Method and intermediate for preparing a JAK inhibitor

Abstract

This invention provides novel methods for preparing ruxolitinib, its salts, and related synthetic intermediate compounds and salts of the intermediates. [Solution] The present invention provides a method for preparing ruxolitinib (compound 1) or a salt thereof, characterized by using the reaction represented by the following reaction formula. JPEG2026090250000268.jpg63165

Description

[Technical Field]

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

[0002] Protein kinases (PKs) are a group of enzymes that regulate a diverse range of important biological processes, including, among others, cell proliferation, survival, and differentiation, organogenesis and morphogenesis, neoangiogenesis, and 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 many human diseases, including cancer. When dysregulated, a subset of protein kinases (also known as oncogenic protein kinases) can induce tumor formation and growth, and further contribute to tumor maintenance and progression (Blume-Jensen P. et al., Nature 2001, 411(6835):355-365). To date, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug discovery.

[0003] Protein kinases can be classified 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).

[0004] The pathway involving JAK and signaling / activator-transcription factor (STAT) is 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 lack endogenous tyrosine kinase activity and therefore require receptor-associated kinases to propagate the phosphorylation cascade. JAK performs this function. Cytokines bind to their receptors, causing receptor dimerization, which allows phosphorylation of specific tyrosine motifs within the cytokine receptor, as does JAK phosphorylating each other. STATs that recognize these phosphotyrosine motifs are recruited to the receptor and are then activated by JAK-dependent tyrosine phosphorylation events. When activated, STAT dissociates from its receptor, dimerizes, translocates to the nucleus, binds to specific DNA sites, and alters transcription (Scott, MJ, CJ Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6):1153-9).

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

[0006] Blocking signaling at the JAK kinase level holds promise for the development of treatments for human cancers. Inhibition of JAK kinases is also expected to have therapeutic benefits in patients with cutaneous immunodisorders and sensitization, such as psoriasis. Therefore, inhibitors of Janus kinase or related kinases are in high demand, and several publications have reported on a class of effective compounds. For example, the JAK inhibitor ruxolitinib, ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile), has been reported in U.S. Patent Applications Publications 2007 / 0135461, 2010 / 190981, and 2008 / 0312259, the disclosures of which are incorporated herein by reference.

[0007] In light of the increasing demand for compounds to treat disorders associated with the inhibition of kinases such as Janus kinase, there is a need for novel and more efficient pathways to ruxolitinib, its salts, and related intermediates. The methods and compounds described herein are helpful in meeting these and other needs. [Overview of the Initiative]

[0008] This disclosure provides, in particular, ruxolitinib, salts thereof, and related synthetic intermediate compounds and methods for preparing salts of intermediates.

[0009] Therefore, this disclosure relates to the compound of formula 3: [ka] or a salt thereof, (i) a salt of formula 2a and (ii) a compound of formula 2b: [ka] This includes reacting with a reagent selected from, In the formula, X - However, the present invention provides a method for preparing ruxolitinib or a salt thereof, which is the counter anion.

[0010] This disclosure further discloses the salt of formula 2c: [ka] Compound of formula 3: [ka] The present invention provides a method for preparing ruxolitinib or a salt thereof, comprising reacting it with L-(+)-tartrate to form ruxolitinib or a salt thereof.

[0011] This disclosure also relates to the salt of formula 2c: [ka] The salt of formula 3a: [ka] The present invention also provides a method for preparing ruxolitinib or a salt thereof, which includes reacting it with to form ruxolitinib or a salt thereof.

[0012] This disclosure will be furthered, (a) Salt of equation 2d: [ka] Reacting with a base, we obtain the salt of formula 2c: [ka] To form, (b) Salt of formula 2c to salt of formula 3a: [ka] Reacting with it to form ruxolitinib or a salt thereof, The present invention provides a method for preparing ruxolitinib or a salt thereof, including the following:

[0013] In some embodiments of the above method, the salt of formula 2d is, (a) Compound of formula 2P: [ka] The compound of formula 1aP is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: [ka] To form, (b) Deprotect the compound of formula 1aP to obtain the compound of formula 1a: [ka] 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 method including, In the formula, P 1 This is an amino protecting group.

[0014] In some embodiments of the above method, the salt of formula 2d is, (a) Compound of formula 22P: [ka] The compound of formula 23P is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: [ka] To form, (b) Reduce the compound of formula 23P to obtain the compound of formula 1a: [ka] 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 method including, In the formula, P 2 This is an amino protecting group.

[0015] In some embodiments of the above method, the salt of formula 3a is, (a) Compound of formula 6a: [ka] When reacted with hydrazine, the compound of formula 7a is obtained: [ka] To form, (b) Reacting the compound of formula 6a with L-tartaric acid to form the salt of formula 3a, It is prepared by a method that includes [a specific method].

[0016] This disclosure will be furthered, (a) [ka] Or the salt, or (b) [ka] or (c) [ka] or (d) [ka] Or the salt, or (e) [ka] Or the salt, or (f) [ka] Or the salt, or (g) [ka] Or the salt, or (h) [ka] Or the salt, or (i) [ka] (In the formula, X - Cl - (Other than the opposing anion), or (j) [ka] or (k) [ka] or (l) [ka] or (m) [ka] or (n) [ka] or (o) [ka] Provides a compound or salt selected from the following.

[0017] This disclosure further relates to salts of formula 2d, selected from form I and form II: [ka] It provides a crystalline form.

[0018] This disclosure also relates to the salt of formula 3a: [ka] It also provides the crystal form. [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 the hexafluorophosphate of compound 2. [Figure 8] This is a DSC thermogram of compound 2, hexafluorophosphate. [Figure 9]This is a TGA thermogram of compound 2, hexafluorophosphate. [Figure 10A] This is the X-ray single crystal structure of compound 3a, showing a single molecule. [Figure 10B] This is the X-ray single crystal structure of compound 3a, showing the repeating units of compound 3a. [Figure 11] This is the XRPD pattern of compound 3a. [Figure 12] This is a DSC thermogram of compound 3a. [Figure 13] This is the TGA thermogram of compound 3a.

[0020] Details of one or more embodiments of the present invention are described in the accompanying drawings and the following description. Other features, purposes, and advantages of the present invention will become apparent from the description and drawings, as well as from the claims. [Modes for carrying out the invention]

[0021] This disclosure provides ruxolitinib, also known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile, and its intermediates, as well as methods for preparing salts and crystalline forms of ruxolitinib and its intermediates. Ruxolitinib (also known as INCB018424) is marketed as a phosphate under the trademark names JAKAFI and JAKAVI, and has the following structure: [ka] It holds.

[0022] (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile is also referred to herein as Compound 1. The compound and various methods for preparing the compound are disclosed herein by reference in U.S. Patent Applications Publications 2007 / 0135461, 2010 / 190981, and 2008 / 0312259.

[0023] The present disclosure Compound of formula 3: [Chemical formula] or a salt thereof, with (i) a salt of formula 2a or a salt thereof, and (ii) a compound of formula 2b: [Chemical formula] reacting with a reagent selected from wherein X - is a counter anion, to provide a method for preparing ruxolitinib or a salt thereof.

[0024] The present disclosure Compound of formula 3: [Chemical formula] or a salt thereof, with (i) a salt of formula 2a, and (ii) a compound of formula 2b: [Chemical formula] reacting with a reagent selected from wherein X - is a counter anion, to provide a method for preparing ruxolitinib or a salt thereof.

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

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

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

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

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

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

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

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

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

[0034] In some embodiments, the reagent is a salt of formula 2a. - Cl - , Br - , I - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - It can be selected from. In some embodiments, X - Cl - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - Selected from. In some embodiments, X - BF4 - In some embodiments, X - PF6 - In some embodiments, X - AsF6 - In some embodiments, X - SbF6 - In some embodiments, X - is ClO4 - In some embodiments, X - Cl - That is the case.

