Process 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 of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 220,752, filed July 12, 2021, the entirety of which is incorporated herein by reference.

[0002] This disclosure relates to baricitinib, its salts, and related synthetic intermediate compounds and processes for preparing them. 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 diverse range of important biological processes, including, among others, cell proliferation, survival and differentiation, organogenesis and morphogenesis, neovascularization, tissue repair, and regeneration. Protein kinases exert their physiological functions by catalyzing the phosphorylation of proteins (or substrates), thereby regulating the cellular activity of substrates in various biological contexts. In addition to their functions in normal tissues / organs, many protein kinases also play more specialized roles in hosts of human diseases, including cancer. A subset of protein kinases (also known as oncogenic protein kinases) can, when dysregulated, induce tumorigenesis and proliferation, and further 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, while non-receptor tyrosine kinases are entirely intracellular. The Janus kinase family of protein tyrosine kinases (JAKs) belongs to the non-receptor type of tyrosine kinase 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] The pathways involving JAKs, signaling molecules, and activators of transcription (STATs) are involved in a wide range of cytokine signaling. Cytokines are small polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. Generally, cytokine receptors do not possess intrinsic tyrosine kinase activity and therefore require receptor-associated kinases to propagate the phosphorylation cascade. JAKs perform this function. Cytokines bind to these receptors, causing receptor dimerization, which allows JAKs to phosphorylate not only each other but also specific tyrosine motifs within the cytokine receptor. STATs that recognize these phosphotyrosine motifs are recruited to the receptor and are then activated by the JAK-dependent tyrosine phosphorylation event. Upon activation, STAT dissociates from its receptor, dimerizes, translocates to the nucleus, binds to a specific DNA site, and alters transcription (Scott, MJ, CJ Godshall, et al. (2002) "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6):1153-9).

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

[0007] Blocking signaling at the JAK kinase level holds promise for the development of treatments for human cancers. JAK inhibition is also expected to have therapeutic benefits in patients with skin immune disorders such as atopic dermatitis, alopecia areata, psoriasis, and skin sensitization. Therefore, JAK inhibitors are in high demand. For example, the JAK inhibitor baricitinib, {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]azetidine-3-yl}acetonitrile, is reported in U.S. Patent No. 8,158,616, filed March 10, 2009, which is incorporated herein by reference in its entirety.

[0008] Given the increasing demand for compounds for the treatment of disorders associated with JAK inhibitors, there is a need for novel and more efficient routes to baricitinib, its salts, and related intermediates. The processes and compounds described herein can help meet these and other needs. [Overview of the Initiative]

[0009] This disclosure relates, in particular, to a process for preparing baricitinib, and the compound of formula 3. [ka] or the salt thereof is reacted 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 - The process is provided wherein the counter anion is provided.

[0010] This disclosure also relates, in particular, to a process for preparing baricitinib, comprising the compound of formula 3. [ka] or the salt thereof is reacted with a reagent selected from (i) the salt of formula 2a and (ii) the compound of formula 2b, [ka] In the formula, X - The process is provided wherein the counter anion is provided.

[0011] This disclosure relates to the compound of formula 3. [ka] or provide the salt therefor.

[0012] This disclosure also relates to the compound of formula 6. [ka] The present invention provides a process for producing a compound of formula 3 or a salt thereof, which includes reacting with hydrazine.

[0013] This disclosure relates to the salt of formula 2c. [ka] This is reacted with the compound in formula 3, [ka] Further providing is a process for preparing baricitinib or a salt thereof, including forming baricitinib or a salt thereof.

[0014] In some embodiments, the salt of formula 2c is the same as the salt of formula 2d. [ka] It is prepared by a process that includes reacting it 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] This is reacted with MeMgBr in the presence of a Grignard catalyst to form the compound of formula 1aP, [ka] (b) Deprotect the compound of formula 1aP to obtain the compound of formula 1a [ka] or to form a salt thereof, (c) Prepared by a process comprising reacting a compound of formula 1a or a salt thereof with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, In the formula, P 1 This is an amino protecting group.

[0016] In some embodiments, the salt of formula 2d is (a) Compound of formula 22P [ka] This is reacted with MeMgBr in the presence of a Grignard catalyst to form the compound of formula 23P, [ka] (b) Reduce the compound of formula 23P to obtain the compound of formula 1a [ka] or to form a salt thereof, (c) Prepared by a process comprising reacting a compound of formula 1a or a salt thereof with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, In the formula, P 2 This is an amino protecting group.

[0017] In some embodiments, the compound of formula 3 or a salt thereof is Compound of formula 6 [ka] It is prepared by a process that includes reacting it with hydrazine.

[0018] Details of one or more embodiments of the present invention are described in the following accompanying drawings and embodiments for carrying out the invention. [Brief explanation of the drawing]

[0019] [Figure 1] This is the X-ray powder diffraction (XRPD) pattern of compound 2d, form I. [Figure 2] This is a differential scanning calorimetry (DSC) thermogram of compound 2d, morphology I. [Figure 3] This is a thermogravimetric analysis (TGA) thermogram of compound 2d, form I. [Figure 4] This is the XRPD pattern of compound 2d, morphology II. [Figure 5] This is a DSC thermogram of compound 2d, form II. [Figure 6] This is a TGA thermogram of compound 2d, form II. [Figure 7]This is the XRPD pattern of compound 2, hexafluorophosphate. [Figure 8] This is a DSC thermogram of compound 2, hexafluorophosphate. [Figure 9] This is a TGA thermogram of compound 2, hexafluorophosphate. [Modes for carrying out the invention]

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

[0021] Baricitinib is also referred to as Compound 1 in this disclosure. 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, the compound of formula 3 is provided herein. [ka] Alternatively, a process for preparing baricitinib or a salt thereof, comprising reacting the 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 - This is the opposite of Anion.

[0023] In some embodiments, the present disclosure relates to the compound of formula 3. [ka] The present invention provides a process for preparing baricitinib or a salt thereof, comprising reacting the 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 - This is the opposite of Anion.

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

[0025] In some embodiments, the reaction between a reagent ((i) a salt of formula 2a or a salt thereof, or (ii) a compound of formula 2b) and a compound of formula 3 or a salt thereof is carried out in a solvent component. The solvent component may 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 is formula C 1~6 It contains alkyl-OH. In some embodiments, the solvent component is ethanol. In some embodiments, the solvent component contains dimethylformamide. In some embodiments, the solvent component contains water, 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 the salt of formula 2a (e.g., hydrochloride of the salt of formula 2a). In some embodiments, the reagent is hydrochloride of the salt of formula 2a. In some embodiments, the hydrochloride of the 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 - is selected from. In some embodiments, X - is Cl - , BF4 - , PF6 - , AsF6 - , SbF6 - , and ClO4 - is selected from. In some embodiments, X - is BF4 - . In some embodiments, X - is PF6 - . In some embodiments, X - is AsF6 - . In some embodiments, X - is SbF6 - . In some embodiments, X - is ClO4<00000​​​​​​​​​​​​In some embodiments, the reaction between a reagent ((i) a salt of formula 2a or a salt thereof, or (ii) a compound of formula 2b) and a compound of formula 3 or a salt thereof is carried out in a solvent component. The solvent component may 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 is formula C 1~6 It contains alkyl-OH compounds. In some embodiments, the solvent component is ethanol. In some embodiments, the solvent component is dimethylformamide. In some embodiments, the solvent component is water, alcohol, or a combination thereof.

[0030] In some embodiments, the reagent is the compound of formula 2b. In some embodiments, the compound of formula 2b is prepared by a process that includes reacting a salt of formula 2a or formula 2c, or a salt thereof, with a base. In some embodiments, the reaction of a salt of formula 2a or formula 2c, or a salt thereof, with a base is carried out in a solvent component containing water. In some embodiments, the base present for the reaction of a salt of formula 2a or formula 2c, or a salt thereof, is a strong base. In some embodiments, the base present for the reaction of a salt of formula 2a or formula 2c, or a salt thereof, is a hydroxide. In some embodiments, the base present for the reaction of a salt of formula 2a or formula 2c, or a salt thereof, is an alkali metal hydroxide. In some embodiments, the base present for the reaction of a salt of formula 2a or formula 2c, or a salt thereof, is sodium hydroxide. In some embodiments, about 10 to about 15 molar equivalents of base are used with respect to a salt of formula 2a or formula 2c, or a salt thereof. In some embodiments, about 12 molar equivalents of a base are used with the salt of formula 2a or formula 2c, or the salt thereof. In some embodiments, the reaction between the salt of formula 2a or formula 2c, or the salt thereof, and the base takes place 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, Compound of formula 1a [ka] Alternatively, it is prepared by a process that includes reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

[0031] In some embodiments, the salt of formula 2a or a salt thereof, or the compound of formula 2b, Compound of formula 5a [ka] Alternatively, it is prepared by a process that includes reacting a salt thereof with a Vilsmeyer 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 between the salt of formula 2a or a salt thereof (or the compound of formula 5a or a salt thereof) and the Vilsmeyer reagent is the 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, morphology I has an XRPD pattern substantially as shown in Figure 1. Morphology I may have a DSC thermogram substantially as shown in Figure 2. In some embodiments, morphology I has a TGA thermogram substantially as shown in Figure 3.

[0036] In some embodiments, form I is 2-theta (±0.2 degrees) and 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. In some embodiments, form I is 2-theta (±0.2 degrees) and 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. In some embodiments, form I is 2-theta (±0.2 degrees) and 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. In some embodiments, form I is 2-theta (±0.2 degrees) and 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. In some embodiments, form I is 2-theta (±0.2 degrees) and 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.

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

[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 is 2-theta (±0.2 degrees) and 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. In some embodiments, form II is 2-theta (±0.2 degrees) and 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. In some embodiments, form II is 2-theta (±0.2 degrees) and 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. In some embodiments, morphology II is 2-theta (±0.2 degrees) and 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. In some embodiments, morphology II is 2-theta (±0.2 degrees) and 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.

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

[0041] In some embodiments, the process of preparing the salt of formula 2a further includes reacting the salt of formula 2d with a base to form the salt of formula 2c. [ka]

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

[0043] In some embodiments, the process for preparing the salt of formula 2a is to prepare the salt of formula 2c. + X - The further step involves reacting with a salt of to form the salt of formula 2a, where, M + is the countercation, X - However, Cl - It is an anti-anion other than those mentioned above.

[0044] In some embodiments, M + M is an alkali metal pair cation. 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 - Selected from. In some embodiments, X - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - Selected from. In some embodiments, X - is BF4 - In some embodiments, X - PF6 - In some embodiments, X - is AsF6 - In some embodiments, X - is SbF6 - In some embodiments, X - is ClO4 - That is the case.

[0045] In some embodiments, the Vilsmeyer 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 the chlorinating agent present for reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 1 to about 4 molar equivalents of the chlorinating agent present for reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 1 to about 3 molar equivalents of the chlorinating agent present for reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 1 molar equivalent of the chlorinating agent present for reaction with dimethylformamide is used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 2 molar equivalents of the chlorinating agent present for reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 3 molar equivalents of the chlorinating agent present for reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 4 molar equivalents of the chlorinating agent present for the reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof. In some embodiments, about 5 molar equivalents of the chlorinating agent present for the reaction with dimethylformamide are used for the compound of formula 1a or 5a or a salt thereof.

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

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

[0049] In some embodiments, the Vilsmeyer reagent is prepared at a temperature of about -10°C to about 60°C. In some embodiments, the Vilsmeyer reagent is prepared at a temperature of about -10°C to about 30°C. In some embodiments, the Vilsmeyer 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 Vilsmeyer reagent is prepared at a temperature of about room temperature to about 60°C. In some embodiments, the Vilsmeyer 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 Vilsmeyer 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 between the compound of formula 1a or 5a or a salt thereof and the Vilsmeyer reagent is carried out at a temperature of about 40°C to about 100°C. In some embodiments, the reaction between the compound of formula 1a or 5a or a salt thereof and the Vilsmeyer reagent is carried out at a temperature of about 70°C to about 100°C. In some embodiments, the reaction between the compound of formula 1a or 5a or a salt thereof and the Vilsmeyer 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 its salt is a hydrochloride salt.

[0052] In some embodiments, the compound of formula 1a or a salt thereof is Prepared by a process involving deprotection of the compound of formula 1aP, [ka] In the formula, P 1 This is an amino protecting group.

