embodiments, the solvent component present to deprotect the compound of formula 1aP comprises a base of formula C 1~6 In some embodiments, the solvent component present for deprotecting the compound of formula 1aP comprises 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 Grignard 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 MeMgBr relative to the compound of formula 2P are utilized. In some embodiments, about 1% to about 10% molar equivalents of Grignard catalyst relative to the compound of formula 2P are utilized. In some embodiments, the reaction of the compound of formula 2P with MeMgBr is carried out in a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 2P with MeMgBr is di-C 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 2P with MeMgBr comprises tetrahydrofuran. In some embodiments, the reaction of the compound of formula 2P with MeMgBr is carried out at a temperature of about -10°C to about 30°C.

[0056] In some embodiments, the compound of formula 2P is Protecting the compound of formula 12a [ka] The compound of formula 2P is prepared by a process comprising forming

[0057] In some embodiments, the protection is achieved by reacting the compound of formula 12a with an alkali metal hydride and P 1 -Y, where 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. 1is 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 are utilized. 1 In some embodiments, a compound of formula 12a is used in combination with an alkali metal hydride and P 1 The reaction of the compound of formula 12a 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 of -Y with the compound of formula 12a is carried out in a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the reaction of the compound of formula 12a with an alkali metal hydride and P 1 The solvent component present for the reaction with -Y is di-C 1~6 In some embodiments, the compound of formula 12a is a 4- to 10-membered alkyl ether or a 4- to 10-membered heterocycloalkyl ether. 1 Solvent components present for reaction with -Y include tetrahydrofuran.

[0058] In some embodiments, the compound of formula 1a or a salt thereof is By reducing the compound of formula 23P [ka] forming a compound of formula 1a or a salt thereof, wherein P 2 is an amino protecting group. The HCl generated by reduction is 2 This results in the removal of

[0059] In some embodiments, the reduction of the compound of formula 23P is accomplished by a process comprising reacting the compound of formula 23P with hydrogen gas in the presence of a catalyst. For example, the catalyst present for the reaction of the compound of formula 23P with hydrogen gas is 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 23P with hydrogen and the catalyst is carried out in a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 23P with hydrogen and the catalyst comprises a polar protic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 23P with hydrogen and the catalyst comprises an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 23P with hydrogen and the catalyst comprises a solvent of formula C 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 23P with hydrogen and a catalyst comprises methanol.

[0060] In some embodiments, the compound of formula 1a or salt thereof is a hydrochloride salt.

[0061] In some embodiments, the compound of formula 23P is Compound of formula 22P [ka] with MeMgCl in the presence of a Grignard catalyst, 2 is an amino protecting group.

[0062] In some embodiments, the Grignard 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 22P are utilized. In some embodiments, about 1% to about 10% molar equivalents of Grignard 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 a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 22P with MeMgCl is di-C 1~6 In some embodiments, the solvent component present for the reaction of compound 22P with MeMgCl comprises tetrahydrofuran. In some embodiments, the reaction of compound 22P with MeMgCl is carried out at a temperature of about -10°C to about 30°C.

[0063] In some embodiments, the compound of formula 22P is Protecting the compound of formula 22a [ka] The compound of formula 22P is prepared by a process comprising forming

[0064] In some embodiments, the protection is achieved by reacting the compound of formula 22a with an alkali metal hydride and P 2 -Y, where 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. 2is 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 are utilized. 2 In some embodiments, the 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 of -Y with the compound of formula 22a is carried out in a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the reaction of the compound of formula 22a with an alkali metal hydride and P 2 The solvent component present for the reaction with -Y is di-C 1~6 In some embodiments, the compound of formula 22a is a 4- to 10-membered alkyl ether or a 4- to 10-membered heterocycloalkyl ether. 2 Solvent components present for reaction with -Y include tetrahydrofuran.

[0065] In some embodiments, the compound of formula 1a or a salt thereof is Compound of Formula 18a [ka] with an acid to form a compound of formula 1a or a salt thereof.

[0066] In some embodiments, the acid present for the reaction of the compound of formula 18a is a strong acid. In some embodiments, the acid present for the reaction of the compound of formula 18a is hydrochloric acid. In some embodiments, the reaction of the compound of formula 18a with the acid is carried out in a solvent component, where the solvent component comprises a polar protic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 18a with the acid comprises an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 18a with the acid comprises an alcohol. 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 18a with an acid comprises isopropyl alcohol.

[0067] In some embodiments, the compound of formula 18a is Compound of Formula 17a [ka] with formamidine acetate and triethyl orthoformate to form a compound of formula 18a or a salt thereof.

[0068] 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. In some embodiments, 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. In some embodiments, the temperature is 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 a solvent component, where the solvent component comprises a polar protic solvent. In some embodiments, the polar protic solvent comprises an alcohol. In some embodiments, the polar protic solvent comprises a compound of formula C 1~6 In some embodiments, the polar protic solvent comprises 1-butanol.

[0069] In some embodiments, the compound of formula 17a is Compound of Formula 20a [ka] with a compound of formula 21a, [ka] The compound of formula 17a is prepared by a process comprising forming

[0070] 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 a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 20a with the compound of formula 21a comprises dimethylformamide.

[0071] In some embodiments, the compound of formula 20a is Compound of Formula 19a [ka] with bromo-1,1-dimethoxyethane and a base to form a compound of formula 20a.

[0072] In some embodiments, the base present for the reaction of the compound of formula 19a with bromo-1,1-dimethoxyethane is an alkali metal carbonate. In some embodiments, the base present for the reaction of the compound of formula 19a with bromo-1,1-dimethoxyethane is cesium carbonate. In some embodiments, about 1 to about 2 molar equivalents of base relative to the compound of formula 19a are utilized. In some embodiments, about 1 to about 2 molar equivalents of bromo-1,1-dimethoxyethane relative to the compound of formula 19a are utilized. 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 a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 19a with bromo-1,1-dimethoxyethane comprises dimethylformamide.

[0073] In some embodiments, the compound of formula 17a is Compound of Formula 16a [ka] with ethyl acetate and a base to form a compound of formula 17a.

[0074] In some embodiments, the base present for the reaction of the compound of formula 16a with ethyl acetate is an alkali metal alkoxide. In some embodiments, the base present for the reaction of the compound of formula 16a with ethyl acetate is potassium tert-butoxide. In some embodiments, about 1 to about 3 molar equivalents of base 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 are utilized relative to the compound of formula 16a. In some embodiments, the reaction of the compound of formula 16a with ethyl acetate and a base is carried out at room temperature. In some embodiments, the reaction of the compound of formula 16a with ethyl acetate and a base is carried out in a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 16a with ethyl acetate is di-C 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 16a with ethyl acetate comprises tetrahydrofuran.

[0075] In some embodiments, the compound of formula 5a or a salt thereof is Compound of Formula 27a [ka] is prepared by a process which comprises hydrolyzing in the presence of a base in water.

[0076] In some embodiments, the base present for the hydrolysis of the compound of formula 27a is an alkali metal hydroxide. In some embodiments, the base present for the hydrolysis of the compound of formula 27a is sodium hydroxide. In some embodiments, about 1 to about 2 molar equivalents of base relative to the compound of formula 27a are utilized. In some embodiments, about 1.5 molar equivalents of base 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 a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the solvent component present for the hydrolysis of the compound of formula 27a comprises tetrahydrofuran, acetone, or a combination thereof.

[0077] 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.

[0078] In some embodiments, the product of hydrolysis of the compound of formula 27a is the sodium salt of the compound of formula 5a. In some embodiments, the process further comprises reacting the sodium salt of the compound of formula 5a with a strong acid to form the compound of formula 5a.

[0079] In some embodiments, the compound of formula 5a is prepared by a process comprising reacting the sodium salt of the compound of formula 5a with a strong acid. In some embodiments, the strong acid present for the reaction of the sodium salt of the compound of formula 5a is hydrochloric acid. In some embodiments, the reaction of the sodium salt of the compound of formula 5a with the strong acid and the hydrolysis of the compound of formula 27a are carried out in a single pot. In some embodiments, the compound of formula 27a is Compound of formula 26P [ka] with a strong acid, wherein P1 is an amino protecting group.

[0080] In some embodiments, P 1 is p-toluenesulfonyl. In some embodiments, the strong acid present for the reaction of the compound of formula 26P is hydrochloric acid. In some embodiments, the reaction of the compound of formula 26P with the strong acid is carried out at room temperature. In some embodiments, the reaction of the compound of formula 26P with the strong acid is carried out in a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 26P with the strong acid is a solvent component of formula C 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 26P with a strong acid comprises ethanol.

[0081] In some embodiments, the compound of formula 26P is Compound of formula 25P [ka] with an alkali metal alkoxide to form a compound of formula 26P, 1 is an amino protecting group.

[0082] In some embodiments, about 0.1 molar equivalents of an alkali metal alkoxide relative to the compound of formula 25P is utilized. In some embodiments, the reaction of the compound of formula 25P with the alkali metal alkoxide is carried out at room temperature. In some embodiments, the alkali metal alkoxide is sodium ethoxide. In some embodiments, the reaction of the compound of formula 25P with the alkali metal alkoxide is carried out in a solvent component, where the solvent component comprises a polar protic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 25P with the alkali metal alkoxide comprises an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 25P with the alkali metal alkoxide comprises a carboxylic acid of formula C. 1~6In some embodiments, the solvent component present for the reaction of the compound of formula 25P with an alkali metal alkoxide comprises ethanol.