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

[0036] In some embodiments, the salt of formula 2a or the compound of formula 2b is Compound of formula 1a: [ka] Alternatively, it may be prepared by a method comprising reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

[0037] In some embodiments, the salt of formula 2a or the compound of formula 2b is Compound of formula 5a: [ka] Alternatively, it may be prepared by a method comprising reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

[0038] In some embodiments, the compound of formula 5a is a salt. For example, the compound of formula 5a is a sodium salt.

[0039] In some embodiments, the reaction with the Vilsmeyer reagent involves the compound of formula 2c: [ka] Generates.

[0040] In some embodiments, after reaction with the Vilsmeyer reagent, the compound of formula 2c is obtained from formula M + X - It is reacted with the salt of, in the formula, M + This is a counter-cation.

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

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

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

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

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

[0046] 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.

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

[0048] In some embodiments, the salt of formula 2a is Salt of formula 2c: [ka] Formula M + X - It may be formed by a method including reacting with a salt of, in the formula, M + It is a countercation, X - Cl - It is an anti-anion other than those mentioned above.

[0049] In some embodiments, M + This is an alkali metal-cation pair. For example, M + Li + kaNa + , or K + In some embodiments, M + Na + In some embodiments, X - , Br - , I - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - Selected from X. - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - Selected from. In some embodiments, X - BF4 - In some embodiments, X - PF6 - In some embodiments, X - AsF6 - In some embodiments, X - SbF6 - In some embodiments, X - is ClO4 - That is the case.

[0050] In some embodiments, the salt of formula 2c is Salt of equation 2d: [ka] It can be produced by a method that includes reacting it with a base.

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

[0052] In some embodiments, the compound of formula 1a or a salt thereof is Compounds of formula 1aP: [ka] It may be prepared by a method that includes deprotecting it. 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 C 1-6 It 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, deprotection is carried out by reacting the compound of formula 1aP with base B3. In some embodiments, base B3 is a hydroxide base. For example, base B3 is ammonium hydroxide. In some embodiments, deprotection is carried out in solvent component S4. In some embodiments, solvent component S4 includes a polar protic solvent. In some embodiments, solvent component S4 includes an alcohol. In some embodiments, solvent component S4 is formula C1-6 It contains alkyl-OH. For example, the solvent component S4 contains methanol.

[0054] In some embodiments, the compound of formula 1aP Compound of formula 2P:

Chemical formula

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

[0056] In some embodiments, the compound of formula 2P Compound of formula 12a:

Chemical formula

[0057] In some embodiments, the protection includes reacting the compound of formula 12a with an alkali metal hydride and P 1 -Y, wherein 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 1 is t-butyldimethylsilyl. In some embodiments, the alkali metal hydride is sodium hydride. In some embodiments, about 1 to about 2 molar equivalents of 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 relative to the compound of formula 12a. 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 S6, where the solvent component S6 comprises an organic solvent. In some embodiments, the solvent component S6 comprises a di-C 1-6 alkyl ether or a 4- to 10-membered heterocycloalkyl ether. In some embodiments, the solvent component S6 comprises tetrahydrofuran.

[0058] In some embodiments, the compound of formula 1a or a salt thereof is prepared by a method comprising reducing a compound of formula 23P:

Chemical formula

[0059] In some embodiments, the reduction of the compound of formula 23P is carried out by a method comprising reacting the compound of formula 23P with hydrogen gas in the presence of a catalyst. For example, the catalyst is Pd 0 ​It 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 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 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 catalyst is carried out at a temperature of about 50°C to about 55°C. In some embodiments, the reaction of the compound of formula 23aP with hydrogen and catalyst is carried out in solvent component S7. In some embodiments, solvent component S7 includes a polar protic solvent. In some embodiments, solvent component S7 includes an alcohol. In some embodiments, solvent component S7 is C 1-6 It contains alkyl-OH groups. For example, solvent component S7 contains methanol.

[0060] In some embodiments, the compound of formula 23P is Compound of formula 22P: [ka] It can be prepared by a method comprising reacting it with MeMgBr in the presence of a Grignard catalyst. In the formula, P 2 This is an amino protecting group.

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

[0062] In some embodiments, the compound of formula 22P is Compound of formula 22a: [ka] It can be prepared by a method that includes protecting and forming the compound of formula 22P.

[0063] In some embodiments, protection is provided by the compound of formula 22a with alkali metal hydride and P 2 -Includes reaction with Y, where Y is a halo. In some embodiments, P 2 is, (R 1 )3Si, and in the formula, R 1 C 1-6 It is alkyl. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. In some embodiments, P 2 P is t-butyldimethylsilyl. In some embodiments, the alkali metal hydride is sodium hydride. In some embodiments, about 1 to about 2 molar equivalents of alkali metal hydride 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 solvent component S9, where solvent component S9 includes an organic solvent. In some embodiments, solvent component S9 is di-C 1-6 It contains alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. For example, solvent component S9 contains tetrahydrofuran.

[0064] In some embodiments, the compound of formula 1a or a salt thereof is Compound of formula 18a: [ka] It can be prepared by a method comprising reacting with acid A1 to form a compound of formula 1a.

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

[0066] In some embodiments, the compound of formula 18a or a salt thereof Compound of formula 17a:

Chemical formula

[0067] 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. For example, 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. For example, the temperature can be about 110°C to about 120°C. In some embodiments, the reaction of the compound of formula 17a with formamidine acetate and triethyl orthoformate is carried out in solvent component S11, where solvent component S11 comprises a polar protic solvent. In some embodiments, solvent component S11 comprises an alcohol. In some embodiments, solvent component S11 comprises a compound of formula C 1-6 It contains alkyl-OH groups. For example, solvent component S11 contains 1-butanol.

[0068] In some embodiments, the compound of formula 17a or a salt thereof is Compound of formula 20a: [ka] Compound of formula 21a: [ka] It can be prepared by a method that includes reacting with to form the compound of formula 17a.

[0069] 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 solvent component S12, where solvent component S12 includes a polar aprotic solvent. For example, solvent component S12 includes dimethylformamide.

[0070] In some embodiments, the compound of formula 20a or a salt thereof is Compound of formula 19a: [ka] It can be prepared by a method comprising reacting with bromo-1,1-dimethoxyethane and base B4 to form the compound of formula 20a.

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

[0072] In some embodiments, the compound of formula 17a or a salt thereof is Compound of formula 16a: [ka] It can be prepared by a method that includes reacting with ethyl acetate and base B5 to form the compound of formula 17a.

[0073] In some embodiments, base B5 is an alkali metal alkoxide. For example, base B5 is potassium tert-butoxide. In some embodiments, about 1 to about 3 molar equivalents of base B5 are 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 B5 are used relative to the compound of formula 16a. In some embodiments, the reaction of the compound of formula 17a with ethyl acetate and base B5 is carried out at room temperature. In some embodiments, the reaction of the compound of formula 17a with ethyl acetate and base B5 is carried out in solvent component S14, where solvent component S14 includes an organic solvent. In some embodiments, solvent component S14 is di-C 1-6 It contains alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. For example, solvent component S14 contains tetrahydrofuran.

[0074] In some embodiments, the compound of formula 5a or a salt thereof is Compound of formula 27a: [ka] It can be prepared by a method that includes hydrolysis in water in the presence of base B6.