[0053] In some embodiments, P 1 is, (R 1 ) Selected from 3Si, in the formula, R 1 is C 1~6It is alkyl. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, P 1 is t-butyldimethylsilyl. In some embodiments, P 1 is trimethylsilyl. In some embodiments, deprotection is carried out by reacting the compound of formula 1aP with a base. In some embodiments, the base present for deprotecting the compound of formula 1aP is a hydroxide base. In some embodiments, the base present for deprotecting the compound of formula 1aP is ammonium hydroxide. In some embodiments, deprotection is carried out in a solvent component. In some embodiments, the solvent component present for deprotecting the compound of formula 1aP includes a polar protic solvent. In some embodiments, the solvent component present for deprotecting the compound of formula 1aP includes an alcohol. In some embodiments, the solvent component present for deprotecting the compound of formula 1aP is formula C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for deprotecting the compound of formula 1aP includes methanol.

[0054] In some embodiments, the compound of formula 1aP is Compound of formula 2P [ka] It is prepared by a process that includes reacting it with MeMgBr in the presence of a Grignard catalyst, In the formula, P 1 This 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 are utilized relative to the compound of Formula 2P. In some embodiments, about 1% to about 10% molar equivalents of the Grignard catalyst are utilized relative to the compound of Formula 2P. 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 contains di-C 1~6 alkyl ether or 4- to 10-membered heterocycloalkyl ether. In some embodiments, the solvent component present for the reaction of the compound of Formula 2P with MeMgBr contains 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 protects the compound of Formula 12a to

Chemical formula

[0057] In some embodiments, the protection includes reacting the compound of Formula 12a with an alkali metal hydride and P 1 -Y, where Y is halo. In some embodiments, P 1 -Y is (R 1 )3Si-Y, where Y is halo and R 1 is C 1~6 alkyl. In some embodiments, P 1 is (R 1 )3Si, where R 1 is C 1~6 alkyl. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, P<000009is t-butyldimethylsilyl. In some embodiments, the alkali metal hydride is sodium hydride. In some embodiments, about 1 to about 2 molar equivalents of the alkali metal hydride are utilized relative to the compound of Formula 12a. In some embodiments, about 1 to about 2 molar equivalents of P 1 -Y are utilized. In some embodiments, the reaction of the compound of Formula 12a with the alkali metal hydride and P 1 -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 the alkali metal hydride and P 1 -Y 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 12a with the alkali metal hydride and P 1 -Y comprises di-C 1~6 alkyl ether or a 4- to 10-membered heterocycloalkyl ether. In some embodiments, the solvent component present for the reaction of the compound of Formula 12a with the alkali metal hydride and P 1 -Y comprises tetrahydrofuran.

[0058] In some embodiments, the compound of Formula 1a or a salt thereof is prepared by a process comprising reducing the compound of Formula 23P to

Chemical formula

[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 0It is carbon. In 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 includes 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 includes an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 23P with hydrogen and the catalyst is C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for the reaction of the compound of formula 23P with hydrogen and a catalyst includes methanol.

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

[0061] In some embodiments, the compound of formula 23P is Compound of formula 22P [ka] It is prepared by a process that includes reacting it with MeMgCl in the presence of a Grignard catalyst, where P 2 This 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 are used relative to the compound of formula 22P. In some embodiments, about 1% to about 10% molar equivalents of the Grignard catalyst are used relative to the compound of formula 22P. In some embodiments, the reaction between compound formula 22P and MeMgCl is carried out in a solvent component. In some embodiments, the solvent component present for the reaction between compound formula 22P and MeMgCl is di-C 1~6 This includes alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. In some embodiments, the solvent component present for the reaction of compound formula 22P with MeMgCl includes tetrahydrofuran. In some embodiments, the reaction of compound formula 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 Protect the compound of formula 22a, [ka] It is prepared by a process that includes forming the compound of formula 22P.

[0064] In some embodiments, protection is provided by the alkali metal hydride and P compound of formula 22a. 2 -Includes reacting with Y (wherein Y is a halo). In some embodiments, P 2 is, (R 1 )3Si, and in the formula, R 1 is C 1~6 It is alkyl. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, P 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 are used relative to the compound of formula 22a. In some embodiments, about 1 to about 2 molar equivalents of P are used relative to the compound of formula 22a. 2 -Y is used. In some embodiments, the compound of formula 22a and alkali metal hydride and P 2 The reaction with -Y is carried out at a temperature of approximately -10°C to approximately 20°C. In some embodiments, the compound of formula 22a is reacted with alkali metal hydride and P 2 The reaction with -Y is carried out in a solvent component, where the solvent component includes an organic solvent. In some embodiments, the compound of formula 22a is reacted with an alkali metal hydride and P 2 -The solvent component present for the reaction with Y is di-C 1~6 It comprises alkyl ethers or 4-10 membered heterocycloalkyl ethers. In some embodiments, the compound of formula 22a and alkali metal hydride and P 2 The solvent components present for the reaction with -Y include tetrahydrofuran.

[0065] In some embodiments, the compound of formula 1a or a salt thereof is Compound of formula 18a [ka] It is prepared by a process that involves reacting it with an acid to form the 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 includes a polar protic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 18a with the acid includes an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 18a with the acid is C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for the reaction of the compound of formula 18a with an acid includes isopropyl alcohol.

[0067] In some embodiments, the compound of formula 18a is Compound of formula 17a [ka] It is prepared by a process that involves reacting it with formamidine acetate and triethyl orthoformate to form the compound of formula 18a or a salt thereof.

[0068] In some embodiments, about 10 to about 15 molar equivalents of formamidine acetate are used 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 used relative to the compound of formula 17a. In some embodiments, about 12 molar equivalents of formamidine acetate are used relative to the compound of formula 17a. In some embodiments, about 6 to about 10 molar equivalents of triethyl orthoformate are used 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 used relative to the compound of formula 17a. In some embodiments, about 8 molar equivalents of triethyl orthoformate are used relative to the compound of formula 17a. In some embodiments, the reaction between the compound of formula 17a and formamidine acetate and triethyl orthoformate is carried out at a temperature of about 100°C to about 150°C. In some embodiments, this 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 includes a polar protic solvent. In some embodiments, the polar protic solvent includes an alcohol. In some embodiments, the polar protic solvent is formula C 1~6 It contains alkyl-OH. In some embodiments, the polar protic solvent includes 1-butanol.

[0069] In some embodiments, the compound of formula 17a is Compound of formula 20a [ka] This is reacted with the compound of formula 21a, [ka] It is prepared by a process that includes forming the compound of formula 17a.

[0070] In some embodiments, about 0.4 to about 1 molar equivalent of the compound of formula 21a is used relative to the compound of formula 20a. In some embodiments, the reaction between the compound of formula 20a and the compound of formula 21a is carried out at room temperature. In some embodiments, the reaction between the compound of formula 20a and the compound of formula 21a is carried out in a solvent component, where the solvent component includes a polar aprotic solvent. In some embodiments, the solvent component present for the reaction between the compound of formula 20a and the compound of formula 21a includes dimethylformamide.

[0071] In some embodiments, the compound of formula 20a is Compound of formula 19a [ka] It is prepared by a process that includes reacting it with bromo-1,1-dimethoxyethane and a base to form the 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 are used relative to the compound of formula 19a. In some embodiments, about 1 to about 2 molar equivalents of bromo-1,1-dimethoxyethane are used relative to the compound of formula 19a. In some embodiments, the reaction of the compound of formula 19a with bromo-1,1-dimethoxyethane is carried out at a temperature of about 70°C to about 100°C. In some embodiments, the reaction of the compound of formula 19a with bromo-1,1-dimethoxyethane is carried out in a solvent component, where the solvent component includes 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 includes dimethylformamide.

[0073] In some embodiments, the compound of formula 17a is Compound of formula 16a [ka] It is prepared by a process that includes reacting it with ethyl acetate and a base to form the 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 used relative to the compound of formula 16a. In some embodiments, about 1 to about 2 molar equivalents of ethyl acetate are used relative to the compound of formula 16a. In some embodiments, about 2 molar equivalents of base are used relative to the compound of formula 16a. In some embodiments, the reaction of the compound of formula 16a with ethyl acetate and the base is carried out at room temperature. In some embodiments, the reaction of the compound of formula 16a with ethyl acetate and the base is carried out in a solvent component, where the solvent component includes 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 This includes alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. In some embodiments, the solvent component present for the reaction of the compound of formula 16a with ethyl acetate includes tetrahydrofuran.

[0075] In some embodiments, the compound of formula 5a or a salt thereof is Compound of formula 27a [ka] It is prepared by a process that includes hydrolysis 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 are used relative to the compound of formula 27a. In some embodiments, about 1.5 molar equivalents of base are used relative to the compound of formula 27a. 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 includes an organic solvent. In some embodiments, the solvent component present for the hydrolysis of the compound of formula 27a includes tetrahydrofuran, acetone, or a combination thereof.

[0077] In some embodiments, the compound of formula 5a or a salt thereof is the sodium salt of the compound of formula 5a.

[0078] In some embodiments, the product of the 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 that includes 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] It is prepared by a process that includes reacting it with a strong acid, in which P1 This 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 C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for the reaction of the compound of formula 26P with a strong acid includes ethanol.

[0081] In some embodiments, the compound of formula 26P is Compound of formula 25P [ka] It is prepared by a process that includes reacting with an alkali metal alkoxide to form a compound of formula 26P, where P 1 This is an amino protecting group.

[0082] In some embodiments, about 0.1 molar equivalents of alkali metal alkoxide are used relative to the compound of formula 25P. In some embodiments, the reaction between the compound of formula 25P and 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 between the compound of formula 25P and the alkali metal alkoxide is carried out in a solvent component, where the solvent component includes a polar protic solvent. In some embodiments, the solvent component present for the reaction between the compound of formula 25P and the alkali metal alkoxide includes an alcohol. In some embodiments, the solvent component present for the reaction between the compound of formula 25P and the alkali metal alkoxide is C 1~6It contains alkyl-OH. In some embodiments, the solvent component present for the reaction of the compound of formula 25P with the alkali metal alkoxide includes ethanol.

[0083] In some embodiments, the compound of formula 27a is Compound of formula 25P [ka] It is prepared by a process that includes reacting it with an alkali metal alkoxide to form the compound of formula 27a.

[0084] In some embodiments, about 1 to about 2 molar equivalents of alkali metal alkoxide are used relative to the compound of formula 25P. In some embodiments, about 1 molar equivalent of alkali metal alkoxide is used relative to the compound of formula 25P. In some embodiments, the reaction between the compound of formula 25P and the alkali metal alkoxide is carried out at a temperature of about 50°C to about 80°C. In some embodiments, the reaction between the compound of formula 25P and the alkali metal alkoxide is carried out in a solvent component, where the solvent component present for the reaction between the compound of formula 25P and the alkali metal alkoxide is formula C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for the reaction of the compound of formula 25P with the alkali metal alkoxide includes ethanol.

[0085] In some embodiments, the compound of formula 25P is Compound of formula 2P [ka] It is prepared by a process that includes reacting it with diethyl malonate and a base, where P 1 This 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 includes a polar aprotic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 2P with diethyl malonate includes dimethylformamide.

[0087] In some embodiments, the compound of formula 2P is prepared by a process that includes protecting the compound of formula 12a to form the compound of formula 2P. In some embodiments, the protection involves protecting the compound of formula 12a with a base and P 1 -Includes reacting with Y (wherein Y is a halo). In some embodiments, P 1 p-toluenesulfonyl is used in some embodiments. 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 includes a polar aprotic solvent. In some embodiments, the compound of formula 12a and P 1 The solvent components present for the reaction of -Y include acetone.

[0088] In some embodiments, the compound of formula 12a is Compound of formula 11a, [ka] Alternatively, it may be prepared by a process that involves reacting its salt 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 includes 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 This includes alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. In some embodiments, the solvent component present for the reaction of the compound of formula 11a or a salt thereof includes 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] Alternatively, a salt thereof may be prepared by a process involving the reaction of (methoxymethyl)triphenylphosphonium chloride and a base.

[0091] In some embodiments, the base present for the reaction of the compound of formula 11a or a salt thereof 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 a salt thereof with (methoxymethyl)triphenylphosphonium chloride is potassium tert-butoxide. In some embodiments, the reaction of the compound of formula 11a or a salt thereof 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 a salt thereof with (methoxymethyl)triphenylphosphonium chloride and a base is carried out in a solvent component, where the solvent component includes 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 (methoxymethyl)triphenylphosphonium chloride is di-C 1~6 This includes alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. In some embodiments, the solvent component present for the reaction of the compound of formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride includes 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 that includes reacting it with ammonia.