[0083] In some embodiments, the compound of formula 27a is Compound of formula 25P [ka] with an alkali metal alkoxide to form a compound of formula 27a.

[0084] In some embodiments, about 1 to about 2 molar equivalents of an alkali metal alkoxide relative to the compound of formula 25P are utilized. In some embodiments, about 1 molar equivalent of an alkali metal alkoxide relative to the compound of formula 25P is utilized. In some embodiments, the reaction of the compound of formula 25P with the alkali metal alkoxide 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 the alkali metal alkoxide is carried out in a solvent component, where the solvent component present for the reaction of the compound of formula 25P with the alkali metal alkoxide is a solvent component of formula C. 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 25P with an alkali metal alkoxide comprises ethanol.

[0085] In some embodiments, the compound of formula 25P is Compound of formula 2P [ka] with diethyl malonate and a base, wherein P 1 is an amino protecting group.

[0086] In some embodiments, the base present for the reaction of the compound of formula 2P with diethyl malonate is an alkali metal carbonate. In some embodiments, the base present for the reaction of the compound of formula 2P with diethyl malonate is cesium carbonate. In some embodiments, the reaction of the compound of formula 2P with the base 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 is carried out in a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 2P with diethyl malonate comprises dimethylformamide.

[0087] In some embodiments, the compound of formula 2P is prepared by a process 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 and P 1 -Y, where Y is halo. 1 is p-toluenesulfonyl. In some embodiments, the compound of formula 12a and P 1 The base present for the reaction of -Y is an alkali metal hydroxide. In some embodiments, the compound of formula 12a and P 1 The base present for the reaction of -Y is sodium hydroxide. In some embodiments, the protection of the compound of formula 12a is carried out in a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the compound of formula 12a and P 1 Solvent components present for the reaction of -Y include acetone.

[0088] In some embodiments, the compound of formula 12a is A compound of formula 11a, [ka] or its salts are prepared by a process which includes reacting with a strong acid.

[0089] In some embodiments, the strong acid present for the reaction of the compound of formula 11a or a salt thereof is hydrochloric acid. In some embodiments, the reaction of the compound of formula 11a or a salt thereof with a strong acid is carried out in a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 11a or a salt thereof with a strong acid is di-C 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 11a or a salt thereof with a strong acid comprises tetrahydrofuran. In some embodiments, the reaction of the compound of formula 11a or a salt thereof with a strong acid is carried out at the reflux temperature of tetrahydrofuran.

[0090] In some embodiments, the compound of formula 11a is Compound of Formula 10a [ka] or its salt is prepared by a process which includes reacting with (methoxymethyl)triphenylphosphonium chloride and a base.

[0091] In some embodiments, the base present for the reaction of the compound of formula 11a or its salt with (methoxymethyl)triphenylphosphonium chloride is an alkali metal alkoxide. In some embodiments, the base present for the reaction of the compound of formula 11a or its salt with (methoxymethyl)triphenylphosphonium chloride is potassium tert-butoxide. In some embodiments, the reaction of the compound of formula 11a or its salt with (methoxymethyl)triphenylphosphonium chloride and a base 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 its salt with (methoxymethyl)triphenylphosphonium chloride and a base is carried out in a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 11a or its salt with (methoxymethyl)triphenylphosphonium chloride is a di-C 1~6 In some embodiments, the solvent component present for the reaction of the compound of formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride comprises tetrahydrofuran.

[0092] In some embodiments, the compound of formula 10a or a salt thereof is Compound of Formula 9a [ka] It is prepared by a process comprising reacting

[0093] 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 a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 9a with ammonia comprises toluene.

[0094] In some embodiments, the compound of formula 9a is Compound of Formula 8a [ka] It is prepared by a process which includes reacting 2-(2-methyl-2-propanediol)-2-propanediol with Vilsmeier reagent formed from dimethylformamide.

[0095] In some embodiments, the Vilsmeier reagent present for reaction with the compound of formula 8a is prepared by a process comprising reacting dimethylformamide with a chlorinating agent. In some embodiments, the chlorinating agent used to prepare the Vilsmeier reagent for reaction with the compound of formula 8a is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride. In some embodiments, the chlorinating agent used to prepare the Vilsmeier reagent for reaction with the compound of formula 8a to form the compound of formula 8a is phosphorus oxychloride. In some embodiments, about 4 to about 6 molar equivalents (e.g., 5 molar equivalents) of the chlorinating agent relative to the compound of formula 8a are utilized. In some embodiments, about 1 to about 3 molar equivalents (e.g., 2 molar equivalents) of dimethylformamide relative to the compound of formula 8a are utilized. In some embodiments, the reaction of dimethylformamide with the chlorinating agent is prepared 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. (eg, about 90° C. to about 120° C., or about 95° C. to about 115° C.). In some embodiments, the compound of formula 12a is Compound of Formula 15a [ka] With a chlorinating agent.

[0096] In some embodiments, the chlorinating agent present for reaction with the compound of formula 15a is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride. In some embodiments, the chlorinating agent present for reaction with the compound of formula 15a 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 a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the solvent component present for reaction with the compound of formula 15a comprises toluene.

[0097] In some embodiments, the compound of formula 15a is (i) Compound of formula 14a [ka] with formamidine acetate and an alkali metal alkoxide to produce a compound of formula 14aa; [ka] (ii) reacting a compound of formula 14aa with a strong acid.

[0098] In some embodiments, the alkali metal alkoxide present for the reaction with the compound of formula 14a is sodium ethoxide. In some embodiments, the reaction of the compound of formula 14a with formamidine acetate and an alkali metal alkoxide 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 alkoxide is carried out in a solvent component, where the solvent component comprises a polar protic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 14a with formamidine acetate and an alkali metal hydroxide comprises an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 14a with formamidine acetate and an alkali metal hydroxide comprises a methyl alcohol. 1~6 In some embodiments, the solvent component present for reaction with the compound of formula 14a comprises ethanol.

[0099] In some embodiments, the strong acid present for the reaction of the compound of formula 14aa is hydrochloric acid.

[0100] In some embodiments, the compound of formula 14a is Compound of Formula 13a [ka] is prepared by a process which includes reacting bromoacetaldehyde diethyl acetal and sodium tert-amyloxide.

[0101] 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 a solvent component, where the solvent component comprises a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 13a with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide comprises dimethylsulfoxide.

[0102] In some embodiments, the compound of formula 3 or salt thereof is Compound of Formula 6 [ka] It is prepared by a process which includes reacting

[0103] In some embodiments, the hydrazine is hydrazine hydrate.

[0104] In some embodiments, about 1 to about 3 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, about 1.5 to about 2.5 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, about 2 to about 2.2 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, about 2.1 molar equivalents of hydrazine are utilized relative to the compound of formula 6.

[0105] In some embodiments, the reaction of the compound of formula 6 is carried out in a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine comprises an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine comprises an aprotic organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine comprises acetonitrile.

[0106] In some embodiments, the reaction of the compound of Formula 6 with hydrazine is carried out at a temperature of about 20° C. to about 30° C. In some embodiments, the reaction of the compound of Formula 6 with hydrazine is carried out at ambient temperature.

[0107] In some embodiments, the compound of formula 6 is Compound of Formula 55 [ka] or its salt with ethanesulfonyl chloride to form a compound of formula 6.

[0108] In some embodiments, about 1 to about 2 molar equivalents of ethanesulfonyl chloride are utilized relative to the compound of Formula 55 or a salt thereof. In some embodiments, about 1.5 molar equivalents of ethanesulfonyl chloride are utilized relative to the compound of Formula 55 or a salt thereof.

[0109] In some embodiments, the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride is accomplished in the presence of a base. In some embodiments, the base present for the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride is a tertiary amine. In some embodiments, the base present for the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride is a tri-(C 1~6 In some embodiments, the base present for the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride is diisopropylethylamine.

[0110] In some embodiments, the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride is carried out in the presence of a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride comprises an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride comprises an aprotic organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 55 or a salt thereof with ethanesulfonyl chloride comprises acetonitrile.

[0111] In some embodiments, the reaction of the compound of Formula 55 or a salt thereof with ethanesulfonyl chloride is carried out at a temperature of about −10° C. to about 30° C. In some embodiments, room temperature is about 0° C. to about 5° C. In some embodiments, the temperature is about 0° C. to about 5° C. and then allowed to warm to room temperature.

[0112] In some embodiments, the compound of formula 55 or a salt thereof is Deprotecting the compound of formula 54 [ka] The compound of formula 55 or a salt thereof may be prepared by a process comprising forming a compound of formula 55 or a salt thereof, wherein P 50 is a protecting group.

[0113] In some embodiments, P 50 is R 50 -OC(O)-, where R 50 is C 1~6 In some embodiments, R 50 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. 50is t-butyl-OC(O)-. In some embodiments, the deprotection of the compound of formula 54 comprises treating the compound of formula 54 with a strong acid. In some embodiments, the strong acid present for the deprotection of the compound of formula 54 is HCl. In some embodiments, the deprotection of the compound of formula 54 is accomplished in a solvent component. In some embodiments, the solvent component present for the deprotection of the compound of formula 54 comprises a polar protic solvent and an organic solvent. In some embodiments, the solvent component present for the deprotection of the compound of formula 54 comprises an aprotic organic solvent. In some embodiments, the solvent component present for the deprotection of the compound of formula 54 comprises water and acetonitrile. In some embodiments, the deprotection of the compound of formula 54 is accomplished at ambient temperature.