[0075] In some embodiments, base B6 is an alkali metal hydroxide. For example, base B6 is sodium hydroxide. In some embodiments, about 1 to about 2 molar equivalents of base B6 are used for the compound of formula 27a. In some embodiments, about 1.5 molar equivalents of base B6 are used for 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 solvent component S15, where solvent component S15 includes an organic solvent. For example, solvent component S15 includes tetrahydrofuran, acetone, or a combination thereof.

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

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

[0078] In some embodiments, the compound of formula 27a is Compound of formula 26P: [ka] It can be prepared by a method including reacting with strong acid A3, where P 1 This is an amino protecting group.

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

[0080] In some embodiments, the compound of formula 26P is Compound of formula 25P: [ka] It can be prepared by a method comprising reacting with alkali metal alkoxide B8 to form a compound of formula 26P, where P 1 This is an amino protecting group.

[0081] In some embodiments, about 0.1 molar equivalents of alkali metal alkoxide B8 are used relative to the compound of formula 25P. In some embodiments, the reaction between the compound of formula 25P and alkali metal alkoxide B8 is carried out at room temperature. In some embodiments, the reaction between the compound of formula 25P and alkali metal alkoxide B8 is carried out in solvent component S17, where solvent component S17 includes a polar protic solvent. For example, alkali metal alkoxide B8 is sodium ethoxide. In some embodiments, solvent component S17 includes an alcohol. In some embodiments, solvent component S17 is C 1-6 It contains alkyl-OH groups. For example, solvent component S17 contains ethanol.

[0082] In some embodiments, the compound of formula 27a is Compound of formula 25P: [ka] It can be prepared by a method that includes reacting with alkali metal alkoxide B9 to form the compound of formula 27a.

[0083] In some embodiments, about 1 to about 2 molar equivalents of alkali metal alkoxide B9 are used relative to the compound of formula 25P. In some embodiments, about 1 molar equivalent of alkali metal alkoxide B9 is used relative to the compound of formula 25P. In some embodiments, the reaction between the compound of formula 25P and alkali metal alkoxide B9 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 alkali metal alkoxide B9 is carried out in solvent component S18, where solvent component S18 is a compound of formula C 1-6 It contains alkyl-OH groups. For example, solvent component S18 contains ethanol.

[0084] In some embodiments, the compound of formula 25P is Compounds of formula 2P: [ka] It can be prepared by a method comprising reacting with diethyl malonate and base B10, where P 1 This is an amino protecting group.

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

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

[0087] In some embodiments, the compound of formula 12a is the compound of formula 11a: [ka] Alternatively, it can be prepared by a method that includes reacting its salt with strong acid A4.

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

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

[0090] In some embodiments, base B12 is an alkali metal alkoxide. For example, base B12 is potassium t-butoxide. In some embodiments, the reaction of the compound of formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and base B12 is carried out at a temperature of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula 11a or a salt thereof with (methoxymethyl)triphenylphosphonium chloride and base B12 is carried out in solvent component S22, where solvent component S22 comprises a polar aprotic solvent. In some embodiments, solvent component S22 is di-C 1-6 It contains alkyl ethers or 4- to 10-membered heterocycloalkyl ethers. For example, solvent component S22 contains tetrahydrofuran.

[0091] In some embodiments, the compound of formula 10a or a salt thereof is the compound of formula 9a: [ka] It can be prepared by a method that includes reacting it with ammonia.

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

[0093] In some embodiments, the compound of formula 9a is the compound of formula 8a: [ka] It can be prepared by a method that includes reacting it with a Vilsmeyer reagent formed from dimethylformamide.

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

[0095] In some embodiments, the compound of formula 12a is the compound of formula 15a: [ka] It can be prepared by a method that includes reacting it with a chlorinating agent.

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

[0097] In some embodiments, the compound of formula 15a is (i) Compound of formula 14a: [ka] Reacting with formamidine acetate and alkali metal hydroxide yields the compound of formula 14aa: [ka] To cause, (ii) Reacting the compound of formula 14aa with strong acid A4, It can be prepared by a method including

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

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

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

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

[0102] In some embodiments, the L-tartrate of formula 3 is Compound 7a: [ka] It can be prepared by a method that includes reacting it with L-tartaric acid.

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

[0104] In some embodiments, the compound of formula 7a is the compound of formula 6a: [ka] It can be prepared by a method that includes reacting it with hydrazine.

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

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

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

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

[0109] In some embodiments, ruxolitinibrinate is (i) Adding the first solvent component to ruxolitinibrinate to produce the first solution, (ii) Concentrating the first solution to produce the second solution, (iii) Adding a second solvent component to the second solution to produce a third solution, (iv) Adding a third solvent component to the third solution to produce a fourth solution, (v) Concentrating the fourth solution to produce a fifth solution, (vi) Isolate ruxolitinibrinate from the fifth solution, It is purified by a method that includes [a specific process].

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

[0111] This disclosure also, (a) Compound of formula 1a or a salt thereof: [ka] This is reacted with the Vilsmeyer reagent formed from dimethylformamide to form the compound of formula 2c: [ka] To cause, (b) Compound of formula 2c is compound of formula 3: [ka] Reacting it with L-tartrate yields ruxolitinib, (c) Reacting ruxolitinib with phosphate to produce ruxolitinibrate, The present invention also provides a method for preparing ruxolitinibulinate, which includes [the specified ingredient].

[0112] In some embodiments, the compound of formula 1a or a salt thereof is (a) Compound of formula 12a: [ka] Reacting with t-butyldimethylsilyl chloride yields the compound of formula 12b: [ka] To cause, (b) The compound of formula 12b is reacted with MeMgBr in the presence of a Grignard catalyst to obtain the compound of formula 12c: [ka] To cause, (c) Deprotecting the compound of formula 12c to produce the compound of formula 1a or a salt thereof, It can be prepared by a method including

[0113] In some embodiments, the compound of formula 1a or a salt thereof is (a) Compound of formula 22a: [ka] The compound of formula 23a is obtained by reacting t-butyldimethylsilyl chloride and MeMgBr in the presence of a Grignard catalyst: [ka] To cause, (b) Reacting the compound of formula 23a with hydrogen and palladium carbon to produce the compound of formula 1a or a salt thereof, It can be prepared by a method including

[0114] In some embodiments, a method for preparing ruxolitinib or a salt thereof is a salt of formula 2a: [ka] Compound of formula 3: [ka] The process involves reacting with L-(+)-tartrate of to form ruxolitinib or a salt thereof, wherein X - It is a counterion.

[0115] In some embodiments, a method for preparing ruxolitinib or a salt thereof is a salt of formula 2c: [ka] Compound of formula 3: [ka] This involves reacting it with L-(+)-tartrate to form ruxolitinib or a salt thereof.

[0116] In some embodiments, a method for preparing ruxolitinib or a salt thereof is a salt of formula 2a: [ka] The salt of formula 3a: [ka] The process involves reacting with to form ruxolitinib or a salt thereof, where X - It is a counterion.

[0117] In some embodiments, a method for preparing ruxolitinib or a salt thereof is a salt of formula 2c: [ka] The salt of formula 3a: [ka] This includes reacting with to form ruxolitinib or a salt thereof.

[0118] In some embodiments, a method for preparing ruxolitinib or a salt thereof is: (a) Salt of equation 2d: [ka] Reacting with a base, we obtain the salt of formula 2c: [ka] To form, (b) Salt of formula 2c to salt of formula 3a: [ka] Reacting with it to form ruxolitinib or a salt thereof, Includes.

[0119] In some embodiments of the above method, the salt of formula 2d is, (a) Compound of formula 2P: [ka] The compound of formula 1aP is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: [ka] To form, (b) Deprotect the compound of formula 1aP to obtain the compound of formula 1a: [ka] 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 method including, In the formula, P 1 is an amino protecting group. In some embodiments, P 1 It is trimethylsilyl.