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

[0094] In some embodiments, the compound of formula 9a is the compound of formula 8a

Chemical formula

[0095] In some embodiments, the Vilsmeier reagent present for the 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 reacting 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 reacting 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 are utilized relative to the compound of formula 8a. In some embodiments, about 1 to about 3 molar equivalents (e.g., 2 molar equivalents) of dimethylformamide are utilized relative to the compound of formula 8a. In some embodiments, the reaction of dimethylformamide with the chlorinating agent is 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 (e.g., about 90°C to about 120°C, or about 95°C to about 115°C). In some embodiments, the compound of formula 12a is the compound of formula 15a

Chemical formula

[0096] In some embodiments, the chlorinating agent present for the 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 the reaction with the compound of formula 15a is phosphorus oxychloride. In some embodiments, the reaction between the compound of formula 15a and the chlorinating agent is carried out at a temperature of about 50°C to about 100°C. In some embodiments, the reaction between the compound of formula 15a and ammonia is carried out in a solvent component, where the solvent component includes an organic solvent. In some embodiments, the solvent component present for the reaction with the compound of formula 15a includes toluene.

[0097] In some embodiments, the compound of formula 15a is (i) Compound of formula 14a [ka] The compound of formula 14aa is produced by reacting it with formamidine acetate and alkali metal alkoxide, [ka] (ii) Prepared by a process including 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 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 alkali metal alkoxide is carried out in a solvent component, where the solvent component includes a polar protic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 14a with formamidine acetate and alkali metal hydroxide includes an alcohol. In some embodiments, the solvent component present for the reaction of the compound of formula 14a with formamidine acetate and alkali metal hydroxide is formula C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for the reaction with the compound of formula 14a includes 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] It is prepared by a process that includes reacting bromoacetaldehyde diethyl acetal with sodium tert-amiloxide.

[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 includes 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 includes dimethyl sulfoxide.

[0102] In some embodiments, the compound of formula 3 or a salt thereof is Compound of formula 6 [ka] It is prepared by a process that includes reacting it with hydrazine.

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

[0104] In some embodiments, about 1 to about 3 molar equivalents of hydrazine are used relative to the compound of formula 6. In some embodiments, about 1.5 to about 2.5 molar equivalents of hydrazine are used relative to the compound of formula 6. In some embodiments, about 2 to about 2.2 molar equivalents of hydrazine are used relative to the compound of formula 6. In some embodiments, about 2.1 molar equivalents of hydrazine are used 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 includes an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine includes an aprotic organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 6 with hydrazine includes acetonitrile.

[0106] In some embodiments, the reaction of the compound of Formula 6 with hydrazine is carried out at a temperature of from 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 the compound of Formula 55

Chemical formula

[0108] In some embodiments, from 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 carried out 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 tri-(C 1~6 alkyl)amine. 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 includes 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 includes 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 includes acetonitrile.

[0111] In some embodiments, the reaction of the compound of formula 55 or its salt 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 heated to room temperature.

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

[0113] In some embodiments, P 50 is R 50 -OC(O)-, and in the formula, R 50 is C 1~6 It is alkyl. In some embodiments, R 50 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, P 50t-butyl-OC(O)-. In some embodiments, deprotection of the compound of formula 54 involves treating the compound of formula 54 with a strong acid. In some embodiments, the strong acid present for deprotection of the compound of formula 54 is HCl. In some embodiments, deprotection of the compound of formula 54 is carried out in a solvent component. In some embodiments, the solvent components present for deprotection of the compound of formula 54 include polar protic solvents and organic solvents. In some embodiments, the solvent components present for deprotection of the compound of formula 54 include aprotic organic solvents. In some embodiments, the solvent components present for deprotection of the compound of formula 54 include water and acetonitrile. In some embodiments, deprotection of the compound of formula 54 is carried out 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] It is prepared by a process that includes reacting with diethylcyanomethyl phosphate and a base to form the compound of formula 54.

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

[0117] In some embodiments, the reaction of the compound of formula 7 with diethylcyanomethyl phosphate and a base is carried out at a temperature of about -20°C to about 30°C. In some embodiments, the temperature is below about -5°C. In some embodiments, the temperature is about -10°C to about -5°C, and then it is heated to room temperature.

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

[0119] In some embodiments, the compound of formula 7 is Oxidizing the compound of formula 56, [ka] It is prepared by a process that includes forming the compound of formula 7.

[0120] In some embodiments, the oxidation of the compound of formula 56 is carried out 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 are used relative to the compound of formula 56. In some embodiments, about 0.01 equivalents of TEMPO are used relative to the compound of formula 56. 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 includes water and organic solvents. In some embodiments, the solvent component present for the oxidation of the compound of formula 56 includes a polar aprotic solvent. In some embodiments, the solvent component present for the oxidation of the compound of formula 56 includes ethyl acetate.

[0122] In some embodiments, the compound of formula 56 is Compound of formula 57 [ka] Alternatively, it may be prepared by a process comprising reacting the salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate. In the formula, P 50 It 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 used relative to the compound of formula 57. In some embodiments, about 1.1 molar equivalents of di-tert-butyl dicarbonate are used 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 the 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 includes an organic solvent. In some embodiments, the solvent component present for the reaction of the compound of formula 57 or a salt thereof with hydrogen, a catalyst, and di-tert-butyl dicarbonate is di-C 1~6 This includes alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. In some embodiments, the solvent components present for the reaction of the 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 a 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 involving the reaction of diphenylmethaneamine with 2-(chloromethyl)oxirane. In some embodiments, about 1 to about 1.1 molar equivalents of diphenylmethaneamine are used relative to 2-(chloromethyl)oxirane. In some embodiments, the reaction of diphenylmethaneamine with 2-(chloromethyl)oxirane is carried out at a temperature of about 20°C to about 80°C. In some embodiments, the reaction of diphenylmethaneamine 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 diphenylmethaneamine with 2-(chloromethyl)oxirane is carried out in a solvent component, where the solvent component includes a polar protic solvent. In some embodiments, the solvent component present for the reaction of diphenylmethaneamine with 2-(chloromethyl)oxirane includes an alcohol. In some embodiments, the solvent component present for the reaction of diphenylmethaneamine with 2-(chloromethyl)oxirane includes a compound of formula C 1~6 It contains alkyl-OH. In some embodiments, the solvent component present for the reaction of diphenylmethaneamine with 2-(chloromethyl)oxirane includes methanol.

[0128] This disclosure relates to the salt of formula 2c. [ka] Reacting with the compound of formula 3, [ka] Further providing is a process for preparing baricitinib or a salt thereof, including forming baricitinib or a salt thereof.

[0129] In some embodiments, the salt of formula 2c is the same as the salt of formula 2d. [ka] It is prepared by a process that includes reacting it 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] This is reacted with MeMgBr in the presence of a Grignard catalyst to form the compound of formula 1aP, [ka] (b) Deprotect the compound of formula 1aP to obtain the compound of formula 1a [ka] or to form a salt thereof, (c) Prepared by a process comprising reacting a compound of formula 1a or a salt thereof with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, In the formula, P 1 is an amino protecting group. In some embodiments, P 1 It is trimethylsilyl.

[0131] In some embodiments, the salt of formula 2d is (a) Compound of formula 22P [ka] This is reacted with MeMgBr in the presence of a Grignard catalyst to form the compound of formula 23P, [ka] (b) Reduce the compound of formula 23P to obtain the compound of formula 1a [ka] or to form a salt thereof, (c) Prepared by a process comprising reacting a compound of formula 1a or a salt thereof with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, In the formula, P 2 is an amino protecting group. In some embodiments, P 1 It is t-butyldimethylsilyl.

[0132] In some embodiments, the compound of formula 3 or a salt thereof is Compound of formula 6 [ka] It is prepared by a process that includes reacting it with hydrazine.

[0133] In some embodiments, what is provided herein is (a) Compound of formula 1a or a salt thereof [ka] This is reacted with the Vilsmeyer reagent formed from dimethylformamide to produce the salt of formula 2c, [ka] (b) Salt of formula 2c and formula M +ClO4 - By reacting with the salt of, the salt of formula 2a is produced, [ka] In the formula, M + X is a countercation, - is ClO4 - That is, (c) Salt of formula 2a is compound of formula 3 [ka] The process for preparing baricitinib or a salt thereof includes reacting it with a salt thereof to form baricitinib or a salt thereof.

[0134] In some embodiments, what is provided herein is (a) Compound of formula 5a [ka] This is reacted with the Vilsmeyer reagent formed from dimethylformamide to produce the salt of formula 2c, [ka] (b) Salt of formula 2c and formula M + ClO4 - By reacting with the salt of, the salt of formula 2a is produced, [ka] In the formula, M + X is a countercation, - is ClO4 - That is, (c) Salt of formula 2a is compound of formula 3 [ka] The process for preparing baricitinib or a salt thereof includes reacting it with a salt thereof to form baricitinib or a salt thereof.

[0135] In some embodiments, what is provided herein is (a) Compound of formula 6 [ka] This is reacted with hydrazine to form the compound of formula 3. [ka] or producing a salt thereof, (b) Compound of formula 3 or a salt thereof and salt of formula 2a [ka] A process for preparing baricitinib or a salt thereof, comprising reacting with to produce baricitinib or a salt thereof, wherein M + X is a countercation, - is ClO4 - That is the case.

[0136] In some embodiments, the compound of formula 1a [ka] or its salt is (a) Compound of formula 12a [ka] It is reacted with trimethylsilyl chloride to produce the compound of formula 2P, [ka] In the formula, P 1 It is trimethylsilyl, (b) Reacting the compound of formula 12b with MeMgBr in the presence of a Grignard catalyst to produce the compound of formula 12c, [ka] (c) Prepared by a process comprising deprotecting the compound of formula 12d to form the 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] The compound of formula 14a is produced by reacting it with bromoacetaldehyde diethyl acetal and sodium tert-amyloxide, [ka] (b) Reacting the compound of formula 14a with formamidine acetate and an alkali metal alkoxide to produce the compound of formula 14aa, [ka] (c) Reacting the compound of formula 14aa with a strong acid to produce the compound of formula 15a, [ka] (d) Prepared by a process comprising reacting the compound of formula 15a with a chlorinating agent to form the compound of formula 12a.

[0138] In some embodiments, the compound of formula 1a [ka] or its salt is (a) Compound of formula 22a, [ka] This is reacted with t-butyldimethylsilyl chloride and alkali metal hydride to produce the compound of formula 22P, [ka] In the formula, P 2It is t-butyldimethylsilyl, (b) Reacting the compound of formula 22P with MeMgBr in the presence of a Grignard catalyst to produce the compound of formula 23a, [ka] (c) Reduce the compound of formula 23a with hydrogen and palladium carbon to form the compound of formula 1a or a salt thereof, where P 2 It is prepared by a process that includes the fact that it is an amino protecting group.

[0139] In some embodiments, the compound of formula 6 is (a) Reacting diphenylmethaneamine with 2-(chloromethyl)oxirane to produce the compound of formula 57 or a salt thereof, [ka] (b) Reacting the compound of formula 57 or a salt thereof with hydrogen, palladium carbon, and di-tert-butyl dicarbonate to produce the compound of formula 56a, [ka] (c) Oxidizing the compound of formula 56a to produce the compound of formula 7a, [ka] (d) Reacting the compound of formula 7a with diethylcyanomethyl phosphate and a base to produce the compound of formula 54a, [ka] (e) Deprotecting the compound of formula 54a to produce the compound of formula 55 or a salt thereof, [ka] (f) It is prepared by a process comprising 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 is provided herein.

[0141] In some embodiments, the following are provided herein: Compound of formula 6 [ka] This is a process for producing the compound of formula 3 or a salt thereof, which involves reacting with hydrazine.

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

[0143] In various parts of this specification, substituents of the compounds of the present invention are disclosed in groups or ranges. The present invention is specifically intended to include any and all individual partial combinations of members of such groups and ranges. For example, the term "C 1~6 "Alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0144] It will be further understood that certain features of the present invention described in relation to separate embodiments may, for clarity, also be provided in combination in a single embodiment. Conversely, various features of the present invention described in relation to a single embodiment may, for brevity, be provided separately or in any preferred partial combination.

[0145] As used herein, the term “alkyl,” when 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, and sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and n-octyl. In some embodiments, the alkyl moiety is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or 2,4,4-trimethylpentyl. In some embodiments, the alkyl moiety is methyl.

[0146] As used herein, the terms “halo” and “halogen,” when used alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodine.

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

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

[0149] As used herein, the terms “react” and “contact” are used as known in the art and generally refer to bringing together chemical reagents in such a manner that their interactions at the molecular level enable them to achieve a chemical or physical transformation. In some embodiments, the reaction involves two reagents, where one equivalent or more of the second reagent is used relative to the first reagent. The reaction steps of the processes described herein can be carried out at times and under conditions suitable for the preparation of the specified product.