[0114] In some embodiments, the compound of formula 55 or a salt thereof is the hydrochloride salt of the compound of formula 55.

[0115] In some embodiments, the compound of formula 54 is Compound of Formula 7 [ka] with diethyl cyanomethyl phosphate and a base to form a compound of formula 54.

[0116] In some embodiments, about 1 to about 1.5 molar equivalents of diethylcyanomethylphosphate are utilized relative to the compound of formula 7. In some embodiments, about 1.2 molar equivalents of diethylcyanomethylphosphate are utilized relative to the compound of formula 7. In some embodiments, the base present for the reaction of the compound of formula 7 with diethylcyanomethylphosphate is an alkali metal alkoxide. In some embodiments, the base present for the reaction of the compound of formula 7 with diethylcyanomethylphosphate is potassium tert-butoxide.

[0117] In some embodiments, the reaction of the compound of Formula 7 with diethylcyanomethylphosphate and a base is carried out at a temperature of about −20° C. to about 30° C. In some embodiments, the temperature is less than about −5° C. In some embodiments, the temperature is about −10° C. to about −5° C. and then allowed to warm to room temperature.

[0118] In some embodiments, the reaction of the compound of formula 7 with diethylcyanomethylphosphate and a base is carried out in a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 7 with diethylcyanomethylphosphate and a base is di-C 1~6 alkyl ether or 4-10 membered heterocycloalkyl ether. In some embodiments, the solvent component present for the reaction of the compound of formula 7 with diethylcyanomethylphosphate and a base comprises tetrahydrofuran.

[0119] In some embodiments, the compound of formula 7 is Oxidizing a compound of formula 56 [ka] The compound of formula 7 is prepared by a process comprising forming

[0120] In some embodiments, the oxidation of the compound of formula 56 is accomplished by a process comprising reacting the compound of formula 56 with TEMPO in the presence of sodium hypochlorite. In some embodiments, about 0.005 to about 0.02 equivalents of TEMPO relative to the compound of formula 56 are utilized. In some embodiments, about 0.01 equivalents of TEMPO relative to the compound of formula 56 are utilized. In some embodiments, the oxidation of the compound of formula 56 is carried out at a temperature of about -10°C to about 20°C. In some embodiments, the temperature is about 0°C to about 5°C.

[0121] In some embodiments, the oxidation of the compound of formula 56 is carried out in a solvent component. In some embodiments, the solvent component present for the oxidation of the compound of formula 56 comprises water and an organic solvent. In some embodiments, the solvent component present for the oxidation of the compound of formula 56 comprises a polar aprotic solvent. In some embodiments, the solvent component present for the oxidation of the compound of formula 56 comprises ethyl acetate.

[0122] In some embodiments, the compound of formula 56 is Compound of Formula 57 [ka] or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate; In the formula, P 50 is tert-butyl-OC(O)-.

[0123] In some embodiments, the catalyst present for the reaction of the compound of formula 57 or a salt thereof with hydrogen and di-tert-butyl dicarbonate is Pd 0 It is carbon.

[0124] In some embodiments, about 1 to about 1.5 molar equivalents of di-tert-butyl dicarbonate are utilized relative to the compound of formula 57. In some embodiments, about 1.1 molar equivalents of di-tert-butyl dicarbonate are utilized relative to the compound of formula 57. In some embodiments, the reaction of the compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate is carried out at a pressure of about 10 psi to about 50 psi. In some embodiments, the reaction of the compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate is carried out at a pressure of about 30 psi. In some embodiments, the reaction of the compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate is carried out at room temperature.

[0125] In some embodiments, the reaction of a compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate is carried out in a solvent component, where the solvent component comprises an organic solvent. In some embodiments, the solvent component present for the reaction of a compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate is di-C 1~6 In some embodiments, the solvent components present for the reaction of a compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate include tetrahydrofuran.

[0126] In some embodiments, the compound of formula 57 or salt thereof is the hydrochloride salt of formula 57.

[0127] In some embodiments, the compound of formula 57 or a salt thereof is prepared by a process comprising the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane. In some embodiments, about 1 to about 1.1 molar equivalents of diphenylmethanamine relative to 2-(chloromethyl)oxirane are utilized. In some embodiments, the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane is carried out at a temperature of about 20° C. to about 80° C. In some embodiments, the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane is carried out at room temperature and then heated to the reflux temperature of methanol. In some embodiments, the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane is carried out in a solvent component, where the solvent component comprises a polar protic solvent. In some embodiments, the solvent component present for the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane comprises an alcohol. In some embodiments, the solvent component present for the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane comprises a compound of formula C 1~6 In some embodiments, the solvent component present for the reaction of diphenylmethanamine with 2-(chloromethyl)oxirane comprises methanol.

[0128] The present disclosure relates to a salt of formula 2c [ka] with a compound of formula 3, [ka] There is further provided a process for preparing baricitinib or a salt thereof, comprising forming baricitinib or a salt thereof.

[0129] In some embodiments, the salt of formula 2c is a salt of formula 2d [ka] with a base to form a salt of formula 2c.

[0130] In some embodiments, the salt of formula 2d is (a) Compound of formula 2P [ka] with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 1aP; [ka] (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; In the formula, P 1 is an amino protecting group. In some embodiments, P 1 is trimethylsilyl.

[0131] In some embodiments, the salt of formula 2d is (a) Compound of formula 22P [ka] with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 23P; [ka] (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; In the formula, P 2 is an amino protecting group. In some embodiments, P 1 is t-butyldimethylsilyl.

[0132] In some embodiments, the compound of formula 3 or salt thereof is Compound of Formula 6 [ka] It is prepared by a process which includes reacting

[0133] In some embodiments provided herein is a method for treating a pulmonary artery disease comprising: (a) A compound of formula 1a or a salt thereof [ka] with the Vilsmeier reagent formed from dimethylformamide to produce a salt of formula 2c; [ka] (b) a salt of formula 2c and a salt of formula M +ClO4 - to produce a salt of formula 2a, [ka] In the formula, M + is the counter cation, and X - is ClO4 - And, (c) reacting a salt of formula 2a with a compound of formula 3 [ka] or a salt thereof to form baricitinib or a salt thereof.

[0134] In some embodiments provided herein is a method for treating a pulmonary artery disease comprising: (a) Compound of Formula 5a [ka] with the Vilsmeier reagent formed from dimethylformamide to produce a salt of formula 2c; [ka] (b) a salt of formula 2c and a salt of formula M + ClO4 - to produce a salt of formula 2a, [ka] In the formula, M + is the counter cation, and X - is ClO4 - And, (c) reacting a salt of formula 2a with a compound of formula 3 [ka] or a salt thereof to form baricitinib or a salt thereof.

[0135] In some embodiments provided herein is a method for treating a pulmonary artery disease comprising: (a) Compound of Formula 6 [ka] is reacted with hydrazine to give a compound of formula 3 [ka] or a salt thereof; (b) a compound of formula 3 or a salt thereof and a salt of formula 2a [ka] to produce baricitinib or a salt thereof, wherein M + is the counter cation, and X - is ClO4 - It is.

[0136] In some embodiments, the compound of formula 1a [ka] or a salt thereof. (a) Compound of Formula 12a [ka] with trimethylsilyl chloride to produce a compound of formula 2P, [ka] In the formula, P 1 is trimethylsilyl, (b) reacting a compound of formula 12b with MeMgBr in the presence of a Grignard catalyst to produce a compound of formula 12c; [ka] (c) deprotecting a compound of formula 12d to form a compound of formula 1a or a salt thereof.

[0137] In some embodiments, the compound of formula 12a [ka] teeth, (a) Compound of Formula 13a [ka] with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide to produce a compound of formula 14a; [ka] (b) reacting a compound of formula 14a with formamidine acetate and an alkali metal alkoxide to produce a compound of formula 14aa; [ka] (c) reacting a compound of formula 14aa with a strong acid to produce a compound of formula 15a; [ka] (d) reacting a compound of formula 15a with a chlorinating agent to form a compound of formula 12a.

[0138] In some embodiments, the compound of formula 1a [ka] or a salt thereof. (a) a compound of formula 22a, [ka] with t-butyldimethylsilyl chloride and an alkali metal hydride to produce a compound of formula 22P; [ka] In the formula, P 2is t-butyldimethylsilyl, (b) reacting a compound of formula 22P with MeMgBr in the presence of a Grignard catalyst to produce a compound of formula 23a; [ka] (c) reducing the compound of formula 23a with hydrogen and palladium on carbon to form a compound of formula 1a, or a salt thereof, wherein P 2 is an amino protecting group.

[0139] In some embodiments, the compound of formula 6 is (a) reacting diphenylmethanamine with 2-(chloromethyl)oxirane to produce a compound of formula 57 or a salt thereof; [ka] (b) reacting a compound of formula 57, or a salt thereof, with hydrogen, palladium on carbon, and di-tert-butyl dicarbonate to produce a compound of formula 56a; [ka] (c) oxidizing the compound of formula 56a to form a compound of formula 7a; [ka] (d) reacting a compound of formula 7a with diethylcyanomethylphosphate and a base to produce a compound of formula 54a; [ka] (e) deprotecting the compound of formula 54a to form a compound of formula 55 or a salt thereof; [ka] (f) reacting a compound of formula 55, or a salt thereof, with ethanesulfonyl chloride to form a compound of formula 6.

[0140] In some embodiments, the compound of formula 3 [ka] or a salt thereof provided herein.