[0120] In other embodiments, the salt of formula 2d is, (a) Compound of formula 22P: [ka] The compound of formula 23P is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: [ka] To form, (b) Reduce the compound of formula 23P to obtain the compound of formula 1a: [ka] 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 method including, In the formula, P 2 is an amino protecting group. In some embodiments, P 1 It is t-butyldimethylsilyl.

[0121] In some embodiments of the above method, the salt of formula 3a is, (a) Compound of formula 6a: [ka] When reacted with hydrazine, the compound of formula 7a is obtained: [ka] To form, (b) Reacting the compound of formula 6a with L-tartaric acid to form the salt of formula 3a, It is prepared by a method that includes [a specific method].

[0122] This disclosure also, [ka] The compound or a salt thereof is also provided.

[0123] In some embodiments, the compound or a salt thereof [ka] Selected from.

[0124] In this specification, [ka] A compound or a salt thereof is provided.

[0125] In this specification, [ka] A compound or a salt thereof is provided.

[0126] In this specification, [ka] A compound or a salt thereof is provided.

[0127] In this specification, [ka] A compound or a salt thereof is provided.

[0128] In this specification, [ka] A compound or a salt thereof is provided.

[0129] In this specification, the salt of formula 2a: [ka] A compound is provided in which, in the formula, X - It is the opposite anion, X - Cl - It is otherwise. In some embodiments, the compound is [ka] Selected from.

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

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

[0132] 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.

[0133] 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 has a 2-theta (±0.2 degrees) configuration with 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.

[0134] 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 of 101°C.

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

[0136] 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, form 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, form II has a 2-theta (±0.2 degrees) configuration with 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.

[0137] 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 of 99°C.

[0138] In some embodiments, as used herein, the hexafluorophosphate of compound 2: [ka] The crystalline form is provided.

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

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

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

[0142] In some embodiments, the crystalline form of the salt of formula 3a is characterized by single-crystal X-ray diffraction to have a monoclinic P21 space group and a cell formula unit (Z) of 4. In some embodiments, the monoclinic P21 space group has unit cell parameters such that a is approximately 7.68 Å, b is approximately 7.60 Å, c is approximately 13.72 Å, and beta is approximately 96.94°.

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

[0144] In some embodiments, this specification provides methods for preparing ruxolitinib and its salts, such as phosphates. For example, ruxolitinib and its phosphates may be prepared according to one or more steps shown in Scheme 1. Scheme 1 [ka]

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

[0146] This disclosure further provides salts of ruxolitinib, which are prepared according to the methods provided herein.

[0147] This disclosure further provides ruxolitinib, which is prepared according to the methods provided herein.

[0148] This disclosure further provides ruxolitinib or pharmaceutically acceptable salts thereof, prepared according to the methods provided herein.

[0149] This disclosure further provides pharmaceutically acceptable salts of ruxolitinib, which are prepared according to the methods provided herein.

[0150] This disclosure further provides ruxolitinibulinate salts, which are prepared according to the methods provided herein.

[0151] In various parts of this specification, substituents of the compounds of the present invention are disclosed in groups or ranges. The present invention is expressly intended to include all individual partial combinations of members of such groups and ranges. For example, "C 1-6 The term "alkyl" is explicitly intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0152] For clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any preferred partial combination.

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

[0154] With respect to the compounds of the present invention in which a variable element appears two or more times, each variable element may be a different part independently selected from the group defining the variable element. For example, if a structure is described as having two R groups present simultaneously on the same compound, these two R groups may represent different parts independently selected from the group defined with respect to R. In another example, if there are optionally multiple substituents, they are specified in the following form: [ka] It is understood that substituent R can appear p times on the ring, and that R can be a different part in each occurrence. Each R group is (CH2)n It is understood that any hydrogen atom bonded to the ring atom may be replaced, including one or both of the hydrogen atoms of . Furthermore, if the variable element Q is defined to contain hydrogen, such as when Q is stated to be CH2, NH, etc., then any floating substituent such as R in the above example may replace the hydrogen of the Q variable element of the ring, as well as the hydrogen of any other non-variable component.

[0155] 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.

[0156] As used herein, the terms “halo” and “halogen,” when used alone or in combination with other terms, refer to fluoro, chloro, bromo, and iodine.

[0157] 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 its ring structure and has 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.

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

[0159] As used herein, the terms “reacting” and “contacting” are used as known in the art and generally refer to bringing 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, with one equivalent or more of the second reagent used relative to the first reagent. The reaction steps of the methods described herein may be carried out over a time suitable for preparing the specified product and under such conditions.

[0160] The compounds of the present invention also include pharmaceutically acceptable salts of the compounds disclosed herein. As used herein, the term “pharmaceutically acceptable salt” refers to a salt formed by adding a pharmaceutically acceptable acid or base to a compound disclosed herein. As used herein, the term “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not cause harmful interactions with the active ingredient. Pharmaceutically acceptable salts, including monosal and disal salts, include, but are not limited to, salts derived from organic and inorganic acids such as acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, and similarly known acceptable acids. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0161] 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. The preparation, formation, and cleavage methods for protecting groups described herein may be modified as necessary to take into account various substituents.

[0162] The reactions 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 (for example, a temperature that 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 more than one solvent. Depending on the specific reaction step, a solvent suitable for that 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.

[0163] Suitable solvents may include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof, and equivalents.

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

[0165] Suitable protic solvents may 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, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, mixtures thereof, and equivalents.

[0166] Suitable aprotic solvents may 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 equivalents.

[0167] 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 equivalents.

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

[0169] The reactions described herein may be carried out at a suitable temperature that can be readily determined by those skilled in the art. The reaction temperature will depend, 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 low temperatures), and the kinetics of the reaction (e.g., high activation energy barriers may require high temperatures). "High temperature" refers to temperatures above room temperature (approximately 22°C).

[0170] The reactions 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 synthetic techniques well known to those skilled in the art.

[0171] In some embodiments, the preparation of the compound may involve the addition of an acid or base to influence, for example, the catalytic action of a desired reaction or the formation of a salt form such as an acid addition salt.

[0172] Examples of acids can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butyric acid, vinylacetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0173] 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 examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, where alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include sodium and potassium salts of amides substituted with methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl, and cyclohexyl.

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

[0175] When compound preparation is carried out according to the method described herein, the desired product may be isolated using conventional isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, and chromatography.

[0176] In some embodiments, the compounds of the present invention and their salts are substantially isolated. "Substantially isolated" means that the compounds are separated at least partially or substantially from the environment in which they were formed or detected. Partial isolation may include, for example, a composition in which the compounds of the present invention are concentrated. Substantial isolation may include a composition 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 the compounds and their salts are common in the art.

[0177] In some embodiments, ruxolitinib, intermediates for preparing ruxolitinib reagents, and their salts may include both the 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 lower melting points often have lower thermodynamic stability, but they are advantageous in that they have high solubility in water and therefore high bioavailability of the drug. Forms with low hygroscopicity are desirable due to their stability against heat and humidity and their ability to withstand degradation during long-term storage.

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

[0179] 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 water vapor sorption (DVS), and solid-state NMR can further help identify the form and determine stability and solvent / water content.

[0180] XRPD patterns of reflections (peaks) are typically considered fingerprints of a particular crystal morphology. It is well known that the relative intensity of XRPD peaks can vary considerably depending, among other things, on sample preparation techniques, crystal size distribution, various filters used, sample placement 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 variations and other factors can affect the 2-theta values. Therefore, the attribution of peaks reported herein, etc., may vary by plus or minus about 0.2° (2-theta), and the terms “substantially” and “about” as used herein in the context of XRPD are intended to encompass the aforementioned variations.