[0150] In some embodiments, the reagent and intermediate may be salts.

[0151] This disclosure also includes pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term “pharmaceutically acceptable salt” means a salt formed by adding a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the expression “pharmaceutically acceptable” means a substance that is acceptable for use in a pharmaceutical application from a toxicological standpoint and does not adversely interact with the active ingredient. Examples of pharmaceutically acceptable salts, including monosal and disal salts, include, but are not limited to, those derived from organic and inorganic acids, such as acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, and similar known acceptable acids. A list of suitable salts can be found in their entirety by reference in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), respectively.

[0152] The preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties 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, formation methods, and cleavage methods described herein may be made as necessary, taking into account various substituents.

[0153] The reactions of the processes described herein may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out, which may range from the freezing temperature to the boiling temperature of the solvent. A given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a solvent suitable for a particular reaction step may be selected. In some embodiments, the reaction may be carried out in the absence of a solvent, for example, when at least one of the reagents is a liquid or a gas.

[0154] Suitable solvents include halogenating 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 similar solvents.

[0155] Suitable solvents 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 similar solvents.

[0156] Suitable protic solvents include, but are not limited to, 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 similar substances.

[0157] Suitable aprotic solvents include, but are not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, mixtures thereof, and similar solvents.

[0158] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane (e.g., n-heptane), ethylbenzene, m-, o-, or p-xylene, octane, indan, nonane, naphthalene, mixtures thereof, and similar materials. Supercritical carbon dioxide and ionic liquids can also be used as solvents.

[0159] The reactions of the processes described herein may be carried out at appropriate temperatures that can be readily determined by those skilled in the art. The reaction temperature depends, for example, on the melting and boiling points of the reagents and solvents (if any), the thermodynamics of the reaction (e.g., violently 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 high temperatures). "High temperature" refers to temperatures higher than room temperature (approximately 22°C). The reactions of the processes described herein may be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are substantially reactive with air may be carried out using air-sensitive synthesis techniques well known to those skilled in the art.

[0160] In some embodiments, the preparation of the compound may involve the addition of an acid or base that affects the catalytic activity of the desired reaction or formation of a salt form, such as an acid addition salt.

[0161] Exemplary acids may be inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Examples of 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-butyric acid, vinylacetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0162] Examples of 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. Examples of alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; examples of metal amides include sodium amide, potassium amide, and lithium amide; examples of metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and examples of metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl, and cyclohexyl-substituted amides.

[0163] This 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, and alkali or organic salts of acidic residues such as carboxylic acids. Generally, salt forms can be prepared by reacting a free base or acid with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid or base in a suitable solvent or in a variety of solvent combinations. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the entire disclosure of which is incorporated herein by reference. When performing the preparation of compounds according to the processes described herein, the desired product can be isolated using common isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like.

[0164] In some embodiments, the compounds of the present invention and their salts are substantially isolated. "Substantially isolated" means that the compounds are at least partially, or substantially, separated from the environment in which they were formed or detected. Partial isolation may include, for example, compositions rich in the compounds of the present invention. Substantial isolation may include compositions containing 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 commonplace in the art.

[0165] In some embodiments, baricitinib, intermediates for preparing baricitinib reagents, and salts thereof may include both anhydrous and solvated / hydrated forms of the substance. Different forms of the same substance have different bulk properties, for example, with respect to hygroscopicity, solubility, and stability. Forms with high melting points often have good thermodynamic stability, which is advantageous for extending the shelf life of drug formulations, including solid forms. Forms with low melting points are often less thermodynamically stable, but they are advantageous in that they have increased water solubility, thereby increasing the bioavailability of the drug. Forms with low hygroscopicity are desirable due to their stability to heat and humidity and are resistant to degradation during long-term storage.

[0166] In some embodiments, the disclosed compounds or salts thereof are crystalline. As used herein, “crystalline” or “crystalline form” means a particular lattice arrangement of a crystalline material. Different crystalline forms of the same material typically have different crystal lattices (e.g., unit cells), which result from different physical properties characteristic of each crystalline form. In some cases, different lattice arrangements have different water or solvent content. Different solid forms and their salt forms 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), and solid-phase NMR, further assist in identifying the form and, moreover, in determining stability and solvent / water content. The XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystal morphology. It is well known that the relative intensity of XRPD peaks can vary widely depending, among other things, on sample preparation techniques, crystal size distribution, the various filters used, sample mounting procedures, and the specific instruments used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the instrument. As used herein, the term “peak” refers to a reflection with a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrument variability and other factors may affect the 2-theta value. Thus, peak assignments such as those reported herein may vary by plus or minus about 0.2° (2-theta), and the terms “substantially” and “about” when used herein in relation to XRPD mean that the aforementioned variability is included.

[0167] Similarly, temperature readings for DSC, TGA, or other thermal experiments can vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. Therefore, the crystalline morphologies reported herein having "substantially" the DSC thermogram shown in any of the drawings, or the term "approximately," should be understood to correspond to such variations.

[0168] Generally, the term "approximately" means ±10%. In some embodiments, the term "approximately" 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 isolation may include, for example, compositions rich in the solid and salt forms. Substantially isolated may include compositions containing 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 are commonplace in the art.

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

[0171] The term "pharmaceutically acceptable" is used herein to mean salts, materials, compositions, and / or dosage forms that, within the bounds of appropriate medical judgment, are suitable for use in contact with human and animal tissues in proportion to a reasonable benefit-risk ratio, without excessive toxicity, irritation, allergic response, or other problems or complications.

[0172] The reactions described herein may be carried out at appropriate temperatures that can be readily determined by those skilled in the art. The reaction temperature depends, for example, on the melting and boiling points of the reagents and solvents (if any), the thermodynamics of the reaction (e.g., violently 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 high temperatures).

[0173] As used herein, the terms “ambient temperature” and “room temperature” or “rt” are understood in the art and generally refer to a temperature close to the temperature of the room in which the reaction takes place, for example, a reaction temperature of about 20°C to about 30°C. Protecting groups described herein (e.g., P 1 , P 2 , P 50 Examples include, but are not limited to, amine protecting groups, as described in detail in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, pages 696-887 (and especially pages 872-887) (2007), which is incorporated herein by reference in its entirety. Examples of protecting groups described herein include CH2OC(=O)C(CH3)3, CH2OCH2CH2Si(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- Dimethylpento-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 Examples include alkyl)silyl (e.g., tri(isopropyl)silyl or t-butyldimethylsilyl), 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl (SEM), N-pivaloyloxymethyl (POM), p-nitrophenylsulfonyl, p-toluenesulfonyl, phenylsulfonyl, methanesulfonyl, etc. In some embodiments, the protecting group is tri(C 1~4The protecting group is an alkyl silyl (e.g., tri(isopropyl)silyl or t-butyldimethylsilyl). In some embodiments, the protecting group is t-butyldimethylsilyl. In some embodiments, the protecting group is p-toluenesulfonyl.

[0174] The present invention will be described in more detail by specific embodiments. The following embodiments are provided for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-essential 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]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile (baricitinib, compound 1) [ka] Step 1.2-(1-(ethylsulfonyl)-3-hydrazineylazetidin)acetonitrile (compound 3): 2-(1-(ethylsulfonyl)azetidine-3-ylidene)acetonitrile (compound 6, 1.0 g, 5.37 mmol) and acetonitrile (10 mL) were added to a flask under nitrogen. Hydrazine hydrate (0.66 g, 11.3 mmol, 2.1 equivalents) was slowly added to the reaction mixture over 30 minutes at a controlled reaction temperature 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 residual reaction mixture was diluted with dichloromethane (CH2Cl2, 20 mL) and washed with brine (10 mL). The organic layer was separated and recovered. The aqueous layer was extracted with another portion of dichloromethane (CH2Cl2, 10 mL) and the organic layer was recovered. The combined organic layers were evaporated under reduced pressure. The crude desired product, 2-(1-(ethylsulfonyl)-3-hydrazinaylazetidine-3-yl)acetonitrile (compound 3, 0.82 g, 72%), was obtained as a gel and used directly in the next step without further purification. For compound 3: 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]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile (baricitinib, compound 1): To a solution of 2-(1-(ethylsulfonyl)-3-hydrazinaylazetidine-3-yl)acetonitrile (compound 3, 0.84 g, 3.85 mmol, 1.32 equivalents) in ethanol (8 mL), vinylamidinium perchlorate (compound 2 perchlorate, 1.0 g, 2.91 mmol) was added all at once. The resulting reaction mixture was stirred at ambient temperature for 16 hours. n-heptane (16 mL) was added to the reaction mixture, and the resulting mixture was stirred at ambient temperature for a further 1 hour. The reaction mixture was filtered, and the solid was washed with n-heptane (10 mL). After drying overnight by drawing air through a moist cake, the desired product, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(ethylsulfonyl)azetidine-3-yl)acetonitrile (baricitinib, compound 1, 1.2 g, 85%), was obtained as a brown solid. In the case of 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)azetidine-3-ylidene)acetonitrile (compound 6) [ka] Step 1. tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (compound 54a): Diethylcyanomethyl phosphate (745 g, 4.20 mol, 1.20 equivalents) and anhydrous tetrahydrofuran (THF, 9 L) were added at room temperature to a four-necked 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 equivalents) was added over 20 minutes while maintaining the reaction temperature below -5°C. The resulting reaction mixture was stirred at -10°C for 3 hours, 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 hours while maintaining the internal temperature below -5°C. The reaction mixture was stirred at -5 to -10°C for 1 hour, then gradually warmed to room temperature and stirred overnight at room temperature. Subsequently, the reaction mixture was diluted with water (4.5 L) and saturated sodium chloride aqueous solution (NaCl, 4.5 L) and extracted with ethyl acetate (RINKAN, 2 × 9 L). The combined organic layer was washed with brine (6 L) and dried over anhydrous sodium sulfate (Na₂SO₄). The organic solvent was removed under reduced pressure, the residue was diluted with dichloromethane (CH₂Cl₂, 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% RINKAN / hexane gradient elution) to obtain tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (compound 54a, 414.7 g, theoretically 679.8 g, yield 61%) 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)azetidine-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 an aqueous solution of 3 N HCl (7 L) were stirred at room temperature for 18 hours. When HPLC showed that all of the starting material (tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate) had been consumed, the reaction mixture was concentrated under reduced pressure and dried. The residue containing the crude desired deprotection product (compound 55a) was then suspended in acetonitrile (12 L), and the resulting suspension was subsequently cooled to 0-5°C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equivalents) was then gradually added while maintaining the internal temperature below 5°C. The resulting homogeneous solution was cooled to 0°C, and while maintaining an internal temperature below 5°C, ethanesulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equivalents) was added over 1 hour. The resulting reaction mixture was gradually warmed to room temperature and stirred overnight at room temperature. Once HPLC indicated the completion of the reaction, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The rotary evaporator bath temperature was set not to exceed 45°C. Subsequently, the concentrated residue was diluted with dichloromethane (CH2Cl2, 10 L), and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back-extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4), and the residue was absorbed onto silica gel (SiO2, 1 kg) under reduced pressure. The rotary evaporator bath temperature was set not to exceed 45°C. Next, the material was packed into a silica gel column (SiO2, 2.5 kg) and eluted with 20-60% ethyl acetate in heptane to obtain 2-(1-(ethylsulfonyl)azetidine-3-ylidene)acetonitrile (compound 6, 882 g, theoretically 968.4 g, yield 91%) 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-Benzhydrylazetidine-3-ol hydrochloride (compound 57a): A solution of diphenylmethaneamine (2737 g, 15.0 mol, 1.04 equivalents) in methanol (MeOH, 6 L) was treated at room temperature with 2-(chloromethyl)oxirane (1330 g, 14.5 mol) from an addition funnel. A slight endothermic reaction was observed during the initial addition. The resulting reaction mixture was stirred at room temperature for 3 days, and then heated under reflux for another 3 days. When TLC indicated that the reaction was 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 obtain the first harvest (1516 g) of the crude desired product. The filtrate was concentrated under reduced pressure, and the resulting semi-solids were diluted with acetone (1 L). Subsequently, these solids were collected by filtration to obtain the second harvest (221 g) of the crude desired product. The crude product, 1-benzhydrylazetidine-3-ol hydrochloride (compound 57a, 1737g, theoretically 3998.7g, yield 43.4%), was found to be pure enough to be used in subsequent reactions without further purification. For compound 57a: 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-benzhydrylazetidine-3-ol hydrochloride (compound 57a, 625 g, 2.27 mol) in 10% solutions of aqueous sodium carbonate (Na2CO3, 5 L) and dichloromethane (CH2Cl2, 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 (CH2Cl2, 2 L). The combined organic extract was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting crude free base of 1-benzhydrylazetidine-3-ol hydrochloride was dissolved in tetrahydrofuran (THF, 6 L), and the solution was placed in a large Parr cylinder. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equivalents) and 20% palladium (Pd) carbon (125 g, 50% water) were added to the Parr cylinder. The container was filled with hydrogen gas (H2) to 30 psi and stirred at room temperature for 18 hours under a constant hydrogen atmosphere (the container was refilled three times to maintain a pressure of 30 psi). When HPLC indicated that the reaction was complete (no further hydrogen was 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 packed into a Biotage 150 column with a minimum amount of dichloromethane (CH2Cl2). The column was eluted with 20-50% ethyl acetate in heptane, and the fractions containing the pure desired product were collected and combined. The solvent was removed under reduced pressure to obtain tert-butyl 3-hydroxyazetidine-1-carboxylate (compound 56a, 357 g, theoretically 393.2 g, yield 90.8%) as a colorless oil, which solidified when left in a 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. Subsequently, the resulting solution was treated at 0-5°C with solid TEMPO (0.5 g, 3.2 mmol, 0.011 equivalents) and a solution of potassium bromide (KBr, 3.9 g, 33.2 mmol, 0.115 equivalents) in water (60 mL). While maintaining the reaction temperature at 0-5°C, saturated aqueous solution of sodium bicarbonate (NaHCO3, 450 mL) and aqueous solution of sodium hypochlorite (NaClO, 10-13% available chlorine, 450 mL) were added. 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 indicated that all starting materials had been consumed, the color of the reaction mixture no longer changed. The reaction mixture was then diluted with ethyl acetate (RINKAN, 500 mL) and the two layers were separated. The organic layer was washed with water (500 mL) and saturated sodium chloride aqueous solution (500 mL) and dried over sodium sulfate (Na₂SO₄). The solvent was then removed under reduced pressure to obtain the crude product, tert-butyl 3-oxoazetidine-1-carboxylate (compound 7a, 48 g, theoretically 49.47 g, 97% yield), which was found to be sufficiently pure and used directly in subsequent reactions 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]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium chloride hydrochloride (chloride hydrochloride of compound 2, or compound 2d) [ka] A solution of oxalyl chloride (21.88 g, 15.1 mL, 169 mmol, 2.25 equivalents) 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 equivalents) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled to less than 10°C during the addition of DMF. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature over 40 minutes. Methyl-7H-pyrrolo[2,3-d]pyrimidine (1a, 10.0 g, 75.1 mmol) was added all at once as a solid at ambient temperature to the in-situ Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, and then warmed to 85–90°C. The reaction mixture was stirred at 85-90°C for 1 hour, then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 100 mL) was added, and the resulting slurry was stirred at ambient temperature for 2 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration, washed with a 1:1 mixture of THF and MTBE (2 × 100 mL), and vacuum-dried to constant weight to obtain the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium chloride hydrochloride (2d, 24.38 g, theoretically 23.72 g, 98.9% by HPLC area%, 90.2% by NMR, yield 92.6%), 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, 244.32 for compound 2 without anion) LCMS(EI) m / e 244.2 (M + (Reference peak).