[0141] In some embodiments, provided herein is a method for treating a pulmonary artery disease comprising: Compound of Formula 6 [ka] with hydrazine.

[0142] In some embodiments, the hydrazine is hydrazine hydrate. In some embodiments, about 1 to about 3 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, about 1.5 to about 2.5 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, about 2 to about 2.2 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, about 2.1 molar equivalents of hydrazine are utilized relative to the compound of formula 6. In some embodiments, the reaction of the compound of formula 6 with hydrazine is carried out in a solvent component. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine comprises an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine comprises an aprotic organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine comprises acetonitrile. In some embodiments, the reaction of the compound of formula 6 with hydrazine is carried out at a temperature of about 20° C. to about 30° C. In some embodiments, the reaction of the compound of formula 6 with hydrazine is carried out at ambient temperature.

[0143] 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, the term "C 1~6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0144] It will be further understood that certain features of the invention that are described in the context of separate embodiments may also be provided in combination in a single embodiment for clarity Conversely, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable subcombination for brevity.

[0145] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be linear 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, n-octyl, and the like. 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.

[0146] As used herein, the terms "halo" and "halogen," employed alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodo.

[0147] As used herein, the term "4-10 membered heterocycloalkyl ether" refers to a non-aromatic ring or ring system that optionally contains one or more alkenylene groups as part of the ring structure having at least one oxygen heteroatom ring member and 4-10 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Examples of 4-10 membered heterocycloalkyl ethers include tetrahydrofuran, tetrahydropyran, dioxane, and the like.

[0148] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, or spectrophotometry (e.g., UV-visible), or the like, or chromatography, e.g., high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), or other related techniques.

[0149] As used herein, the terms "reacting" and "contacting" are used as known in the art and generally refer to bringing together chemical reagents 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, where one or more equivalents of the second reagent relative to the first reagent are used. The reaction steps of the processes described herein may be carried out for times and under conditions suitable for the preparation of the specified product.

[0150] In some embodiments, the reagents and intermediates may be salts.

[0151] The present disclosure also includes 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 term "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, those derived from organic and inorganic acids, such as, but not limited to, acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, and similar known acceptable acids. 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.

[0152] Preparation of compounds may involve protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemical nature of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d.Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be made as necessary to take into account various substituents.

[0153] The reactions of the processes described herein can be carried out in a suitable solvent that can be easily selected by those 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, which can range, for example, 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 two or more solvents. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected. 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.

[0154] 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.

[0155] 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.

[0156] 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, neopentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, mixtures thereof, and the like.

[0157] 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, dimethylsulfoxide, 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.

[0158] Suitable hydrocarbon solvents may 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. Supercritical carbon dioxide and ionic liquids may also be used as solvents.

[0159] The reactions of the processes described herein may be carried out at any suitable temperature, which may be readily determined by one of ordinary skill in the art. The reaction temperature depends, for example, on the melting and boiling points of the reagents and solvents (if present), the thermodynamics of the reaction (e.g., highly exothermic reactions may need to be carried out at reduced temperatures), and the kinetics of the reaction (e.g., high activation energy barriers may require elevated temperatures). "Elevated temperature" refers to a temperature higher than room temperature (about 22°C). The reactions of the processes 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.

[0160] In some embodiments, preparation of compounds may involve the addition of acids or bases to affect catalysis of a desired reaction or the formation of a salt form, such as an acid addition salt.

[0161] Exemplary acids may 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.

[0162] 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 oxides, 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.

[0163] The present disclosure also includes salt forms of the compounds described herein.Exemplary 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 free base or acid with stoichiometric or excess amount of desired salt-forming inorganic or organic acid or base in appropriate 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. In carrying out the preparation of compounds according to the processes described herein, conventional isolation and purification procedures such as concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography, and the like can be used to isolate the desired product.

[0164] In some embodiments, the compounds of the present invention and their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, compositions enriched in the compounds of the present invention. Substantial separation can include compositions that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the present invention or their salts. Methods for isolating compounds and their salts are routine in the art.

[0165] In some embodiments, baricitinib, intermediates for preparing baricitinib 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 that include solid forms. Forms with low melting points are often less thermodynamically stable, but they are advantageous in terms of increasing water solubility and thus increasing the bioavailability of the drug. Forms with low hygroscopicity are desirable for their stability to heat and humidity, and are resistant to degradation during long-term storage.

[0166] In some embodiments, the disclosed compound or its salt is crystalline.As used herein, "crystalline" or "crystal form" refers to a certain lattice arrangement of crystalline material.Different crystal forms of the same material typically have different crystal lattices (e.g., unit cells), which are due to the different physical properties characteristic of each crystal form.In some cases, different lattice arrangements have different water or solvent contents. 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 aid in the identification of the forms, as well as in determining stability and solvent / water content. XRPD patterns of reflections (peaks) are typically considered as fingerprints of a particular crystal morphology. It is well known that the relative intensities of XRPD peaks can vary widely 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 can be observed or existing peaks can 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, instrumental variations and other factors can affect 2-theta values. Thus, peak assignments such as those reported herein can 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 meant to encompass the above-mentioned variations.

[0167] Similarly, temperature readings for DSC, TGA, or other thermal experiments may vary by about ±3° C. depending on the instrument, the particular settings, sample preparation, etc. Thus, crystalline forms reported herein having "substantially" the DSC thermograms shown in any of the figures, or the term "about," are understood to accommodate such variations.

[0168] Generally, the term "about" means ±10%. In some embodiments, the term "about" means ±5%.

[0169] In some embodiments, the solid and salt forms are substantially isolated. "Substantially isolated" means that the solid, salt, 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 that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the solid and salt forms. Methods for isolating the solid and salt forms thereof are routine in the art.

[0170] In some embodiments, the solid forms and salt forms described herein may be found together with other substances, such as water and solvents (eg, hydrates and solvates), or may be isolated.

[0171] The phrase "pharmacologically 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.

[0172] The reactions described herein may be carried out at any suitable temperature, which may be readily determined by one of skill in the art. The reaction temperature depends, for example, on the melting and boiling points of the reagents and solvent (if present), the thermodynamics of the reaction (e.g., highly exothermic reactions may need to be carried out at reduced temperatures), and the kinetics of the reaction (e.g., high activation energy barriers may require elevated temperatures).

[0173] As used herein, the expressions "ambient temperature" and "room temperature" or "rt" are understood in the art and generally refer to a temperature, e.g., a reaction temperature that is close to the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C. Protecting groups as described herein (e.g., P 1 , P 2 , P 50 Protective groups such as those detailed in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, pages 696-887 (and, in particular, pages 872-887) (2007), which is incorporated herein by reference in its entirety. Examples of protecting groups as 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- Dimethylpent-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 1~4In some embodiments, the protecting group is p-toluenesulfonyl.

[0174] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. 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. EXAMPLES

[0175] Example 1. Preparation of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (baricitinib, compound 1) [ka] Step 1. 2-(1-(ethylsulfonyl)-3-hydrazineylazetidin-3-yl)acetonitrile (compound 3): A flask under nitrogen was charged with 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (compound 6, 1.0 g, 5.37 mmol) and acetonitrile (10 mL). Hydrazine hydrate (0.66 g, 11.3 mmol, 2.1 equiv.) was added slowly to the reaction mixture over 30 minutes with the reaction temperature controlled below 25° C. The reaction was completed after stirring at ambient temperature for 2 hours. After completion, the reaction solvent was evaporated under reduced pressure. The remaining reaction mixture was diluted with dichloromethane (CH2Cl2, 20 mL) and washed with brine (10 mL). The organic layer was separated and collected. The aqueous layer was extracted with another portion of dichloromethane (CH2Cl2, 10 mL) and the organic layer was collected. The combined organic layers were evaporated under reduced pressure. The crude desired product, 2-(1-(ethylsulfonyl)-3-hydrazineylazetidin-3-yl)acetonitrile (compound 3, 0.82 g, 72%), was obtained as a gel, which was used directly in the next step without further purification. 1 H NMR(CDCl3,400MHz)δ3.97(d,J=8.8Hz,2H),3.68(d,J=8.9Hz,2H),3.35(br,3H),2.99(q,J=7.4Hz,2H),2.93(s,2H),1.33(t,J=7.4Hz,3H)ppm; 13 C NMR(CDCl3,101MHz)δ117.22,57.43,55.36,45.72,24.69,7.86ppm;C7H 14 N4O2S(MW:218.28),LCMS(EI)m / e 219.2(M + +H).

[0176] Step 2. 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (baricitinib, compound 1): To a solution of 2-(1-(ethylsulfonyl)-3-hydrazineylazetidin-3-yl)acetonitrile (compound 3, 0.84 g, 3.85 mmol, 1.32 equiv.) in ethanol (8 mL) was added vinamidinium perchlorate (compound 2 perchlorate, 1.0 g, 2.91 mmol) in one portion. The resulting reaction mixture was stirred at ambient temperature for 16 h. n-heptane (16 mL) was added to the reaction mixture and the resulting mixture was stirred at ambient temperature for an additional 1 h. The reaction mixture was filtered and the solids were washed with n-heptane (10 mL). After drying overnight by drawing air through the wet cake, the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (baricitinib, compound 1, 1.2 g, 85%), was obtained as a brown solid. For baricitinib (compound 1): 1 H NMR(DMSO-d6,300MHz)δ 12.15(s,1H),8.94(s,1H),8.72(s,1H),8.49(s,1H),7.63(d,1H),7.09(d, 1H),4.62(d,2H),4.25(d,2H),3.71(s,2H),3.24(q,2H),1.26(t,3H)ppm;C 16 H 17 N7O2S(MW,371.42),LCMS(EI)m / e 372(M + +H).