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

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

[0183] 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, a composition in which the solid and salt forms are concentrated. Substantial isolation may include a composition 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 common in the art.

[0184] 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.

[0185] The term "pharmaceutically acceptable" is used herein to mean salts, materials, compositions, and / or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, given a reasonable benefit-risk ratio.

[0186] The salt-forming reactions described herein may be carried out at appropriate temperatures that can be readily determined by those skilled in the art. The reaction temperature will depend, 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 low temperatures), and the kinetics of the reaction (e.g., high activation energy barriers may require high temperatures).

[0187] As used herein, the terms “ambient temperature” and “room temperature” or “room temperature (rt)” are understood in the art and generally refer to temperature, for example, reaction temperature, i.e., the temperature of the room in which the reaction is approximately carried out, e.g., about 20°C to about 30°C.

[0188] Protecting groups described herein (e.g., P 1 P 2 This includes, but is not limited to, the protecting groups for amines described in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, pp. 696–887 (and especially pp. 872–887) (2007), which is incorporated herein by reference in its entirety. Examples of protecting groups described herein include CH2OC(=O)C(CH3)3, 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), and 2,4-di Methylpenta-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.

[0189] In some embodiments, one or more constituent atoms of the compounds (products or synthetic intermediates) presented herein may be replaced or substituted with isotopes of the atom in natural or unnatural abundance. In some embodiments, the compound contains at least one deutherium atom. For example, in some embodiments, one or more hydrogen atoms in the compounds presented herein may be replaced or substituted with deutherium atoms (e.g., substituting -CH3 with -CD3, etc.). 1-6 (One or more hydrogen atoms of the alkyl group may be replaced by deutherium atoms.) In some embodiments, the compound contains two or more deutherium atoms. In some embodiments, the compound contains 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, or 1-8 deutherium atoms.

[0190] In some embodiments, one or more hydrogen atoms of ruxolitinib or a salt thereof are replaced with deutherium atoms. In some embodiments, the CH2 group of the cyclopentyl ring of ruxolitinib or a salt thereof is replaced with CD2 group.

[0191] In some embodiments, one or more hydrogen atoms in the compound of formula 3 or its salt are replaced with deutherium atoms. In some embodiments, the CH2 group of the cyclopentyl ring in the compound of formula 3 or its salt is replaced with CD2 group.

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

[0193] The present invention will be described in more detail with reference to specific examples. The following examples are presented for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize various less important parameters that can be changed or modified to produce essentially the same results. [Examples]

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

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

[0196] Embodiment 1. A method for preparing ruxolitinib or a salt thereof, Compound of formula 3: [ka] or a salt thereof, the salt of formula 2a or a salt thereof, or a compound of formula 2b: [ka] This includes reacting with a reagent, In the formula, X - However, the method is a counter-anion.

[0197] 2. The method according to Embodiment 1, wherein the compound of Formula 3 or the salt thereof is a chiral salt of the compound of Formula 3.

[0198] 3. The method according to Embodiment 2, wherein the chiral salt is prepared by reacting the compound of Formula 3 with an optically active form of an acid selected from mandelic acid, 2-chloromandelic acid, camphor sulfonic acid, tartaric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camhor sulfonic acid, dibenzoyl tartaric acid, di-p-toluyl tartaric acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid, and 2-acrylamido-7,7-dimethylbicyclo[2,2,1]heptane-1-methylenesulfonic acid.

[0199] 4. The method according to Embodiment 2, wherein the chiral salt is the L-(+)-tartrate salt of the compound of Formula 3.

[0200] 5. The compound of formula 3 or the salt thereof, formula 3a: [ka] The method according to Embodiment 2, having the following characteristics.

[0201] 6. The method according to any one of Embodiments 1 to 6, wherein about 1 to about 1.5 molar equivalents of the reagent are used relative to the compound of Formula 3 or a salt thereof.

[0202] 7. The method according to any one of Embodiments 1 to 6, wherein the reaction between the reagent and the compound of Formula 3 or its salt is carried out in solvent component S1.

[0203] 8. The method according to Embodiment 7, wherein the solvent component S1 contains water.

[0204] 9. The method according to Embodiment 7, wherein the solvent component S1 includes an alcohol.

[0205] 10. The method according to Embodiment 7, wherein the solvent component S1 contains ethanol.

[0206] 11. The method according to Embodiment 7 or 8, wherein the solvent component S1 comprises dimethylformamide.

[0207] 12. The method according to Embodiment 7 or 8, wherein the solvent component S1 comprises water, alcohol, or a combination thereof.

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

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

[0210] 15.X - However, Cl - , Br - , I - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - A method according to any one of embodiments 1 to 13, selected from the above.

[0211] 16.X - However, Cl - BF4 - PF6 - AsF6 - SbF6 - , and ClO4 - A method according to any one of embodiments 1 to 13, selected from the above.

[0212] 17.X - However, BF4 - The method according to any one of Embodiments 1 to 13.

[0213] 18.X - However, PF annotation -The method according to any one of Embodiments 1 to 13.

[0214] 19.X - However, AsF6 - The method according to any one of Embodiments 1 to 13.

[0215] 20.X - However, SbF6 - The method according to any one of Embodiments 1 to 13.

[0216] 21.X - However, ClO4 - The method according to any one of Embodiments 1 to 13.

[0217] 22.X - However, Cl - The method according to any one of Embodiments 1 to 13.

[0218] 23. The reagent is the hydrochloride salt of the salt of formula 2a, where X - However, Cl - The method according to any one of Embodiments 1 to 12.

[0219] 24. The method according to any one of Embodiments 1 to 12, wherein the reagent is the compound of Formula 2b.

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

[0221] 26. The method according to Embodiment 25, wherein the reaction between the salt of formula 2a and the base B1 is carried out in a solvent component S2 containing water.

[0222] 27. The method according to Embodiment 25 or 26, wherein the base B1 is a strong base.

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

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

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

[0226] 31. The method according to any one of Embodiments 25 to 30, wherein a salt of formula 2a or about 10 to about 15 molar equivalents of base B1 relative to the salt is used.

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

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

[0229] 34. The salt of formula 2a or the compound of formula 2b, The compound of formula 1a: [ka] The method according to any one of Embodiments 1 to 33, which is prepared by a method comprising reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

[0230] 35. The salt of formula 2a or the compound of formula 2b, The compound of formula 5a: [ka] The method according to any one of Embodiments 1 to 33, which is prepared by a method comprising reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

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

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

[0233] 38. The reaction with the Vilsmeyer reagent yields the compound of formula 2c: [ka] A method according to any one of embodiments 34 to 37, for generating [the specified product].

[0234] 39. After reaction with Vilsmeyer's reagent, the compound of formula 2c is obtained, + X - It is reacted with the salt of, in the formula, M + However, the method according to Embodiment 38, wherein the countercation is present.

[0235] 40. The method according to any one of Embodiments 34 to 39, wherein the Vilsmeyer reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent.

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

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

[0238] 43. The method according to Embodiment 40, wherein the chlorinating agent is oxalyl chloride.

[0239] 44. The method according to Embodiment 40, wherein the chlorinating agent is phosphorus oxychloride.

[0240] 45. The method according to Embodiment 40, wherein the chlorinating agent is triphosgene.

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

[0242] 47. The method according to any one of Embodiments 40 to 45, wherein about 1 to about 4 molar equivalents of the chlorinating agent are used relative to the compound of formula 1a or 5a, or the salt thereof.

[0243] 48. The method according to any one of Embodiments 40 to 45, wherein about 1 to about 3 molar equivalents of the chlorinating agent are used relative to the compound of formula 1a or 5a, or the salt thereof.