[0183] The crystalline form I of compound 2d was characterized by XRPD, DSC, and TGA. X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) results were obtained using a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE® detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder 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 scanning speed 2 degrees / min.

[0184] XRPD analysis confirmed that compound 2d in morphology I is a crystalline solid. The XRPD patterns of compound 2d, crystalline morphology I, are shown in Figure 1, and the peak data are provided in Table 1. [Table 1]

[0185] Differential Scanning Calorimetry (DSC): DSCs were obtained from a TA Instruments Discovery DSC2500 differential scanning calorimetry instrument equipped with an autosampler. The 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 a single endothermic peak with an onset temperature of 55.6°C and a maximum of 100.6°C. The DSC thermogram of compound 2d, crystalline form I is provided in Figure 2.

[0186] Thermogravimetric Analysis (TGA): TGA results were obtained using a TA Instruments Discovery TGA5500 thermogravimetric analyzer equipped with an autosampler. Typical experimental conditions for TGA were as follows: gradient from 25°C to 300°C at 10°C / min, nitrogen purge gas flow at 25 mL / min, and platinum sample holder. TGA analysis of compound 2d, crystalline form I, revealed an 8.0% weight loss below 100°C and a significant weight loss above 175°C, due to decomposition. A 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]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride hydrochloride (compound 2d) A solution of oxalyl chloride (43.76 g, 30.2 mL, 338 mmol, 2.25 equivalents) 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 equivalents) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled to less than 10°C during the addition of DMF. The ice bath was removed, and the reaction mixture was gradually warmed to ambient temperature over 40 minutes. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (hydrochloride of compound 1a, 25.44 g, 150 mmol) was added in one solid batch at ambient temperature to the in-situ Vilsmeier reagent. The resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, and then warmed to 85–90°C. The reaction mixture was stirred at 85-90°C for 1 hour, then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 200 mL) was added, and the resulting slurry was stirred at ambient temperature for 48 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration, washed with a 1:1 mixture of THF and MTBE (2 × 200 mL), and vacuum-dried to constant weight to obtain the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium chloride hydrochloride (compound 2d, 46.17 g, theoretically 47.43 g, 99.5% by HPLC area%, 95.2% by NMR, yield 92.7%), as a yellow to brown crystalline solid (form II) containing 2.3% DMF, 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, 244.32 for compound 2 without anion) LCMS(EI) m / e 244.2 (M + (Reference 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) results were obtained using a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder 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 scanning speed 2 degrees / min.

[0189] The crystalline form II of compound 2d was confirmed to be a crystalline solid by XRPD analysis. The XRPD patterns of compound 2d, crystalline form II, are shown in Figure 4, and the peak data are provided in Table 2. [Table 2]

[0190] Differential Scanning Calorimetry (DSC): DSCs were obtained from a TA Instruments Discovery DSC2500 differential scanning calorimetry instrument equipped with an autosampler. The 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 a single endothermic peak with an onset temperature of 46.6°C and a maximum of 99.2°C. A DSC thermogram of compound 2d, crystalline form II is provided in Figure 5.

[0191] Thermogravimetric Analysis (TGA): TGA results were obtained using a TA Instruments Discovery TGA5500 thermogravimetric analyzer equipped with an autosampler. Typical experimental conditions for TGA were as follows: gradient from 25°C to 300°C at 10°C / min, nitrogen purge gas flow at 25 mL / min, and 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. A 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]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium chloride hydrochloride (2d) [ka] A solution of phosphorus oxochloride (POCl3, 17.25 g, 10.5 mL, 112.5 mmol, 1.5 equivalents) 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 equivalents) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled to less than 10°C during the addition of DMF. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (hydrochloride of compound 1a, 12.72 g, 75.0 mmol) was added in one solid batch at ambient temperature to the in situ-formed Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, after which it was warmed to 75–80°C. The reaction mixture was stirred at 75-80°C for 1 hour, then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 100 mL) was added, and the resulting slurry was stirred at ambient temperature for 2 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration and washed with a 1:1 mixture of THF and MTBE (2 × 100 mL) to obtain the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride hydrochloride (compound 2d, 27.83 g, theoretically 23.72 g, 96.1% by HPLC area%, 69.0% by NMR, yield 81.0%), as a yellow to brown crystalline (morphology I) solid containing 11.49% DMF, 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, 244.32 for compound 2 without anion) LCMS(EI) m / e 244.2 (M + (Reference peak).

[0193] Example 7: Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium 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 equivalents) 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 equivalents) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled to less than 10°C during the addition of DMF. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (hydrochloride of compound 1a, 12.72 g, 75.0 mmol) was added in one solid batch at ambient temperature to the in situ-formed Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, after which it was warmed to 75–80°C. The reaction mixture was stirred at 75-80°C for 1 hour, then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (100 mL) was added, and the resulting slurry was stirred at ambient temperature for 2 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration and washed with a 1:1 mixture of THF and MTBE (2 × 100 mL) to obtain the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride hydrochloride (compound 2d), as a yellow to brown wet cake. Subsequently, the wet cake was dissolved in water (120 mL), and the pH of the resulting aqueous solution was adjusted to 7-8 by treatment with 50% sodium hydroxide aqueous 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 Celite bed, 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]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c, purity exceeding 99.0% by HPLC area percentage), was used in the subsequent reaction without further treatment.

[0194] Example 8: Synthesis of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c) using triphosgene [ka] A solution of triphosgene ((CCl3O)2CO, 37.4 g, 126 mmol, 1.5 equivalents) 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 equivalents) was added dropwise to the solution to form the corresponding Vilsmeier reagent. The internal temperature was controlled to less than 10°C during the addition of DMF. The ice batch was removed, and the reaction mixture was gradually warmed to ambient temperature over 40 minutes. Methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (hydrochloride of compound 1a, 14.25 g, 84.0 mmol) was added in one solid batch at ambient temperature to the in situ-formed Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, after which it was warmed to 80–90°C. The reaction mixture was stirred at 80-90°C for 1 hour, then gradually cooled to ambient temperature. Anhydrous tetrahydrofuran (THF, 112 mL) was added, and the resulting slurry was stirred at ambient temperature for 12 hours, followed by 2 hours at 0-5°C. The solid was collected by filtration, washed with a 1:1 mixture of THF and MTBE (2 × 200 mL), and vacuum-dried to constant weight to obtain the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c), 28.3 g, theoretically 23.5 g, 98.8% by HPLC area%, 64.9% by HPLC, yield 78.2%), 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, 244.32 for compound 2 without anion) LCMS(EI) m / e 244.2 (M + (Reference peak).

[0195] Example 9: Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium salt [ka] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2) To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL), sodium perchlorate (NaClO4, 1.933 g, 15.79 mmol, 1.50 equivalents) was added at ambient temperature. After stirring at 20-25°C for 12 hours, the slurry was cooled in an ice bath for 2 hours. The solid was filtered, washed with cold H2O (3 × 2 mL), and dried under vacuum to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium perchlorate (perchlorate 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 ClN5O4(MW, 343.77 for perchlorate of compound 2, 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Reference peak).

[0196] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium tetrafluoroborate (tetrafluoroborate of compound 2) To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL), sodium tetrafluoroborate (NaBF4, 1.733 g, 15.79 mmol, 1.50 equivalents) was added at ambient temperature. After stirring at 20-25°C for 12 hours, the slurry was cooled in an ice bath for 2 hours. The solid was filtered, washed with cold H2O (3 × 2 mL), and dried under vacuum to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium tetrafluoroborate (tetrafluoroborate of compound 2, 1.80 g, theoretically 3.49 g, yield 51.6%), as a white solid, which was used in subsequent reactions 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 compound 2 tetrafluoroborate, 244.32 for compound 2 without anion) m / e 244.2 (M + (Reference peak).

[0197] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium hexafluorophosphate (hexafluorophosphate of compound 2) In Example 4, a solution of crude (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride hydrochloride (compound 2d, 25.61 g, 91.6 mmol) was prepared from 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.19 g, 91.6 mmol) in water (80 mL). The pH of the solution was adjusted to 7-8 by adding aqueous sodium hydroxide (NaOH) at 0-5°C. 7.69 g of charcoal was added to the resulting aqueous solution, and the mixture was stirred at ambient temperature for 2-4 hours. The charcoal was removed by filtration through a Celite bed, and the wet charcoal cake was washed with water (15 mL). Next, sodium hexafluorophosphate (NaPF6, 20.08 g, 120 mmol, 1.31 equivalents) was added to the combined aqueous solution at ambient temperature. After stirring at 20-25°C for 1 hour, the slurry was cooled in an ice bath for 30 minutes. The solid was filtered, washed with cold H2O (2 × 25 mL), and dried under vacuum to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium hexafluorophosphate (hexafluorophosphate of compound 2, 24.30 g, theoretically 35.81 g, yield 67.9%, 98.7% by HPLC area%), as a white crystalline solid, which was used in subsequent reactions without further purification. The crude hexafluorophosphate of compound 2 can be purified by recrystallization from water to produce a pure product as a white crystalline solid. For hexafluorophosphate 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) = 711.1 Hz) 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, 244.32 for compound 2 without anion) LCMS(EI) m / e 244.2(M + (Reference peak). The crystallinity of hexafluorophosphate in compound 2 was characterized by XRPD, DSC, and TGA.