[0177] Example 2: Preparation of 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (Compound 6) [ka] Step 1. tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (compound 54a): Diethyl cyanomethyl phosphate (745 g, 4.20 mol, 1.20 equiv.) and anhydrous tetrahydrofuran (THF, 9 L) were added at room temperature to a four-neck flask equipped with a thermowell, an addition funnel, and a nitrogen protection tube. The solution was cooled to −14° C. in an ice-methanol bath, and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv.) was added over 20 min while maintaining the reaction temperature below −5° C. The resulting reaction mixture was stirred at −10° C. for 3 h, and a solution of tert-butyl 3-oxoazetidine-1-carboxylate (compound 7a, 600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h while maintaining the internal temperature below −5° C. The reaction mixture was stirred at -5 to -10 °C for 1 h, then gradually warmed to room temperature and stirred at room temperature overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2 x 9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The organic solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CHCl2, 4 L) and then absorbed onto silica gel (SiO2, 1.5 Kg). The crude product absorbed onto silica gel was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc / hexane gradient elution) to give tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (compound 54a, 414.7 g, theoretical 679.8 g, 61% yield) as a white solid. For compound 54a: 1 HNMR(CDCl3,300MHz),δ 5.40(m,1H),4.70(m,2H),4.61(m,2H),1.46(s,9H)ppm;C 10 H 14 N2O 2( MW, 194.23), LCMS(EI) m / e 217(M + +Na).

[0178] Step 2. 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (Compound 6): A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (compound 54a, 1000 g, 5.2 mol) in acetonitrile (7 L) and 3N aqueous HCl (7 L) was stirred at room temperature for 18 h. When HPLC showed that all starting material (tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate) had been consumed, the reaction mixture was concentrated to dryness under reduced pressure. The residue containing the crude desired deprotected product (compound 55a) was then suspended in acetonitrile (12 L) and the resulting suspension was then cooled to 0-5 °C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv.) was then added slowly while keeping the internal temperature below 5 °C. The resulting homogeneous solution was cooled to 0°C and ethanesulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv.) was added over 1 h while maintaining the internal temperature below 5°C. The resulting reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. When HPLC showed the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator was set not to exceed 45°C. The concentrated residue was then diluted with dichloromethane (CHCl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride (10 L). The aqueous phase was back-extracted with dichloromethane (CHCl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (NaSO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set not to exceed 45°C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60% ethyl acetate in heptane to give 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (compound 6, 882 g, theoretical 968.4 g, 91% yield) as an off-white solid. For compound 6: 1 H NMR(CDCl3,300MHz)δ 5.46(m,1H),4.77(m,2H),4.70(m,2H),3.05(q,2H),1.39(t,3H)ppm;C7H 10N2O2S(MW,186.23),LCMS(EI)m / e 187(M + +H).

[0179] Example 3: Preparation of tert-butyl 3-oxoazetidine-1-carboxylate (compound 7a) [ka] Step 1. 1-Benzhydrylazetidin-3-ol hydrochloride (compound 57a): A solution of diphenylmethanamine (2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 L) was treated with 2-(chloromethyl)oxirane (1330 g, 14.5 mol) via addition funnel at room temperature. A slight endotherm was observed during the initial addition. The resulting reaction mixture was stirred at room temperature for 3 days and then warmed to reflux for an additional 3 days. When TLC indicated that the reaction was deemed complete, the reaction mixture was cooled first to room temperature and then to 0-5° C. in an ice bath. The solids were collected by filtration and washed with acetone (4 L) to give a first crop of crude desired product (1516 g). The filtrate was concentrated under reduced pressure and the resulting semi-solid was diluted with acetone (1 L). The solids were then collected by filtration to give a second crop of crude desired product (221 g). The crude product, 1-benzhydrylazetidin-3-ol hydrochloride (compound 57a, 1737 g, theoretical 3998.7 g, 43.4% yield), was found to be pure enough for use in subsequent reactions without further purification. 1 C 16 H 18 ClNO (free base of 57a, C 16 H 17 NO MW,239.31),LCMS(EI)m / e 240(M + +H).

[0180] Step 2. tert-Butyl 3-hydroxyazetidine-1-carboxylate (compound 56a): A suspension of 1-benzhydrylazetidin-3-ol hydrochloride (compound 57a, 625 g, 2.27 mol) in a 10% solution of aqueous sodium carbonate (Na2CO3, 5 L) and dichloromethane (CHCl2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated and the aqueous layer was extracted with dichloromethane (CHCl2, 2 L). The combined organic extracts were dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting crude free base of 1-benzhydrylazetidin-3-ol hydrochloride was dissolved in tetrahydrofuran (THF, 6 L) and the solution was placed in a large Parr bomb. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv.) and 20% palladium (Pd) on carbon (125 g, 50% moisture) were added to the Parr bomb. The vessel was charged with hydrogen gas (H2) to 30 psi and stirred under a constant hydrogen atmosphere (the vessel was refilled three times to maintain the pressure at 30 psi) at room temperature for 18 hours. When HPLC indicated the reaction was complete (no more hydrogen was being taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrate was concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimal amount of dichloromethane (CH2Cl2). The column was eluted with 20-50% ethyl acetate in heptane and fractions containing pure desired product were collected and combined. The solvent was removed under reduced pressure to give tert-butyl 3-hydroxyazetidine-1-carboxylate (compound 56a, 357 g, theoretical 393.2 g, 90.8% yield) as a colorless oil that solidified upon standing in vacuum at room temperature. For compound 56a: 1 HNMR (CDCl3, 300MHz), δ 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.

[0181] Step 3. tert-Butyl 3-oxoazetidine-1-carboxylate (Compound 7a): A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (compound 56a, 50 g, 289 mmol) in ethyl acetate (400 mL) was cooled to 0 °C. The resulting solution was then treated with solid TEMPO (0.5 g, 3.2 mmol, 0.011 equiv.) and a solution of potassium bromide (KBr, 3.9 g, 33.2 mmol, 0.115 equiv.) in water (60 mL) at 0-5 °C. Saturated aqueous sodium bicarbonate (NaHCO3, 450 mL) and aqueous sodium hypochlorite (NaClO, 10-13% available chlorine, 450 mL) were added while maintaining the reaction temperature at 0-5 °C. Upon addition of the sodium hypochlorite solution, the color of the reaction mixture changed immediately. As additional amounts of sodium hypochlorite solution were added, the color of the reaction mixture gradually faded. When TLC showed that all starting material had been consumed, the color of the reaction mixture no longer changed. The reaction mixture was then diluted with ethyl acetate (EtOAc, 500 mL) and the two layers were separated. The organic layer was washed with water (500 mL) and saturated aqueous sodium chloride solution (500 mL) and dried over sodium sulfate (Na2SO4). The solvent was then removed under reduced pressure to give the crude product tert-butyl 3-oxoazetidine-1-carboxylate (compound 7a, 48 g, theoretical 49.47 g, 97% yield), which was found to be sufficiently pure and was used directly in the subsequent reaction without further purification. For crude compound 7a: 1 HNMR (CDCl3, 300MHz), δ 4.65 (s, 4H), 1.42 (s, 9H) ppm.

[0182] Example 4. Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (the chloride hydrochloride of compound 2, or compound 2d) [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 addition of DMF. The ice batch was removed and the reaction mixture was allowed to warm gradually 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 at ambient temperature as a solid into the in situ generated Vilsmeier reagent and the resulting slurry was stirred at ambient temperature for 5-10 min to ensure complete mixing before warming to 85-90 °C. The reaction mixture was stirred at 85-90° C. for 1 h and then cooled slowly to ambient temperature. Anhydrous tetrahydrofuran (THF, 100 mL) was charged and the resulting slurry was stirred at ambient temperature for 2 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 (2×100 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 hydrochloride (2d, 24.38 g, 23.72 g theoretical, 98.9% by HPLC area %, 90.2% by NMR, 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: 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).

[0183] Crystalline form I of compound 2d was characterized by XRPD, DSC, and TGA. X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) was 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, 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 speed 2 degrees / min.

[0184] 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 FIG. 1 and the peak data is provided in Table 1. [Table 1]

[0185] 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 nitrogen gas flow rate of 50 mL / min. DSC analysis of compound 2d, crystalline form I, revealed one 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.

[0186] Thermogravimetric analysis (TGA): TGA was obtained from a TA Instruments thermogravimetric analyzer, Discovery TGA5500 equipped with an autosampler. The general experimental conditions for TGA were as follows: 25°C to 300°C ramp at 10°C / min, nitrogen purge gas flow of 25mL / min, platinum sample holder. TGA analysis of compound 2d, crystalline form I, revealed a weight loss of 8.0% 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.

[0187] Example 5: 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 addition of DMF. The ice bath was removed and the reaction mixture was allowed to warm gradually to ambient temperature over 40 min. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (the hydrochloride salt of compound 1a, 25.44 g, 150 mmol) was charged in one portion as a solid into the in situ generated Vilsmeier reagent at ambient temperature and 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 h and then cooled slowly to ambient temperature. Anhydrous tetrahydrofuran (THF, 200 mL) was charged and the resulting slurry was stirred at ambient temperature for 48 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 x 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 hydrochloride (compound 2d, 46.17 g, 47.43 g theoretical, 99.5% by HPLC area %, 95.2% by NMR, 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).