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

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

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

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

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

[0249] 54. The method according to any one of Embodiments 34 to 53, wherein the preparation of the Vilsmeyer reagent is carried out in solvent component S3.

[0250] 55. The method according to Embodiment 54, wherein the solvent component S3 includes an organic solvent.

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

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

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

[0254] 59. The method according to any one of Embodiments 34 to 57, wherein the Vilsmeyer reagent is prepared at a temperature of approximately -10°C to approximately 30°C.

[0255] 60. The method according to any one of Embodiments 34 to 57, wherein the Vilsmeyer reagent is prepared at a temperature of approximately room temperature to approximately 60°C.

[0256] 61. The method according to any one of Embodiments 34 to 60, wherein the reaction between the compound of Formula 1a or 5a, or the salt thereof, and the Vilsmeyer reagent is carried out at a temperature of about 40°C to about 100°C.

[0257] 62. The method according to any one of Embodiments 34 to 60, wherein the reaction between the compound of Formula 1a or 5a, or the salt thereof, and the Vilsmeyer reagent is carried out at a temperature of about 70°C to about 100°C.

[0258] 63. The method according to any one of Embodiments 34 to 60, wherein the reaction between the compound of Formula 1a or 5a, or the salt thereof, and the Vilsmeyer reagent is carried out at a temperature of about 40°C to about 60°C.

[0259] 64. The product of the reaction with the Vilsmeyer reagent is given by formula 2d: [ka] The method according to any one of embodiments 34 to 63, having the characteristics of the present invention.

[0260] 65. The salt of formula 2a above is Salt of the above formula 2c: [ka] Formula M + X - Formed by a method including reacting with a salt of, in the formula, M + However, it is a counter-cation, X - However, Cl - Other anti-anion types, The method according to any one of Embodiments 1 to 64.

[0261] 66.M + The method according to embodiment 65, wherein the alkali metal is paired with a cation.

[0262] 67.M + However, Li + kaNa + , or K + The method according to embodiment 65.

[0263] 68.M + However, Na + The method according to embodiment 65.

[0264] 69.X - However, Br - , I - BF4 - PF6 -AsF6 - SbF6 - , and ClO4 - A method according to any one of embodiments 65 to 68, selected from the above.

[0265] 70. The salt of formula 2c above is Salt of equation 2d: [ka] The method according to any one of embodiments 38 to 69, which is produced by a method comprising reacting with a base.

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

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

[0268] 73. The method according to Embodiment 71 or 72, wherein the reaction between the salt of formula 2d and base B2 is carried out in a solvent component containing water.

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

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

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

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

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

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

[0275] 80. The compound of formula 1a or the salt thereof, Compounds of formula 1aP: [ka] Prepared by a method that includes deprotecting, In the formula, P 1 However, the method according to embodiment 34 or 79, wherein the amino protecting group is present.

[0276] 81.P 1 However, (R 1 ) Selected from 3Si, in the formula, R 1 However, C 1-6 The method according to embodiment 80, wherein the alkyl group is alkyl.

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

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

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

[0280] 85. The method according to Embodiment 84, wherein the base B3 is a hydroxide base.

[0281] 86. The method according to Embodiment 84 or 85, wherein the base B3 is ammonium hydroxide.

[0282] 87. The method according to any one of embodiments 80 to 86, wherein the deprotection is performed in solvent component S4.

[0283] 88. The method according to Embodiment 87, wherein the solvent component S4 includes a polar protic solvent.

[0284] 89. The method according to Embodiment 87 or 88, wherein the solvent component S4 contains an alcohol.

[0285] 90. The solvent component S4 is of formula C 1-6 The method according to any one of embodiments 87 to 89, comprising an alkyl-OH group.

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

[0287] 92. The compound of formula 1aP described above, Compounds of formula 2P: [ka] It is prepared by a method that includes reacting it with MeMgBr in the presence of a Grignard catalyst, In the formula, P 1 The method according to any one of embodiments 80 to 91, wherein the amino protecting group is an amino protecting group.

[0288] 93. The method according to Embodiment 92, wherein the catalyst is an iron catalyst.

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

[0290] 95. The method according to any one of embodiments 92 to 94, wherein about 1 to about 2 molar equivalents of MeMgCl are used for the compound of formula 2P.

[0291] 96. The method according to any one of embodiments 92 to 95, wherein about 1% to about 10% molar equivalent of the catalyst is used relative to the compound of formula 2P.

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

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

[0294] 99. The method according to Embodiment 97 or 98, wherein the solvent component S5 comprises tetrahydrofuran.

[0295] 100. The method according to any one of embodiments 92 to 99, wherein the reaction between the compound of formula 2P and MeMgCl is carried out at a temperature of about -10°C to about 30°C.

[0296] 101. The compound of formula 2P described above, Compound of formula 12a: [ka] The method according to any one of Embodiments 91 to 100, which is prepared by a method comprising protecting and forming the compound of formula 2P.

[0297] 102. The protection provided by the compound of formula 12a is an alkali metal hydride and P 1 The method according to Embodiment 101, comprising reacting with -Y, wherein Y is a halo.

[0298] 103.P 1 -Y is (R 1 )3Si-Y, where Y is halo and R 1 However, C 1-6 The method according to embodiment 102, wherein the alkyl group is used.

[0299] 104.P1 However, (R 1 )3Si, and in the formula, R 1 However, C 1-6 The method according to embodiment 103, wherein the alkyl group is used.

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

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

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

[0303] 108. The method according to any one of embodiments 102 to 107, wherein about 1 to about 2 molar equivalents of the alkali metal hydride are used relative to the compound of formula 12a.

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

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

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

[0307] 112. The solvent component S6 is di-C 1-6The method according to Embodiment 111, comprising an alkyl ether or a 4- to 10-membered heterocycloalkyl ether.

[0308] 113. The method according to Embodiment 111 or 112, wherein the solvent component S6 comprises tetrahydrofuran.

[0309] 114. The compound of formula 1a or the salt thereof, Compound of formula 23P: [ka] Prepared by a method including the reduction of In the formula, P 2 However, the method according to any one of Embodiments 34 and 79-113, wherein the amino protecting group is an amino protecting group.

[0310] 115. The method according to Embodiment 114, wherein the reduction of the compound of formula 23P is carried out by a method comprising reacting the compound of formula 23P with hydrogen gas in the presence of a catalyst.

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

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

[0313] 118. The method according to any one of embodiments 115 to 117, wherein 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.

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

[0315] 120. The method according to Embodiment 119, wherein the solvent component S7 comprises a polar protic solvent.

[0316] 121. The method according to Embodiment 119 or 120, wherein the solvent component S7 comprises an alcohol.

[0317] 122. The solvent component S7 is of formula C 1-6 The method according to any one of embodiments 119 to 121, comprising an alkyl-OH group.

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

[0319] 124. The compound of formula 23P described above, Compound of formula 22P: [ka] It is prepared by a method that includes reacting it with MeMgBr in the presence of a Grignard catalyst, In the formula, P 2 The method according to any one of embodiments 114 to 123, wherein the amino protecting group is an amino protecting group.

[0320] 125. The method according to Embodiment 124, wherein the catalyst is an iron catalyst.

[0321] 126. The method according to Embodiment 125, wherein the iron catalyst is iron(III) acetylacetonate.

[0322] 127. The method according to any one of embodiments 124 to 126, wherein about 1 to about 2 molar equivalents of MeMgCl are used for the compound of formula 22P.

[0323] 128. The method according to any one of Embodiments 124 to 127, wherein about 1% to about 10% molar equivalent of the catalyst is used relative to the compound of formula 22P.