[0198] X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) was obtained using a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV and 25 mA, and (3) sample powder 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 scanning speed 2 degrees / min. The hexafluorophosphate of compound 2 was confirmed to be a crystalline solid by XRPD analysis. The XRPD pattern of the hexafluorophosphate of compound 2 is shown in Figure 7, and peak data are provided in Table 3. [Table 3-1] [Table 3-2]

[0199] Differential Scanning Calorimetry (DSC): DSCs were obtained from a TA Instruments Discovery DSC2500 differential scanning calorimetry instrument equipped with an autosampler. The 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 compound 2 hexafluorophosphate revealed one endothermic peak at an onset temperature of 231.7°C and a maximum of 232.7°C, attributed to melting, and a second endothermic peak at an onset temperature of 241.1°C and a maximum of 242.1°C, attributed to decomposition. The DSC thermogram of compound 2 hexafluorophosphate is shown in Figure 8.

[0200] Thermogravimetric Analysis (TGA): TGA results were obtained using a TA Instruments Discovery TGA5500 thermogravimetric analyzer equipped with an autosampler. Typical experimental conditions for TGA were as follows: a gradient from 25°C to 300°C at 10°C / min, a nitrogen purge gas flow of 25 mL / min, and a platinum sample holder. TGA analysis of a crystalline sample of compound 2 hexafluorophosphate revealed significant weight loss above 250°C due to decomposition. The TGA thermogram of compound 2 hexafluorophosphate is shown in Figure 9.

[0201] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium hexafluoroarsenate (hexafluoroarsenate of compound 2): To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL), sodium hexafluoroarsenate (NaAsF6, 3.35 g, 15.79 mmol, 1.50 equivalents) was added at ambient temperature. After stirring at 20-25°C for 12 hours, the slurry was cooled in an ice bath for 2 hours. The solid was filtered, washed with cold H2O (3 × 2 mL), and dried under vacuum to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium hexafluoroarsenate (hexafluoroarsenate of compound 2, 4.51 g, theoretically 4.56 g, yield 99%), as a white solid, which was used in subsequent reactions without further purification. In the case of 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, 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Reference peak).

[0202] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium hexafluoroantimonate (hexafluoroantimonate of compound 2) To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (compound 2c, 2.94 g, 10.525 mmol) in water (8.06 mL), sodium hexafluoroantimonate (NaSbF6, 4.08 g, 15.79 mmol, 1.50 equivalents) was added at ambient temperature. After stirring at 20-25°C for 12 hours, the slurry was cooled in an ice bath for 2 hours. The solid was filtered, washed with cold H2O (3 × 2 mL), and dried under vacuum to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium hexafluoroantimonate (hexafluoroantimonate of compound 2, 2.61 g, theoretically 5.05 g, yield 51.7%), as a white solid, which was used in subsequent reactions without further purification. In the case of 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 + (Reference peak).

[0203] Example 10: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2) Method 1 [ka] While maintaining an internal temperature below 50°C, oxalyl chloride (20.0 mL, 228 mmol, 3.04 equivalents) was gradually added to DMF (107 mL, 1378 mmol, 18.4 equivalents) over 15 minutes. After addition, the resulting slurry was cooled to ambient temperature and stirred at ambient temperature for 2 hours. 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 10.0 g, 75 mmol) was added to the slurry at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 16 hours, followed by 5.5 hours at 50°C. The reaction mixture was cooled to ambient temperature and quenched with ice (60 g). The quenched reaction mixture was concentrated under vacuum to obtain a residue, which was then dissolved in water (50 mL). Subsequently, sodium perchlorate (NaClO4, 20.23 g, 165 mmol, 2.2 equivalents) was added to the aqueous solution at ambient temperature. The resulting mixture was cooled in an ice bath, after which sodium hydroxide (NaOH, 7.5 g, 188 mmol, 2.5 equivalents) was gradually added. The solid was recovered by filtration, washed with water (30 mL), and vacuum-dried to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2, 18.7 g, theoretically 25.78 g, yield 72.5%), as a gray solid, which was used in subsequent reactions 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 ClN5O4(MW, 343.77 for perchlorate of compound 2, 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Reference peak).

[0204] Method 2 [ka] To a solution of 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acetate (compound 5a, 354 mg, 2.0 mmol) in anhydrous DMF (2.92 g, 3.1 mL, 40 mmol, 20 equivalents), phosphorus oxychloride (POCl3, 920 mg, 0.56 mL, 6.0 mmol, 3.0 equivalents) was added at ambient temperature. Subsequently, the resulting reaction mixture was heated to 80-90°C and stirred for 30 minutes. After the reaction was complete, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was quenched by pouring it onto ice (10 g). The solution was then concentrated under reduced pressure, and the resulting residue was treated with water (3 mL). This aqueous solution was neutralized to pH 7-8 with NaOH aqueous solution, and then treated with activated carbon (50 mg). The mixture was stirred at ambient temperature for 30 minutes, and then filtered through a Celite bed. The Celite bed was washed with water (2 mL). The combined filtrate and washing solution were then treated with solid sodium perchlorate (NaClO4, 367 mg, 3.0 mmol, 1.5 equivalents) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour, followed by stirring at 0-5°C for 1 hour. The solid was then collected by filtration, washed with water (2 × 2 mL), and vacuum-dried to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2, 330 mg, theoretically 688 mg, yield 48%), as a gray solid, which was used in subsequent reactions without further purification. For 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 ClN5O4(MW, 343.77 for perchlorate of compound 2, 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M +(Reference peak).

[0205] Method 3 [ka] To a solution of sodium acetate 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) (compound 5b, 1.70 g, 8.54 mmol) in anhydrous DMF (12.48 g, 13.2 mL, 171 mmol, 20 equivalents), phosphorus oxychloride (POCl3, 3.93 g, 2.4 mL, 25.6 mmol, 3.0 equivalents) was added at ambient temperature. Subsequently, the resulting reaction mixture was heated to 80-90°C and stirred at 80-90°C for 30 minutes. After the reaction was complete, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was quenched by pouring it onto ice (40 g). The solution was then concentrated under reduced pressure, and the resulting residue was treated with water (10 mL). This aqueous solution was neutralized to pH 7-8 with NaOH aqueous solution, and then treated with activated carbon (200 mg). The mixture was stirred at ambient temperature for 30 minutes, and then filtered through a Celite bed. The Celite bed was washed with water (5 mL). Subsequently, the combined filtrate and washing solution were treated with solid sodium perchlorate (NaClO4, 1.57 g, 12.8 mmol, 1.5 equivalents) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour, followed by stirring at 0-5°C for 1 hour. The solid was then recovered by filtration, washed with water (2 × 5 mL), and vacuum-dried to obtain the desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2, 1.3 g, theoretically 2.94 g, yield 44.3%), as an off-white solid, which was used in subsequent reactions 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 18ClN5O4(MW, 343.77 for perchlorate of compound 2, 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Reference peak).

[0206] Example 11: Preparation of 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)malonaldehyde ((E)-3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acrylaldehyde (compound 2b) While maintaining the internal temperature below 50°C, oxalyl chloride (12.00 mL, 137 mmol, 3.64 equivalents) was added dropwise to DMF (50 mL, 646 mmol, 17.18 equivalents). [ka]

[0207] The resulting mixture was stirred at ambient temperature for 30 minutes. 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 5.00 g, 37.6 mmol) was added as a solid all at once, and the resulting reaction mixture was stirred at room temperature for 3 days, followed by stirring at 50°C for 4 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature and quenched with ice (30 g). Sodium hydroxide (NaOH, 16.1 g, 403 mmol, 10.72 equivalents) was added to the quenched reaction mixture, and the mixture was stirred at room temperature for 26 hours. Additional sodium hydroxide (NaOH, 2.2 g, 55.0 mmol, 1.46 equivalents) was added, and the mixture was stirred at 40°C for 4 hours. Once the hydrolysis reaction was complete, the mixture was cooled to 0-5°C in an ice batch, and then the pH was adjusted to 5-6 by adding concentrated HCl solution. The mixture was gradually warmed to ambient temperature and stirred at ambient temperature for 2 hours. The solid was recovered by filtration, washed with cold water, and vacuum-dried to obtain the crude desired product, 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)malonaldehyde ((E)-3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acrylaldehyde (compound 2b, 6.33 g, theoretically 7.113 g, yield 89%), as a gray 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 + (Reference 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): A 5 L four-necked flask equipped with a mechanical stirrer, addition funnel, condenser, thermocouple, and N2 sweep into NaOH scrubbing aqueous solution was filled with phosphorus oxychloride (POCl3, 1 L, 10.572 mol, 4.82 equivalents) and cooled in an ice / salt bath. Subsequently, N,N-dimethylformamide (DMF, 320 mL, 4.138 mol, 1.85 equivalents) was added dropwise to the flask at 0 ± 2 °C. After adding approximately 100 mL of DMF over about 0.5 hours, crystallization occurred and the reaction temperature rose from 0 to 10 °C. The addition was stopped and the mixture was cooled again to about 2 °C. The remaining DMF was added over 2.5 hours at below 8 °C. The suspension was very viscous and difficult to stir. After the addition of DMF was complete, the mixture was stirred at 3–5 °C for 0.5 hours. 4,6-dihydroxypyrimidine (compound 8a, 250 g, 2.232 mol) was added gradually as a solid. After adding about one-third of the 4,6-dihydroxypyrimidine, the reaction mixture became more fluid, a slow exothermic reaction occurred, and the reaction temperature rose to about 12°C over 0.5 hours. The remaining 4,6-dihydroxypyrimidine was added gradually over 0.25 hours, and the reaction temperature rose from 12 to 27°C. The reaction temperature was maintained at 25-27°C with intermittent cooling, during which time the yellow suspension became more dilute and then more concentrated again. After the exothermic reaction subsided after about 1 hour, the reaction mixture was slowly heated. At about 55°C, the reaction mixture became extremely concentrated, and a second mild exothermic reaction occurred. The heating mantle was removed, but the reaction temperature continued to rise to about 63°C, remained at this temperature for several minutes, and then decreased. When heating of the mixture was resumed, a mild reflux (about 100°C) was eventually achieved. At approximately 95°C, a stable and fairly rapid release of HCl gas began, and the reaction mixture gradually became dilute and darkened. After about 0.5 hours, a clear brown solution was formed, and the reflux temperature slowly rose to 115°C over 1.25 hours. After a total of 2.5 hours of reflux, the reaction mixture was cooled to ambient temperature and stirred overnight at ambient temperature. Excess POCl3 (as much as possible) was removed under reduced pressure (bath temperature 45-50°C). The thick residual brown oil was very slowly poured into cold H2O (5L) in a 20L separation funnel, and ice was added as needed to maintain the aqueous mixture near room temperature.The aqueous mixture was extracted with RINKAN (2 × 3 L, followed by 1 × 2 L). The combined RINKAN extract was washed with H2O (2 × 2.5 L), saturated aqueous solution of NaHCO3 (1 L), and brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure (bath temperature 35°C) to obtain crude 4,6-dichloropyrimidine-5-carbaldehyde (compound 9a, 270 g, theoretically 395 g, 68.4%) as a yellow-orange solid. 20 g of this crude material was purified by Kugellohr distillation (oven temperature 90-100°C, 225 mTorr) to obtain 15.3 g of pure 4,6-dichloropyrimidine-5-carbaldehyde (compound 9a) as a white solid, which turned yellow when left 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 7 M NH3 in MeOH (265 mL, 1.855 mol, 2.0 equivalents) 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 hours at ambient temperature. The reaction temperature was slowly increased from 20 to 26°C, forming a yellow suspension. Gentle cooling was applied to maintain the reaction temperature below 26°C. The suspension was stirred at ambient temperature for 3.5 hours, after which the solid was recovered by filtration. The solid was washed with ELISA (1 L). The filtrate was concentrated under reduced pressure, and the solid was pulverized with toluene and n-heptane (2:1 v / v, 600 mL), filtered, and dried to obtain 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 HCl (1.25 L) for 1.5 hours, filtering, and then stirring in THF (750 mL) for 1 hour, filtering. Both filtrates in HCl and THF were concentrated under reduced pressure, and the resulting solid was pulverized with toluene and n-heptane (2:1 v / v, 450 mL), filtered, and dried to obtain 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, theoretically 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)pyrimidine-4-ylamine (compound 11a): A suspension of (methoxymethyl)triphenylphosphonium chloride (276.0 g, 0.807 mol, 1.1 equivalents) in THF (1.5 L) was cooled to -2°C in an ice / salt bath, and 1 M potassium tert-butoxide (KO) in THF (807 mL, 0.807 mol, 1.1 equivalents) was added. tBu) was added over 1.5 hours at -2 to -3°C. The dark reddish-orange mixture was stirred at -2 to -3°C for 1 hour. Subsequently, 4-amino-6-chloropyrimidine-5-carbaldehyde (compound 10a, 115.2 g, 0.7338 mol, 1.0 equivalent) was added gradually to the reaction mixture in solid form, while rinsing the container and funnel with THF (200 mL). During the addition, the reaction temperature rose from -3 to 13°C, and a brown color was produced. 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 hours. The reaction mixture was cooled to -2°C and then quenched by the slow addition of saturated aqueous solution of NH4Cl (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned into ELISA (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble substances at the interface, and then extracted with 2N HCl (4 × 250 mL), followed by 3N HCl (2 × 250 mL). The combined HCl extract was back-extracted with HCl (500 mL), then filtered through Celite to remove insoluble substances. The filtrate was cooled in an ice / brine bath, adjusted to pH 8 with 6N NaOH aqueous solution, and extracted with HCl (3 × 1 L). The combined HCl extract was washed with brine (1 L), dried over Na2SO4, and stirred with charcoal (10 g) and silica gel (10 g) for 1 hour. The mixture was filtered through Celite while washing the Celite pad with HCl (1 L). The filtrate was concentrated, and residual HCl was co-evaporated with n-heptane (500 mL). The resulting light brown solid was pumped under high vacuum for 2 hours to obtain crude 6-chloro-5-(2-methoxyvinyl)pyrimidine-4-ylamine (compound 11a, 72.3 g, theoretically 136.2 g, 53.1%). The crude desired product, compound 11a, was used in the next reaction without further purification. A sample of the crude product compound 11a (2.3 g) was purified by silica gel column chromatography eluted with 0%~35% siRNA / n-heptane to obtain 1.7 g of pure 6-chloro-5-(2-methoxyvinyl)pyrimidine-4-ylamine (compound 11a) as a white solid, which was found to be a 1:2 mixture of E / Z isomers.In the case of 6-chloro-5-(2-methoxyvinyl)pyrimidine-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): A concentrated hydrochloric acid aqueous solution (HCl, 5 mL) was added to a solution of crude 6-chloro-5-(2-methoxyvinyl)pyrimidine-4-ylamine (compound 11a, 70.0 g, 0.3784 mol) in THF (700 mL), and the resulting reaction mixture was heated under reflux for 7.5 hours. Upon warming, a light suspension formed, which gradually redissolved. When the reaction was deemed complete by monitoring by HPLC, the reaction mixture was cooled to ambient temperature and stirred overnight at ambient temperature. Solid NaHCO3 (15 g) was added to the reaction mixture, and the resulting mixture was stirred at ambient temperature for 1 hour. Carbon (7 g), silica gel (7 g), and Na2SO4 (20 g) were added, and the mixture was heated to 40°C over 1 hour. Subsequently, the mixture was cooled to ambient temperature and filtered through Celite while washing with THF (1 L) on a Celite pad. The filtrate was concentrated under reduced pressure, and the resulting solid was dried under reduced pressure to obtain crude 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 58.1 g, theoretically 58.1 g, 100%) as a yellowish-brown solid. This crude desired product, compound 12, was dissolved in toluene (1.0 L) at 50-55°C and treated with activated carbon (3 g). The mixture was filtered through Celite while still warm, and the Celite pad was washed with warm toluene (250 mL). The filtrate was concentrated to approximately 500 mL, and the suspension was allowed to stand overnight at ambient temperature. Next, the suspension was cooled to 0-5°C over 2 hours, and the solid was recovered by filtration. The solid was dried to obtain pure 4-chloro-7H-[pyrrolo[2,3-d]pyrimidine (compound 12a, 54.5 g, theoretically 58.1 g, 94%) as yellowish-brown crystals. For compound 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) is heated at 5°C with sodium tert-amyloxide ( t AmONa (158.8 kg) was added gradually. The mixture was then heated to 70-75°C, and ethyl cyanoacetate (191 kg, 1689 mol, total 3298 mol, 5.0 equivalents) was added. The mixture was stirred at 70-75°C for 30 minutes, after which bromoacetaldehyde diethyl acetal (130.4 kg, 665.2 mol) was added. The resulting reaction mixture was then heated to 90°C and stirred at 90°C until the reaction was complete. The reaction mixture was cooled to 5°C, and 16% ammonium chloride (NH4Cl) aqueous solution was added. The mixture was stirred for 30 minutes, after which ethyl acetate (490 kg) was added. 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% sodium chloride aqueous solution (NaCl, 318 kg) and brine (325 kg). The organic solution was dried with 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 obtain crude ethyl 2-cyano-4,4-diethoxybutanoate (compound 14a, 146.6 kg, theoretically 152.5 kg, 96.1%) as a yellow to brown oil, which was used directly in subsequent reactions without further purification.