[0188] The crystalline form II of compound 2d was characterized by XRPD, DSC, and TGA. X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) was 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, 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 speed 2 degrees / min.

[0189] 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 FIG. 4 and the peak data is provided in Table 2. [Table 2]

[0190] 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 nitrogen gas flow rate of 50 mL / min. DSC analysis of compound 2d, crystalline form II, revealed one 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.

[0191] Thermogravimetric analysis (TGA): TGA was obtained from a TA Instruments thermogravimetric analyzer, Discovery TGA5500 equipped with an autosampler. The general experimental conditions for TGA were as follows: 25°C to 300°C ramp at 10°C / min, nitrogen purge gas flow of 25mL / 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.

[0192] Example 6: 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 addition of DMF. The ice batch was removed and the reaction mixture was allowed to warm gradually 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 and 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 h and then cooled slowly to ambient temperature. Anhydrous tetrahydrofuran (THF, 100 mL) was charged and the resulting slurry was stirred at ambient temperature for 2 h followed by 2 h 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 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, 96.1% by HPLC area %, 69.0% by NMR, 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. 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).

[0193] 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 or compound 2c) using POCl3 [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 addition of DMF. The ice batch was removed and the reaction mixture was allowed to warm gradually 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 at ambient temperature as a solid into the in situ generated Vilsmeier reagent and 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 h and then cooled slowly to ambient temperature. Anhydrous tetrahydrofuran (100 mL) was charged and the resulting slurry was stirred at ambient temperature for 2 h followed by 2 h 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 solution (NaOH, 19.06 g) at 0-5° C. The neutralized aqueous solution was then treated with charcoal (5.5 g) and stirred at ambient temperature for 12 hours. The charcoal was removed by filtration through a bed of Celite, and the Celite bed was washed with water (50 mL). The resulting aqueous solution containing the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (compound 2c, purity by HPLC area % >99.0%), was used in the subsequent reaction without further treatment.

[0194] 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 ((CCl3O)2CO, 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 allowed to warm gradually 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 at ambient temperature as a solid into the in situ generated Vilsmeier reagent and 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 cooled slowly 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, 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 subsequent reactions without further purification. For 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).

[0195] 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 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 perchlorate (NaClO4, 1.933 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)arylidene)-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 compound 2 perchlorate salt and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0196] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium tetrafluoroborate (tetrafluoroborate 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 (NaBF4, 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)arylidene)-N-methylmethanaminium tetrafluoroborate (tetrafluoroborate of compound 2, 1.80 g, theoretical 3.49 g, 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) m / e 244.2 (M + , base peak).

[0197] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluorophosphate (hexafluorophosphate 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), generated from 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.19 g, 91.6 mmol) via the corresponding Vilsmeier reaction described in Example 4, in water (80 mL), aqueous sodium hydroxide (NaOH) was added 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 bed of celite, and the wet charcoal cake was washed with water (15 mL). Sodium hexafluorophosphate (NaPF6, 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 of compound 2, 24.30 g, 35.81 g theoretical, 67.9% yield, 98.7% by HPLC area%) as a white crystalline solid, which was used in subsequent reactions without further purification. The crude hexafluorophosphate salt of compound 2 can be purified by recrystallization from water to produce 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 compound 2 hexafluorophosphate salt, 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak). The crystallinity of hexafluorophosphate of compound 2 was characterized by XRPD, DSC and TGA.

[0198] X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) was 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, 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 FIG. 7, and the peak data is provided in Table 3. [Table 3-1] [Table 3-2]

[0199] 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 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 due to melting, and a second endothermic peak with an onset of 241.1 °C and a maximum of 242.1 °C due to decomposition. The DSC thermogram of the hexafluorophosphate salt of compound 2 is shown in Figure 8.

[0200] Thermogravimetric Analysis (TGA): TGA was obtained from a TA Instruments Thermogravimetric Analyzer, Discovery TGA5500 equipped with an autosampler. General experimental conditions for the TGA were as follows: 25° C. to 300° C. ramp at 10° C. / min, nitrogen purge gas flow 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 shown in FIG. 9.

[0201] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluoroarsenate (hexafluoroarsenate 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 (NaAsF6, 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 of compound 2, 4.51 g, theoretical 4.56 g, 99% yield) as a white solid, which was used in the subsequent reaction without further purification. For the hexafluoroarsenate 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 compound 2 hexafluoroarsenate and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0202] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium hexafluoroantimonate (hexafluoroantimonate 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) at ambient temperature was added sodium hexafluoroantimonate (NaSbF6, 4.08 g, 15.79 mmol, 1.50 equiv.). 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 of compound 2, 2.61 g, theoretical 5.05 g, 51.7% yield) as a white solid, which was used in subsequent reactions without further purification. For hexafluoroantimonate 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, 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0203] 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 charged slowly over 15 min into DMF (107 mL, 1378 mmol, 18.4 equiv) while maintaining the internal temperature below 50° C. After addition, the resulting slurry was cooled to ambient temperature and stirred at ambient temperature for 2 h. 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 h followed by 50° C. for 5.5 h. The reaction mixture was cooled to ambient temperature and quenched with ice (60 g). The quenched reaction mixture was concentrated under vacuum 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 added slowly. The solid was collected by filtration, washed with water (30 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 (perchlorate of compound 2, 18.7 g, theoretical 25.78 g, 72.5% yield) as a grey 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 compound 2 perchlorate salt and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0204] Method 2 [ka] To a solution of 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 5a, 354 mg, 2.0 mmol) in anhydrous DMF (2.92 g, 3.1 mL, 40 mmol, 20 equiv.) at ambient temperature was added phosphorus oxychloride (POCl3, 920 mg, 0.56 mL, 6.0 mmol, 3.0 equiv.). 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 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 charcoal (50 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 (2 mL). The combined filtrate and washing solution was 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 h, followed by stirring at 0-5 °C for 1 h. The solid was then collected by filtration, washed with water (2 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 perchlorate (perchlorate of compound 2, 330 mg, theoretical 688 mg, 48% yield) as a grey solid, which was used in the subsequent reaction without further purification. For the perchlorate 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 compound 2 perchlorate salt and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M +, base peak).

[0205] 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.) at ambient temperature was added phosphorus oxychloride (POCl3, 3.93 g, 2.4 mL, 25.6 mmol, 3.0 equiv.). 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 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 charcoal (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 washing solution was 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 stirring at 0-5 °C for 1 h. 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)arylidene)-N-methylmethanaminium perchlorate (perchlorate of compound 2, 1.3 g, theoretical 2.94 g, 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 compound 2 perchlorate salt and 244.32 for compound 2 without anion) LCMS (EI) m / e 244.2 (M + , base peak).

[0206] 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) 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. [ka]

[0207] The resulting mixture was stirred at ambient temperature for 30 min. 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 followed by stirring at 50 °C for 4 h. 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 h. 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 an ice batch 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 give 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, theoretical 7.113 g, 89% yield) as a grey powder, which was used directly in the subsequent reaction without further purification. For compound 2b: 1 H 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).

[0208] Example 12: 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 4-neck flask equipped with a mechanical stirrer, addition funnel, condenser, thermocouple, and N2 sweep into 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. Crystallization occurred after approximately 100 mL of DMF was added over approximately 0.5 h, and the reaction temperature rose from 0 to 10 °C. The addition was stopped and the mixture was cooled again to approximately 2 °C. The remaining DMF was added over 2.5 h at <8 °C. The suspension was very viscous and difficult to stir. Once the addition of DMF 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 had been added, the reaction mixture became more fluid and a slow exotherm occurred, causing the reaction temperature to rise to approximately 12°C over 0.5 hours. The remaining 4,6-dihydroxypyrimidine was added portionwise over 0.25 hours, causing the reaction temperature to rise from 12 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 hour, 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 rise to approximately 63°C and remained at this temperature for several minutes before decreasing. Heating of the mixture was resumed, and eventually a gentle reflux (approximately 100°C) was achieved. At about 95°C, a steady and fairly rapid evolution of HCl gas began and the reaction mixture gradually thinned and darkened. After about 0.5 h, a clear brown solution resulted and the reflux temperature slowly increased to 115°C over 1.25 h. After a total of 2.5 h of reflux, the reaction mixture was cooled to ambient temperature and stirred at ambient temperature overnight. Excess POCl3 (as much as possible) was removed under reduced pressure (bath temperature 45-50°C). The thick residual brown oil was poured very slowly into cold H2O (5 L) in a 20 L separatory funnel, ice being added as needed to keep 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 NaHCO3 (1 L), brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure (bath temperature 35° C.) to give crude 4,6-dichloropyrimidine-5-carbaldehyde (compound 9a, 270 g, theoretical 395 g, 68.4%) as a yellow-orange solid. A 20 g aliquot 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. For 4,6-dichloropyrimidine-5-carbaldehyde: 1 H NMR (300MHz, CDCl3) δ 10.46(s,1H),8.89(s,1H)ppm.

[0209] Step 2. 4-Amino-6-chloropyrimidine-5-carbaldehyde (compound 10a): A solution of 7M NH3 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) over 1.25 h at ambient temperature. The reaction temperature slowly increased from 20 to 26 °C, forming a yellow suspension. Gentle cooling was applied to keep the reaction temperature below 26 °C. The suspension was stirred at ambient temperature for 3.5 h, after which 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 h, filtering, followed by stirring in THF (750 mL) for 1 h, 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, theoretical 146.5 g) was 78.6%. For 4-amino-6-chloropyrimidine-5-carbaldehyde: 1 HNMR(300MHz,DMSO-d6)δ 10.23(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).