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

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

[0326] 131. The method according to Embodiment 129 or 130, wherein the solvent component S8 comprises tetrahydrofuran.

[0327] 132. The method according to any one of Embodiments 124 to 131, wherein the reaction between the compound of formula 2P and MeMgCl is carried out at a temperature of about -10°C to about 30°C.

[0328] 133. The compound of formula 22P is, Compound of formula 22a: [ka] The method according to any one of Embodiments 124 to 132, prepared by a method comprising protecting and forming the compound of Formula 22P.

[0329] 134. The protection provided by the above formula 22a is an alkali metal hydride and P 2 The method according to Embodiment 133, comprising reacting with -Y, wherein Y is a halo.

[0330] 135.P 2 However, (R 1 )3Si, and in the formula, R 1 However, C 1-6 The method according to Embodiment 134, wherein the alkyl group is used.

[0331] 136.R 1 The method according to Embodiment 135, wherein the compound is methyl, ethyl, propyl, isopropyl, butyl, or t-butyl.

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

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

[0334] 139. The method according to any one of embodiments 134 to 138, wherein about 1 to about 2 molar equivalents of the alkali metal hydride are used relative to the compound of formula 22a.

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

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

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

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

[0339] 144. The method according to Embodiment 142 or 143, wherein the solvent component S9 comprises tetrahydrofuran.

[0340] 145. The compound of formula 1a or the salt thereof, Compound of formula 18a: [ka] The method according to any one of Embodiments 34 and 79-113, which is prepared by a method comprising reacting with acid A1 to form a compound of formula 1a.

[0341] 146. The method according to Embodiment 145, wherein the acid A1 is a strong acid.

[0342] 147. The method according to Embodiment 145 or 146, wherein the acid A1 is hydrochloric acid.

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

[0344] 149. The method according to Embodiment 148, wherein the solvent component S10 contains an alcohol.

[0345] 150. The solvent component S10 is of formula C 1-6 The method according to embodiment 148 or 149, comprising an alkyl-OH group.

[0346] 151. The method according to any one of Embodiments 148 to 150, wherein the solvent component S10 contains isopropyl alcohol.

[0347] 152. The compound of formula 18a or a salt thereof, Compound of formula 17a: [ka] The method according to any one of Embodiments 148 to 151, which is prepared by a method comprising reacting with formamidine acetate and triethyl orthoformate to form the compound of Formula 17a.

[0348] 153. The method according to Embodiment 152, wherein about 10 to about 15 molar equivalents of formamidine acetate are used, given that the compound of formula 17a is about 10 to about 15.

[0349] 154. The method according to Embodiment 152 or 153, wherein about 6 to about 10 molar equivalents of triethyl orthoformate are used relative to the compound of formula 17a.

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

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

[0352] 157. The method according to Embodiment 156, wherein the solvent component S11 contains an alcohol.

[0353] 158. The solvent component S11 is of formula C 1-6 The method according to embodiment 156 or 157, comprising an alkyl-OH group.

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

[0355] 160. The compound of formula 17a or a salt thereof, Compound of formula 20a: [ka] Compound of formula 21a: [ka] The method according to any one of Embodiments 152 to 159, which is prepared by a method comprising reacting with to form the compound of formula 17a.

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

[0357] 162. The method according to Embodiment 160 or 161, wherein the reaction between the compound of Formula 20a and the compound of Formula 21a is carried out at room temperature.

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

[0359] 164. The method according to Embodiment 163, wherein the solvent component S12 comprises dimethylformamide.

[0360] 165. The compound of formula 20a or a salt thereof, Compound of formula 19a: [ka] The method according to any one of Embodiments 160 to 164, which is prepared by a method comprising reacting with bromo-1,1-dimethoxyethane and base B4 to form the compound of formula 20a.

[0361] 166. The method according to Embodiment 165, wherein the base B4 is an alkali metal carbonate.

[0362] 167. The method according to Embodiment 165 or 166, wherein the base B4 is cesium carbonate.

[0363] 168. The method according to any one of embodiments 165 to 167, wherein about 1 to about 2 molar equivalents of base B4 are used with respect to the compound of formula 19a.

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

[0365] 170. The method according to any one of embodiments 165 to 169, wherein the reaction between the compound of formula 19a and bromo-1,1-dimethoxyethane is carried out at a temperature of about 70°C to about 100°C.

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

[0367] 172. The method according to Embodiment 171, wherein the solvent component S13 is dimethylformamide.

[0368] 173. The compound of formula 17a or a salt thereof, Compound of formula 16a: [ka] The method according to any one of Embodiments 152 to 159, which is prepared by a method comprising reacting with ethyl acetate and base B5 to form a compound of formula 17a.

[0369] 174. The method according to Embodiment 173, wherein the base B5 is an alkali metal alkoxide.

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

[0371] 176. The method according to any one of embodiments 173 to 175, wherein about 1 to about 3 molar equivalents of base B5 are used with respect to the compound of formula 16a.

[0372] 177. The method according to any one of embodiments 173 to 176, wherein about 1 to about 2 molar equivalents of ethyl acetate are used relative to the compound of formula 16a.

[0373] 178. The method according to any one of Embodiments 172 to 177, wherein the reaction of the compound of formula 17a with ethyl acetate and base B5 is carried out at room temperature.

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

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

[0376] 181. The method according to Embodiment 179 or 180, wherein the solvent component S14 comprises tetrahydrofuran.

[0377] 182. The compound of formula 5a or the salt thereof, Compound of formula 27a: [ka] The method according to any one of embodiments 35 to 79, which is prepared by a method comprising hydrolyzing in water in the presence of base B6.

[0378] 183. The method according to Embodiment 182, wherein the base B6 is an alkali metal hydroxide.

[0379] 184. The method according to Embodiment 182 or 183, wherein the base B6 is sodium hydroxide.

[0380] 185. The method according to any one of embodiments 182 to 184, wherein about 1 to about 2 molar equivalents of the base B6 are used with respect to the compound of formula 27a.

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

[0382] 187. The method according to any one of Embodiments 182 to 186, wherein the hydrolysis of the compound of formula 27a is carried out in a solvent component S15, and the solvent component S15 comprises an organic solvent.

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

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

[0385] 190. The method according to any one of Embodiments 182 to 188, wherein the compound of formula 5a or the salt thereof is the compound of formula 5a.

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

[0387] 192. The method according to Embodiment 191, wherein the strong acid A2 is hydrochloric acid.

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

[0389] 194. The compound of formula 27a is, Compound of formula 26P: [ka] It is prepared by a method that includes reacting with strong acid A3, where P 1 The method according to any one of embodiments 182 to 193, wherein the amino protecting group is an amino protecting group.

[0390] 195.P 1 The method according to Embodiment 194, wherein the p-toluenesulfonyl is used.

[0391] The method according to Embodiment 194 or 195, wherein 196.A3 is hydrochloric acid.

[0392] 197. The method according to any one of Embodiments 194 to 196, wherein the reaction between the compound of formula 26P and strong acid A3 is carried out at room temperature.

[0393] 198. The method according to any one of Embodiments 194 to 197, wherein the reaction between the compound of formula 26P and the strong acid A3 is carried out in solvent component S16.

[0394] 199. The solvent component S16 is of formula C 1-6 The method according to any one of embodiments 194 to 198, comprising an alkyl-OH group.

[0395] 200. The method according to Embodiment 199, wherein the solvent component S16 contains ethanol.

[0396] 201. The compound of formula 26P described above, Compound of formula 25P: [ka] It is prepared by a method comprising reacting with alkali metal alkoxide B8 to form a compound of formula 26P, where P 1 The method according to any one of Embodiments 194 to 200, wherein the amino protecting group is an amino protecting group.