[0213] Step 2.7H-pyrrolo[2,3-d]pyrimidine-4-ol (compound 15a): 1558 kg of 18% sodium ethoxide (EtONa) solution in ethanol and formamidine acetate (153.5 kg, 1474.4 mol) were added to the reaction vessel. The mixture was stirred at ambient temperature for 1 hour, after which ethyl 2-cyano-4,4-diethoxybutanoate (compound 14a, 269.8 kg, 1176.7 mol, 1.25 equivalents) was added. 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 783 kg of 21% aqueous ammonium chloride solution (NH4Cl) was added. The resulting mixture was stirred at 0°C for 30 minutes and concentrated under reduced pressure. The residual solution was cooled to 20-30°C and then filtered. The cake was again slurryed 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 heated to 30°C until the cyclization reaction was complete. Subsequently, the mixture was cooled to 5°C and aqueous ammonium hydroxide solution (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 obtain 7H-pyrrolo[2,3-d]pyrimidine-4-ol (compound 15a, 99.6 kg, theoretically 159 kg, 62.6%) as an off-white to 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]pyrimidine-4-ol (compound 15a, 99.6 kg, 737 mol) was added at ambient temperature to a solution of DIEA (128.4 kg, 99.5 mol, 1.35 equivalents) in toluene (500 kg), and the resulting mixture was cooled to 0°C. Subsequently, POCl3 (338 kg, 2202 mol, 3.0 equivalents) 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 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 until it became a thick slurry, cooled to 0°C, and then filtered. The cake was dried under reduced pressure to obtain pure 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 71.9 kg, theoretically 113.2 kg, 63.5%) as yellow to brown crystals. The 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) produced by this synthesis method 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 g, 7726 mmol, 1.211 equivalents) in THF (4.0 L) was cooled to 0-5°C in an ice bath, and then 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 980.0 g, 6381 mmol) was added. The mixture was stirred at 0-15°C for 30 minutes, and then a solution of TBDMS-Cl (1165 g, 7728 mmol, 1.211 equivalents) in THF was added at 0-15°C. The resulting mixture was stirred at 0-15°C for 1-2 hours. The mixture was cooled to -10°C, and iron(III) acetylacetonate (Fe(acac)3, 113 g, 319 mmol, 0.05 equivalents) was added. A solution of methylmagnesium bromide in THF (3260 mL, 9780 mmol, 1.53 equivalents) was slowly added to the mixture, and the internal temperature was controlled to less than 15°C. The resulting reaction mixture was stirred at 15-30°C for 2 hours. Once the coupling reaction was complete, an aqueous solution of ammonium chloride (NH4Cl, 8.0 L) was added to quench the reaction mixture, and the internal temperature was controlled to less than 10°C during quenching. Methyl tert-butyl ether (MTBE, 5.0 L) was added to the quenched reaction mixture, and the resulting mixture was filtered through a Celite bed. The Celite bed was washed with MTBE (2 × 500 mL). The two phases of the combined filtrate and washing solution were separated, and the aqueous phase was extracted with MTBE (2 × 5.0 L). The combined organic extract was concentrated under reduced pressure, and the residue was dissolved in methanol (MeOH, 5.0 L). Next, the solution was treated with a 26-28% aqueous ammonium hydroxide solution (NH4OH, 1.0 L), and the resulting mixture was stirred at 15-40°C for 16 hours. After the N-TBDMS deprotection reaction was complete, the reaction mixture was concentrated under reduced pressure, and n-heptane (2 × 4.0 L) was added 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 hour. The solid was recovered by filtration and washed with n-heptane (2 × 1.0 L) to obtain the crude desired product, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 840 g, theoretically 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 hours. The mixture was filtered through a Celite bed, 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), after which n-heptane (8.0 L) was introduced. The resulting mixture was stirred at ambient temperature for 14 hours. The solid was recovered by filtration, washed with a mixture of ethyl acetate and n-heptane, followed by n-heptane, and dried to a constant weight to obtain purified methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 1325 g, theoretically 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 (reference 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 turbid mixture of potassium tert-butoxide (18.31 g, 163 mmol, 2.12 equivalents) in THF (100 mL) was cooled in an ice bath, and then a solution of 4,4-dimethoxybutanenitrile (compound 16a, 10.00 g, 77 mmol) and ethyl acetate (7.46 g, 85 mmol, 1.1 equivalents) in THF (20 mL) was added over 15 minutes. The mixture was warmed to room temperature and stirred at ambient temperature for 3 hours. Subsequently, the in situ-formed 2-acetyl-4,4-dimethoxybutanenitrile was treated at ambient temperature with formamidine acetate (65.0 g, 624 mmol, 8.1 equivalents), 1-butanol (80 mL), and triethyl orthoformate (56.2 mL, 337 mmol, 4.38 equivalents). The resulting mixture was heated to 110-120°C and stirred for 1 hour. Additional triethyl orthoformate (26.5 mL, 159 mmol, 2.06 equivalents) was added. The mixture was stirred for a further 16 hours at 110°C. Additional formamidine acetate (31.38 g, 302 mmol, 3.92 equivalents) and triethyl orthoformate (56.5 mL, 115 mmol, 1.5 equivalents) were added in three portions over 24 hours. The mixture was heated for a further 24 hours and concentrated under reduced pressure to obtain a residue. The residue was treated with water (150 mL) and MeTHF (210 mL). The resulting mixture was passed through a Celite bed (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 HCl solution in IPA (5.5 M, 50.8 g), water (31 mL), and concentrated HCl (12 M, 15.6 g). This mixture was stirred at room temperature for 3 days. Concentrated NH4OH aqueous solution (38.6 g, 28-30%) was added, and the mixture was concentrated to obtain the residue, which was then ground with THF (170 mL, 2 × 150 mL).The filtrates were combined and concentrated to obtain a residue, which was dissolved in DCM (30 mL). This residue was purified by column chromatography using silica gel (SiO2, 120 g) that elutes with 0% to 100% siRNA in DCM to obtain the desired product, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 5.1 g, theoretically 10.25 g, 49.8% in 3 steps), as an off-white crystalline solid. This compound is identical in all comparable aspects to the compound obtained in 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 equivalent) at ambient temperature. The resulting mixture was stirred at ambient temperature. Next, 2-bromo-1,1-dimethoxyethane (8.36 g, 49.5 mmol, 1.0 equivalent) was added to the mixture, and the resulting reaction mixture was heated to 80°C over 5-8 hours. The reaction mixture was cooled to ambient temperature and then quenched with water (20 mL). Subsequently, the quenched reaction mixture was extracted with ethyl acetate (3 × 20 mL), the combined organic extract was 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 obtain 2-acetyl-4,4-dimethoxybutanamide (compound 20a, 5.8 g, theoretically 9.37 g, 61.9%) as a concentrated 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 equivalents). The resulting reaction mixture was stirred at ambient temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (10 mL), and the quenched reaction mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extract was 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 obtain 2-acetyl-4,4-dimethoxybutanenitrile (compound 17a, 280 mg, theoretically 724 mg, 38.7%) as a concentrated oil. For 2-acetyl-4,4-dimethoxybutanenitrile: 1 ¹H NMR (DMSO-d6, 400MHz, a mixture of ketone and enol forms was obtained): δ 10.7 (br.s, 1 / 2H for the enol form's -OH), 4.38 (m, 1H), 3.25 (m, 6H for two OMe groups, and 1 / 2H for the ketone form's -CH-), 2.25-2.50 (m, 2H), 2.15 and 2.25 (s, 3H); C8H 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 and subsequently treated with HCl to obtain 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]pyrimidine-4-yl) hydrochloride (hydrochloride of compound 1a) 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (compound 22a, 200 g, 1.064 mol) and THF (1.2 L) were added to a reaction vessel under nitrogen. [ka] After cooling the contents of the reaction vessel to below -5°C, 60% NaH (51 g, 1.28 mol, 1.2 equivalents) in mineral oil was added little by little. The internal temperature was maintained at -5 to 5°C during the addition of NaH. After the addition, stirring was continued for 30 minutes, and then a solution of TBDMS-Cl (193 g, 1.28 mol, 1.2 equivalents) in THF (200 mL) was slowly added while maintaining the internal temperature at -5 to 5°C. The reaction mixture was stirred for 30 minutes, and then Fe(acac)3 (18.8 g, 53.2 mmol, 0.05 equivalents) was added, followed by the addition of a 3.0 M MeMgCl solution in THF (532 mL, 1.596 mol, 1.5 equivalents) at -5 to 5°C. The reaction mixture was kept for another hour, during which time the completion of the coupling reaction was indicated by HPLC IPC. The reaction mixture was then poured into a solution of EDTA disodium dihydrate (200 g) in water (2.0 L) while controlling the internal temperature to below 15°C. The two-phase 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 separated into phases. The aqueous phase was separated and extracted with MTBE (1.0 L). The organic phases were combined and washed sequentially with 3% citric acid aqueous solution (2 × 400 mL) and brine (600 mL). After drying with Na₂SO₄, the organic phase was filtered and concentrated to dryness. The residue was dissolved in petroleum ether (2.0 L), and all insoluble substances were removed by filtration through a thin layer of silica gel. The filtrate was concentrated to obtain the crude desired product, 7-(tert-butyldimethylsilyl)-2-chloro-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 22a, 300g), as an oily residue, which was used directly in subsequent reactions 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-carbon (Pd / C, 30 g) in methanol (1.8 L) was vigorously stirred at 50-55°C for 3 hours under 1 atm of hydrogen. After confirmation of the completion of the reaction by HPLC, the reaction mixture was cooled to 20-25°C and filtered. The filtrate was washed with methanol, and the filtrate was concentrated to dryness. The residue was suspended in ethyl acetate ( Depositphotos, 225 mL) and stirred at 10-15°C for 1 hour. The solid was collected by filtration, washed with ethyl acetate, and vacuum-dried at 40-45°C to obtain 4-methyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (hydrochloride of compound 1a, 151.5 g, theoretically 180.5 g, 84% yield in 2 steps) as a pale 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 ¹³C NMR (DMSO-d6, 125MHz) δppm 154.0, 151.0, 144.0, 131.6, 117.2, 103.1, 17.6; C7H8ClN3 (MW, 169.61; for free bases, C7H7N3, MW 133.15) LC-MS (EI) m / e 134.1 (M + +H (reference peak).