[0210] 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 diluted with 1 M potassium tert-butoxide (KO tBu) was added over 1.5 h at -2 to -3 °C. The deep red-orange mixture was stirred at -2 to -3 °C for 1 h. Subsequently, 4-amino-6-chloropyrimidine-5-carbaldehyde (compound 10a, 115.2 g, 0.7338 mol, 1.0 equiv.) was added portionwise to the reaction mixture as a solid form 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 H2O (1 L). The organic phase was filtered to remove insoluble material at the interface and then extracted with 2N HCl (4×250 mL) followed by 3N 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 6N aqueous NaOH, and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, 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 light 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, theoretical 136.2 g, 53.1%). The crude desired product compound 11a was used in the next reaction without further purification. A sample of crude compound 11a (2.3 g) was purified by silica gel column chromatography eluting with 0%-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 (300MHz, DMSO-d6) For E-isomer: δ 8.02(s,1H),7.08(bs,2H),6.92(d,1H,J=13.1),5.35(d,1H,J=13.0Hz),3.68(s,3H)ppm, For Z-isomer: δ 8.06(s,1H),7.08(bs,2H),6.37(d,1H,J=6.8Hz),5.02(d,1H,J=6.7Hz),3.69(s,3H)ppm;C7H8ClN3O(MW,185.61),LCMS(EI)m / e 186 / 188(M + +H).

[0211] 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 h. 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 h. Charcoal (7 g), silica gel (7 g), and Na2SO4 (20 g) were added and the mixture was heated to 40 °C for 1 h. 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 (12a, 58.1 g, theoretical 58.1 g, 100%) as a tan solid. The crude desired product, 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 about 500 mL and the suspension was allowed to stand overnight at ambient temperature. The suspension was then cooled to 0-5 °C over 2 h and the solid was collected by filtration. The solid was dried to give pure 4-chloro-7H-[pyrrolo[2,3-d]pyrimidine (12a, 54.5 g, theoretical 58.1 g, 94%) as tan crystals. For 12a: 1 H NMR(400MHz,DMSO-d6)δ 12.58(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).

[0212] Example 13: Alternative preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) [ka] Step 1. Ethyl 2-cyano-4,4-diethoxybutanoate (Compound 14a): A mixture of ethyl cyanoacetate (compound 13a, 182 Kg, 1609 mol) and DMSO (325 Kg) was added with sodium tert-amyloxide ( t AmONa, 158.8 Kg) was added in portions. The mixture was then warmed to 70-75°C and ethyl cyanoacetate (191 Kg, 1689 moles, total 3298 moles, 5.0 equiv.) was charged. The mixture was stirred at 70-75°C for 30 minutes, followed by addition of bromoacetaldehyde diethyl acetal (130.4 Kg, 665.2 moles). 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, followed by addition of ethyl acetate (490 Kg). 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 solution (NaCl, 318 Kg) and brine (325 Kg). The organic solution was dried over sodium sulfate (Na2SO4) 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, theoretical 152.5 Kg, 96.1%) as a yellow-brown oil, which was used directly in the subsequent reaction without further purification.

[0213] Step 2. 7H-Pyrrolo[2,3-d]pyrimidin-4-ol (Compound 15a): The reaction vessel was charged with 18% sodium ethoxide in ethanol (EtONa) solution (1558 Kg) and formamidine acetate (153.5 Kg, 1474.4 moles). The mixture was stirred at ambient temperature for 1 hour, followed by charging ethyl 2-cyano-4,4-diethoxybutanoate (compound 14a, 269.8 Kg, 1176.7 moles, 1.25 equivalents). The reaction mixture was heated to 75°C and stirred at 75°C until no unreacted ethyl 2-cyano-4,4-diethoxybutanoate (compound 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 then filtered. The cake was reslurried with water (493 Kg) and then 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 aqueous ammonium hydroxide (NH4OH, 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, theoretical 159 Kg, 62.6%) as an off-white-yellow solid, which was used in the subsequent reaction without further purification.

[0214] 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, 99.5 3 mol, 1.35 eq) in toluene (500 Kg) at ambient temperature and the resulting mixture was cooled to 0° C. Subsequently, POCl3 (338 Kg, 2202 mol, 3.0 eq) was 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 (Na2CO3, 700 Kg), and 2-methyltetrahydrofuran (MeTHF, 1200 Kg) were added. Subsequently, the resulting mixture was filtered. The organic phase of the filtrate was separated, washed with brine (424 Kg), dried over sodium sulfate (Na2SO4) and then 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 then filtered. The filtrate was concentrated to a thick slurry, cooled to 0° C. and then filtered. The cake was dried under reduced pressure to give pure 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 71.9 Kg, theoretical 113.2 Kg, 63.5%) as yellow-brown crystals. The 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) produced by this synthesis is identical in all comparable aspects to the compound obtained by Example 12. 1 H NMR(400MHz,DMSO-d6)δ 12.58(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).

[0215] Example 14. 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 being charged with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 980.0 g, 6381 mmol). The mixture was stirred at 0-15 °C for 30 min before being charged with a solution of TBDMS-Cl (1165 g, 7728 mmol, 1.211 equiv) in THF 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 charged with iron(III) acetylacetonate (Fe(acac)3, 113 g, 319 mmol, 0.05 equiv). 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. Once the coupling reaction was complete, an aqueous solution of ammonium chloride (NH4Cl, 8.0 L) was charged to quench the reaction mixture, controlling the internal temperature below 10 °C during 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 x 500 mL). The two phases of the combined filtrate and washing solution were separated, and the aqueous phase was extracted with MTBE (2 x 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 (NH4OH, 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 x 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 x 1.0 L) to give the crude desired product 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 840 g, theoretical 849.6 g, 98.9%) as a brown powder, which was purified by recrystallization in a mixture of ethyl acetate and n-heptane.

[0216] 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 h. The mixture was filtered through a bed of Celite and the Celite bed was washed with MeOH (2×8.0 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) before introducing n-heptane (8.0 L). The resulting mixture was stirred at ambient temperature for 14 h. The solid was collected by filtration, washed with a mixture of ethyl acetate and n-heptane, followed by n-heptane, and dried to constant weight to give purified methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 1325 g, theoretical 1640 g, 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)δ 12.10(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)δ 158.7,151.3,151.2,126.5,117.6,99.6,21.3ppm;C7H7N3(MW,133.15)LCMS(EI)m / e 134.1(M + +H, base peak).

[0217] Example 15. 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, followed by the addition of 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) over a period of 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 h. Additional triethyl orthoformate (26.5 mL, 159 mmol, 2.06 equiv.) was added. The mixture was stirred at 110 °C for an additional 16 h. 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 h. The mixture was heated for an additional 24 h and concentrated under reduced pressure to a residue. 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 which 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 (SiO2, 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, theoretical 10.25 g, 49.8% for three steps) as an off-white crystalline solid, which is identical in all comparable aspects to the compound obtained by Example 14.

[0218] 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 (Cs2CO3, 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 subsequently quenched with water (20 mL). The quenched reaction mixture was subsequently extracted with ethyl acetate (3 × 20 mL) and the combined organic extracts were washed with water (2 × 10 mL), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel (SiO2) column chromatography to give 2-acetyl-4,4-dimethoxybutanamide (compound 20a, 5.8 g, theoretical 9.37 g, 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).

[0219] 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 equiv.). The resulting reaction mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction, 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 (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel (SiO2) column chromatography to give 2-acetyl-4,4-dimethoxybutanenitrile (compound 17a, 280 mg, theoretical 724 mg, 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 was obtained) δ 10.7 (br.s, 1 / 2H for the enol form -OH), 4.38 (m, 1H), 3.25 (m, 6H for the two OMe and 1 / 2H for the ketone form -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 14 above.

[0220] Example 16. Preparation of 4-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) hydrochloride (the hydrochloride salt of compound 1a) A reaction vessel 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). [ka] After cooling the contents of the reaction vessel to below -5 °C, 60% NaH in mineral oil (51 g, 1.28 moles, 1.2 equiv.) was added in portions. The internal temperature was kept at -5 to 5 °C during the addition of NaH. After the addition, stirring was continued for 30 min, followed by the slow addition of a solution of TBDMS-Cl (193 g, 1.28 moles, 1.2 equiv.) in THF (200 mL) by keeping the internal temperature at -5 to 5 °C. Stirring of the reaction mixture was continued for 30 min, followed by the addition of Fe(acac)3 (18.8 g, 53.2 mmol, 0.05 equiv.) followed by the addition of a 3.0 M solution of MeMgCl in THF (532 mL, 1.596 moles, 1.5 equiv.) at -5 to 5 °C. The reaction mixture was kept for an additional hour, by which time IPC by HPLC showed the coupling reaction was complete, after which the reaction mixture was 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 solution (2×400 mL) and brine (600 mL). After drying over Na2SO4, the organic phase was filtered and concentrated to dryness. The residue was dissolved 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.

[0221] 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 atm hydrogen at 50-55 °C for 3 h. After completion of the reaction was confirmed by IPC by HPLC, the reaction mixture was cooled to 20-25 °C and then 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 h. 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 of compound 1a, 151.5 g, theoretical 180.5 g, 84% yield for two steps) as a light yellow crystalline powder. For the hydrochloride of compound 1a: 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-d6, 125 MHz) δ ppm 154.0, 151.0, 144.0, 131.6, 117.2, 103.1, 17.6; C7H8ClN3 (MW, 169.61; C7H7N3, MW 133.15 for free base) LCMS (EI) m / e 134.1 (M + +H, base peak).