[0222] Example 17.2 Preparation of sodium (7H-pyrrolo[2,3-d]pyrimidine-4-yl)acetate (5b) and 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acetic acid (compound 5a) [ka] Step 1. 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (compound 24a): A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 18.0 g, 117 mmol) in acetone (180 mL) was mixed with 50% aqueous sodium hydroxide solution (NaOH, 14.07 g, 176 mmol, 1.5 equivalents) at ambient temperature. The resulting mixture was then stirred at ambient temperature until a clear solution was obtained. p-toluenesulfonyl chloride (pTsCl, 25.7 g, 135 mmol, 1.15 equivalents) was added to the solution at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the solid was washed with acetone and discarded. The filtrate was then concentrated under reduced pressure, and the residue was treated with methyl tert-butyl ether (MTBE, 180 mL) and n-heptane (180 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The solid was recovered by filtration, washed with n-heptane (180 mL), and dried to a constant weight in a vacuum oven to obtain the desired product, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (compound 24a, 32.1 g, theoretically 36.0 g, yield 89.2%), as an off-white powder, which was used in the subsequent reaction 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 2.2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl) diethyl 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 equivalents) in anhydrous DMF (30 mL) was treated with solid cesium carbonate (Cs2CO3, 18.53 g, 56.9 mmol, 2.5 equivalents) at ambient temperature. Subsequently, the resulting reaction mixture was heated to 50-60°C and stirred for 2-3 hours. After the reaction was complete, the reaction mixture was cooled to ambient temperature and then treated with water (H2O, 80 mL). Next, the quenched reaction mixture was stirred at ambient temperature for 1 hour, followed by 1 hour at 0-5°C. The solid was recovered 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 obtain the desired product, 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)malonate diethyl (compound 25a, 6.2 g, theoretically 9.81 g, yield 63.2%), as an off-white powder, which was used in subsequent reactions without further purification. In the case of 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)malonate diethyl: 1 C 20 H 21 N3O6S(MW,431.46),LCMS(EI)m / e 432.3(M + +H).

[0224] Step 3.2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate (compound 26a): A solution of 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)diethyl malonate (compound 25a, 4.0 g, 9.27 mmol) in ethanol (EtOH, 20 mL) was treated at ambient temperature with a solution of 21% sodium ethoxide (NaOEt, 21% by weight, 0.30 g, 0.927 mmol, 0.10 equivalents) in ethanol. 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. Next, the residue was purified by silica gel (SiO2) column chromatography to obtain the desired product, ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate (compound 26a, 2.08 g, theoretically 3.33 g, yield 62.6%), as an off-white powder, which was used in subsequent reactions without further purification. In the case of ethyl 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate: 1 C 17 H 17 N3O4S(MW,359.40),LCMS(EI)m / e 360.2(M + +H).

[0225] Step 4. 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate (compound 27a): A solution of 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)diethyl malonate (compound 25a, 4.0 g, 9.27 mmol) in ethanol (EtOH, 20 mL) was treated at ambient temperature with a solution of 21% sodium ethoxide (NaOEt, 21% by weight, 3.0 g, 9.27 mmol, 1.0 equivalent) in ethanol. The resulting reaction mixture was heated to 65-75°C and stirred at 65-75°C for 12 hours. The reaction mixture was quenched with 1.0 N aqueous hydrochloric acid solution, and the resulting mixture was concentrated under reduced pressure. Next, the residue was purified by silica gel (SiO2) column chromatography to obtain the desired product, ethyl 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate (compound 27a, 1.3 g, theoretically 1.9 g, yield 68.3%), as an off-white powder, which was used in subsequent reactions without further purification. In the case of ethyl 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate: 1 C 10 H 11 N3O2(MW,205.22),LCMS(EI)m / e 206.2(M + +H).

[0226] Step 5.2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)sodium acetate (compound 5b): A solution of 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate (compound 27a, 1.2 g, 5.85 mmol) in acetone (10 mL) and THF (10 mL) was treated at ambient temperature with an aqueous solution of 6N sodium hydroxide (6N NaOH, 1.462 mL, 8.77 mmol, 1.5 equivalents). The resulting reaction mixture was stirred at ambient temperature for 5 hours. The solid was recovered by filtration, and the isolated solid was suspended in methanol (MeOH, 4.0 mL). Next, acetone (15 mL) was added to the resulting suspension, and the mixture was stirred at ambient temperature for 1 hour. The solid was recovered by filtration, washed with acetone (2 × 5 mL), and vacuum-dried to obtain the desired product, 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)sodium acetate (compound 5b, 1.1 g, theoretically 1.164 g, yield 94.5%), as an off-white powder, which was used in subsequent reactions without further purification. For 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)sodium acetate: 1 ¹H NMR (DMSO-d6, 400MHz) δ 8.36 (s, 1H), 7.37 (d, 1H), 6.40 (d, 1H), 3.61 (s, 2H) ppm; C8H6N3NaO2 (MW, 199.15; for the corresponding acid, C8H7N3O2, MW 177.16), LC-MS (EI) m / e 178.1 (M + +H).

[0227] Step 6.2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acetic acid (compound 5a): A solution of 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)ethyl acetate (compound 27a, 1.2 g, 5.85 mmol) in acetone (10 mL) and THF (10 mL) was treated at ambient temperature with an aqueous solution of 6 N sodium hydroxide (6 N NaOH, 1.462 mL, 8.77 mmol, 1.5 equivalents). The resulting reaction mixture was stirred at ambient temperature for 5 hours. Subsequently, the reaction mixture was treated with an aqueous solution of 1 N hydrochloric acid (1 N HCl, 9.0 mL) and then concentrated under reduced pressure. Next, the residue was purified by silica gel (SiO2) column chromatography to obtain the desired product, 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acetic acid (compound 5a, 0.83 g, theoretically 1.04 g, yield 79.8%), as an off-white solid, which was used in subsequent reactions without further purification. In the case of 2-(7H-pyrrolo[2,3-d]pyrimidine-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 be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included in the appended claims. All references, including all patents, patent applications, and publications cited herein, are incorporated herein by reference in their entirety. Further embodiments of the present invention include the following: [Aspect 1] A process for preparing baricitinib or a salt thereof, Compound of formula 3, [ka] Alternatively, the salt thereof may be (i) the salt of formula 2a and (ii) the compound of formula 2b. [ka] This includes reacting with a reagent selected from, In the formula, X - The process wherein the pair anion is the anode. [Aspect 2] The process according to claim 1, wherein the reagent is the compound of formula 2b. [Aspect 3] A salt of formula 2a, or a salt thereof, or a compound of formula 2b, Compound of formula 1a,

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Claims

1. A process for preparing baricitinib or a salt thereof, Compound of formula 3: 【Chemistry 1】 or a salt thereof, (i) a salt of formula 2a, and (ii) a compound of formula 2b: 【Chemistry 2】 [In the formula, X- represents the pair anion.] This includes reacting with a reagent selected from the following: The aforementioned process.

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

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

4. The process according to claim 3, wherein the Vilsmeyer 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 product of the reaction with the Vilsmeyer reagent is the salt of formula 2d: 【Chemistry 4】 The process according to claim 3.

7. The salt of formula 2d above is reacted with a base to form the salt of formula 2c: 【Transformation 5】 The process according to claim 6, further comprising forming a

8. The product of the reaction with the Vilsmeyer reagent is the salt of formula 2c: 【Transformation 6】 The process according to claim 3.

9. The salt of formula 2c is given by formula M ＋ X － The process according to claim 8, further comprising reacting with a salt of [wherein M+ is a countercation and X- is a counteranion other than Cl-] to form a salt of formula 2a.

10. The compound of formula 1a or a salt thereof is a compound of formula 1aP: 【Transformation 7】 [In the formula, P1 is an amino protecting group.] The process according to any one of claims 3 to 9, which is prepared by a process that includes deprotecting the

11. The compound of formula 1aP is the compound of formula 2P: 【Transformation 8】 [In the formula, P1 is an amino protecting group.] The process according to claim 10, wherein the product is prepared by a process comprising reacting it with MeMgBr in the presence of a Grignard catalyst.

12. The compound of formula 2P is the compound of formula 12a: 【Chemistry 9】 The process according to claim 11, which is prepared by a process comprising protecting and forming the compound of formula 2P.

13. The compound of formula 12a is the compound of formula 11a: 【Chemistry 10】 The process according to claim 12, wherein the salt thereof is prepared by a process comprising reacting it with a strong acid.

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

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

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

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

18. The compound of formula 15a is, (i) Compound of formula 14a: 【Chemistry 15】 This is reacted with formamidine acetate and alkali metal alkoxide to form compound 14aa: 【Chemistry 16】 To generate, (ii) Reacting the compound of formula 14aa with a strong acid, The process according to claim 17, which is prepared by a process including the following:

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

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

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

22. The compound of formula 22P is the compound of formula 22a: 【Chemistry 20】 The process according to claim 21, which is prepared by a process comprising protecting and forming the compound of formula 22P.

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

24. The compound of formula 18a is the compound of formula 17a: 【Chemistry 22】 The process according to claim 23, wherein the compound 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 the compound of formula 20a: 【Chemistry 23】 Compound of formula 21a: 【Chemistry 24】 The process according to claim 24, which is prepared by a process comprising reacting with to form a compound of formula 17a.

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

27. The compound of formula 3 or its salt is the compound of formula 6: 【Chemistry 26】 The process according to any one of claims 1 to 9, comprising a process of reacting with hydrazine.

28. A process for preparing baricitinib or a salt thereof, Salt of formula 2c: 【Chemistry 27】 The compound of formula 3: 【Chemistry 28】 This includes reacting with to form the baricitinib or a salt thereof, The aforementioned process.

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

30. The salt of the above formula 2d is (a) Compound of formula 2P: 【Transformation 30】 The compound of formula 1aP is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: 【Chemistry 31】 To form, (b) Deprotect the compound of formula 1aP to obtain the compound of formula 1a: 【Chemistry 32】 or to form a salt thereof, (c) Reacting the compound of formula 1a or a salt thereof with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, Prepared by a process including, In the formula, P １ is an amino protecting group. The process according to claim 29.

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

32. Compound of formula 3: 【Transformation 34】 or its salt.

33. A process for producing the compound or a salt thereof according to claim 32, Compound of formula 6: 【Chemistry 35】 This includes reacting it with hydrazine. The aforementioned process.

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