[0222] Example 17. 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 equiv.) 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 equiv.) was added to the solution at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 1 h. Upon completion of the reaction, the reaction mixture was filtered and the solid was discarded after washing with acetone. 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 h. 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, theoretical 36.0 g, 89.2% yield) as an off-white powder, which was used in subsequent reactions without further purification. In the case of 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).

[0223] 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 (Cs2CO3, 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 before being treated with water (H2O, 80 mL). The quenched reaction mixture was then stirred at ambient temperature for 1 h followed by 0-5 °C for 1 h. 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, 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)diethyl malonate (compound 25a, 6.2 g, theoretical 9.81 g, 63.2% yield), as an off-white powder, which was used in subsequent reactions without further purification. For 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)diethyl malonate: 1 C 20 H 21 N3O6S(MW,431.46),LCMS(EI)m / e 432.3(M + +H).

[0224] Step 3. Ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 26a): A solution of 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)diethyl 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 give the desired product, ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 26a, 2.08 g, theoretical 3.33 g, 62.6% yield) as an off-white powder, which was used in the subsequent reaction without further purification. 1 C 17 H 17 N3O4S(MW,359.40),LCMS(EI)m / e 360.2(M + +H).

[0225] 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 solution, and the resulting mixture was concentrated under reduced pressure. The residue was then purified by silica gel (SiO2) column chromatography to give the desired product, ethyl 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acetate (compound 27a, 1.3 g, theoretical 1.9 g, 68.3% yield), as an off-white powder, which was used in the subsequent reaction without further purification. 1 C 10 H 11 N3O2(MW,205.22),LCMS(EI)m / e 206.2(M + +H).

[0226] 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 6N sodium hydroxide (6N NaOH, 1.462 mL, 8.77 mmol, 1.5 equiv.) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 h. 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 h. The solid was collected by filtration, washed with acetone (2×5 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, theoretical 1.164 g, 94.5% yield), as an off-white powder, which was used in subsequent reactions without further purification. 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; C8H7N3O2 for the corresponding acid, MW 177.16); LCMS (EI) m / e 178.1 (M + +H).

[0227] Step 6. 2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)acetic acid (compound 5a): A solution of 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ethyl acetate (compound 27a, 1.2 g, 5.85 mmol) in acetone (10 mL) and THF (10 mL) was treated with an aqueous solution of 6N sodium hydroxide (6N NaOH, 1.462 mL, 8.77 mmol, 1.5 equiv.) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was then treated with an aqueous solution of 1N hydrochloric acid (1N HCl, 9.0 mL) before being 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, theoretical 1.04 g, 79.8% yield) as an off-white solid, which was used in the subsequent reaction without further purification. For 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).

[0228] In addition to those described herein, various modifications of the present invention will become 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 cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. A process for preparing baricitinib or a salt thereof, comprising reacting a compound of formula 3: or a salt thereof with a reagent selected from (i) a salt of formula 2a, and (ii) a compound of formula 2b: 【Chemical 1】 wherein X− is a counter anion 【Chemical 2】 The above process.

2. The process according to claim 1, wherein the reagent is the compound of formula 2b.

3. The process according to claim 1, wherein the salt of formula 2a or the compound of formula 2b is prepared by a process comprising reacting a compound of formula 1a: or a salt thereof with a Vilsmeier reagent formed from dimethylformamide.

4. 【Chemical Formula 3】 The process according to claim 3, wherein the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a chlorinating agent.

5. The process according to claim 4, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

6. The process according to claim 3, wherein the product of the reaction with the Vilsmeier reagent is a salt of formula 2d:

7. The process according to claim 6, further comprising reacting the salt of formula 2d with a base to form a salt of formula 2c: [Chemical Formula 4]

8. The process according to claim 3, wherein the product of the reaction with the Vilsmeier reagent is a salt of formula 2c:

9. [Chemical Formula 5]

10. The process according to any one of claims 3 to 9, wherein the compound of formula 1a or a salt thereof is prepared by a process comprising deprotecting a compound of formula 1aP: wherein P1 is an amino protecting group 【Chemical Formula 6】

11. The process according to claim 10, wherein the compound of formula 1aP is prepared by a process comprising reacting a compound of formula 2P: The salt of formula 2c with a salt of formula M ＋ X － wherein M⁺ is a counter cation and X⁻ is a counter anion other than Cl⁻, to form a salt of formula 2a, the process according to claim 8, further comprising. wherein P1 is an amino protecting group with MeMgBr in the presence of a Grignard catalyst. 【Chemical 7】

12. The process according to claim 11, wherein the compound of formula 2P is prepared by a process comprising protecting a compound of formula 12a: to form the compound of formula 2P.

13. 【Chemical Formula 8】 The process according to claim 12, wherein the compound of formula 12a is prepared by a process comprising reacting a compound of formula 11a: or a salt thereof with a strong acid.

14. The process according to claim 13, wherein the compound of formula 11a or a salt thereof is a compound of formula 10a: 【Chemical Formula 9】 ​ ​ ​ 【Chemical Formula 10】 ​ ​ ​ 【Chemical 11】 The process according to claim 13, which is prepared by a process comprising reacting the compound or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and a base.

15. The compound of formula 10a or a salt thereof is prepared by a process comprising reacting the compound of formula 9a: 【Chemical Formula 12】 The process according to claim 14, which is prepared by a process comprising reacting with ammonia.

16. The compound of formula 9a is prepared by a process comprising reacting the compound of formula 8a: 【Chemical 13】 The process according to claim 15, which is prepared by a process comprising reacting with a Vilsmeier reagent formed from dimethylformamide.

17. The compound of formula 12a is prepared by a process comprising reacting the compound of formula 15a: 【Chemical 14】 The process according to claim 12, which is prepared by a process comprising reacting with a chlorinating agent.

18. The compound of formula 15a is (i) The compound of formula 14a: 【Chemical Formula 15】 is reacted with formamidine acetate and an alkali metal alkoxide to produce a compound of formula 14aa: 【Chemical 16】 and (ii) reacting the compound of formula 14aa with a strong acid, The process according to claim 17, which is prepared by a process comprising.

19. The compound of formula 14a is prepared by a process comprising reacting the compound of formula 13a: 【Chemical 17】 with bromoacetaldehyde diethyl acetal and sodium tert - amyloxide. The process according to claim 18.

20. The compound of formula 1a or a salt thereof is prepared by a process comprising reducing the compound of formula 23P: 【Chemical 18】 [wherein, P ２ is an amino protecting group] The process according to any one of claims 3 to 9, which is prepared by a process comprising.

21. The compound of formula 23P is the compound of formula 22P: 【Chemical Formula 19】 [wherein, P2 is an amino - protecting group] The process according to claim 20, which is prepared by a process comprising reacting with MeMgCl in the presence of a Grignard catalyst.

22. The compound of formula 22P is prepared by a process comprising protecting the compound of formula 22a: 【Chemical 20】 to form the compound of formula 22P. The process according to claim 21.

23. The compound of formula 1a or a salt thereof is prepared by a process comprising reacting the compound of formula 18a: 【Chemical Formula 21】 with an acid to form the compound of formula 1a or a salt thereof. The process according to any one of claims 3 to 9.

24. The compound of formula 18a is the compound of formula 17a: 【Chemical 22】 The process according to claim 23, which is prepared by a process comprising reacting with formamidine acetate and triethyl orthoformate to form the compound of formula 18a.

25. The compound of formula 17a is a compound of formula 20a: 【Chemical 23】 Reacting with a compound of formula 21a: 【Chemical 24】 The process according to claim 24, which is prepared by a process comprising reacting to form the compound of formula 17a.

26. The salt of formula 2a or the compound of formula 2b is a compound of formula 5a: 【Chemical 25】 Or a salt thereof, prepared by a process comprising reacting with a Vilsmeier reagent formed from dimethylformamide, the process according to claim 1 or 2.

27. The compound of formula 3 or a salt thereof is a compound of formula 6: 【Chemical 26】 The process according to any one of claims 1 to 9, which is formed by a process comprising reacting with hydrazine.

28. A process for preparing baricitinib or a salt thereof, A salt of formula 2c: 【Chemical 27】 Reacting with a compound of formula 3: 【Chemical formula 28】 To form the baricitinib or a salt thereof, Said process.

29. The salt of formula 2c is prepared by a process comprising reacting a salt of formula 2d: 【Chemical 29】 With a base to form the salt of formula 2c, the process according to claim 28.

30. The salt of formula 2d is (a) A compound of formula 2P: 【Chemical 30】 Reacting with MeMgBr in the presence of a Grignard catalyst to form a compound of formula 1aP: 【Chemical 31】 To form, (b) Deprotecting the compound of formula 1aP to form a compound of formula 1a: 【Chemical 32】 Or a salt thereof, (c) Reacting the compound of formula 1a or a salt thereof with a Vilsmeier reagent formed from dimethylformamide and a chlorinating agent to form the salt of formula 2d, Prepared by a process comprising, wherein P １ is an amino protecting group The process according to claim 29.

31. The compound of formula 3 or a salt thereof is prepared by a process comprising reacting a compound of formula 6: 【Chemical 33】 With hydrazine, the process according to any one of claims 28 to 30.

32. A compound of formula 3: 【Chemical 34】 Or a salt thereof.

33. A process for producing the compound according to claim 32 or a salt thereof, A compound of formula 6: 【Chemical 35】 Reacting with hydrazine, Said process.

Images