[0397] 202. The method according to Embodiment 201, wherein approximately 0.1 molar equivalents of alkali metal alkoxide B8 are used relative to the compound of formula 25P.

[0398] 203. The method according to Embodiment 201 or 202, wherein the reaction between the compound of formula 25P and alkali metal alkoxide B8 is carried out at room temperature.

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

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

[0401] 206. The method according to Embodiment 204 or 205, wherein the solvent component S17 contains an alcohol.

[0402] 207. The solvent component S17 is of formula C 1-6 The method according to any one of embodiments 204 to 206, comprising an alkyl-OH group.

[0403] 208. The method according to any one of Embodiments 204 to 207, wherein the solvent component S17 contains ethanol.

[0404] 209. The compound of formula 27a is, Compound of formula 25P: [ka] The method according to any one of Embodiments 182 to 193, which is prepared by a method comprising reacting with alkali metal alkoxide B9 to form the compound of formula 27a.

[0405] 210. The method according to Embodiment 209, wherein about 1 to about 2 molar equivalents of alkali metal alkoxide B9 are used relative to the compound of formula 25P.

[0406] 211. The method according to Embodiment 209, wherein about 1 molar equivalent of alkali metal alkoxide B9 is used relative to the compound of formula 25P.

[0407] 212. The method according to any one of embodiments 209 to 211, wherein the reaction between the compound of formula 25P and alkali metal alkoxide B9 is carried out at a temperature of about 50°C to about 80°C.

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

[0409] 214. The method according to Embodiment 213, wherein the solvent component S18 contains ethanol.

[0410] 215. The compound of formula 25P described above, Compounds of formula 2P: [ka] It is prepared by a method comprising reacting diethyl malonate and base B10, where P 1 The method according to any one of embodiments 201 to 214, wherein the amino protecting group is an amino protecting group.

[0411] 216. The method according to Embodiment 215, wherein the base B10 is an alkali metal carbonate.

[0412] 217. The method according to Embodiment 215 or 216, wherein the base B10 is cesium carbonate.

[0413] 218. The method according to any one of embodiments 215 to 217, wherein the reaction between the compound of formula 2P and base B10 is carried out at a temperature of about 40°C to about 70°C.

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

[0415] 220. The method according to Embodiment 219, wherein the solvent component S19 contains dimethylformamide.

[0416] 221. The method according to any one of Embodiments 215 to 220, wherein the compound of formula 2P is prepared by a method comprising protecting the compound of formula 12a to form the compound of formula 2P.

[0417] 222. The protection described above protects the compound of formula 12a from base B11 and P 1 The method according to Embodiment 221, comprising reacting with -Y, wherein Y is a halo.

[0418] 223.P 1 The method according to Embodiment 222, wherein the p-toluenesulfonyl is used.

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

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

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

[0422] 227. The method according to Embodiment 226, wherein the solvent component S20 contains acetone.

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

[0424] 229. The method according to Embodiment 228, wherein the strong acid A4 is hydrochloric acid.

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

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

[0427] 232. The method according to Embodiment 230 or 231, wherein the solvent component S21 contains tetrahydrofuran.

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

[0429] 234. The compound of formula 11a or a salt thereof, Compound of formula 10a: [ka] The method according to any one of Embodiments 228 to 233, or the method according to any one of Embodiments 228 to 233, which is prepared by a method comprising reacting a salt thereof with (methoxymethyl)triphenylphosphonium chloride and base B12.

[0430] 235. The method according to Embodiment 234, wherein the base B12 is an alkali metal alkoxide.

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

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

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

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

[0435] 240. The method according to Embodiment 238 or 239, wherein the solvent component S22 contains tetrahydrofuran.

[0436] 241. The compound of formula 10a or a salt thereof, Compound of formula 9a: [ka] The method according to any one of embodiments 238 to 240, which is prepared by a method comprising reacting with ammonia.

[0437] 242. The method according to Embodiment 241, wherein the reaction between the compound of formula 9a and ammonia is carried out at a temperature of about 40°C to about 70°C.

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

[0439] 244. The method according to Embodiment 243, wherein the solvent component S23 contains toluene.

[0440] 245. The compound of formula 9a is, Compound of formula 8a: [ka] The method according to any one of Embodiments 241 to 244, which is prepared by a method comprising reacting with a Vilsmeyer reagent formed from dimethylformamide.

[0441] 246. The method according to Embodiment 245, wherein the Vilsmeyer reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent.

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

[0443] 248. The method according to Embodiment 246 or 247, wherein the chlorinating agent is phosphorus oxychloride.

[0444] 249. The compound of formula 12a is, Compound of formula 15a: [ka] The method according to any one of embodiments 101-113 and 221-237, which is prepared by a method comprising reacting with a chlorinating agent.

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

[0446] 251. The method according to Embodiment 249 or 250, wherein the chlorinating agent is phosphorus oxychloride.

[0447] 252. The method according to any one of Embodiments 249 to 251, wherein 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.

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

[0449] 254. The method according to Embodiment 253, wherein the solvent component S24 contains toluene.

[0450] 255. The compound of formula 15a is, (i) Compound of formula 14a: [ka] Reacting with formamidine acetate and alkali metal hydroxide yields the compound of formula 14aa: [ka] To cause, (ii) Reacting the compound of formula 14aa with strong acid A4, The method according to any one of embodiments 249 to 254, prepared by a method including the following.

[0451] 256. The method according to Embodiment 255, wherein the alkali metal hydroxide is sodium ethoxide.

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

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

[0454] 259. The method according to Embodiment 258, wherein the solvent component S25 contains an alcohol.

[0455] 260. The solvent component S25 is of formula C 1-6 The method according to embodiment 258 or 259, comprising an alkyl-OH group.

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

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

[0458] 263. The compound of formula 14a is, Compound of formula 13a: [ka] The method according to any one of Embodiments 258 to 262, which is prepared by a method comprising reacting with bromoacetaldehyde diethyl acetal and sodium tert-amiloxide.

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

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

[0461] 266. The method according to Embodiment 265, wherein the solvent component S26 comprises dimethyl sulfoxide.

[0462] 267. The method according to any one of Embodiments 1 to 266, wherein the compound of Formula 3a or the salt thereof is the L-tartrate salt of the compound of Formula 3.

[0463] 268. The L-tartrate in formula 3 above is Compound 7a: [ka] The method according to Embodiment 267, which is prepared by a method comprising reacting with L-tartaric acid.

[0464] 269. The method according to Embodiment 268, wherein approximately 1 molar equivalent of L-tartaric acid is used relative to the compound of formula 7a.

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

[0466] 271. The method according to Embodiment 270, wherein the solvent component S27 comprises water and an organic solvent.

[0467] 272. The method according to Embodiment 270 or 271, wherein the solvent component S27 comprises about 1:1(v) water-to-organic solvent.

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

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

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

[0471] 276. The method according to any one of embodiments 268 to 275, wherein the reaction of the compound of formula 7a and L-tartaric acid further comprises sowing a salt of formula 3a.

[0472] 277. The compound of formula 7a above, The compound of formula 6a: [ka] The method according to any one of embodiments 268 to 276, which is prepared by a method comprising reacting with hydrazine.

[0473] 278. The method according to Embodiment 277, wherein approximately 2 to approximately 3 equivalents of hydrazine are used relative to compound 6a.

[0474] 279. The method according to Embodiment 278, wherein the hydrazine is hydrazine hydrate.

[0475] 280. The method according to Embodiment 278 or 279, wherein the reaction of the compound of Formula 6a with hydrazine is carried out at a temperature of about -10°C to about 30°C.

[0476] 281. The method according to any one of Embodiments 1 to 280, wherein the salt of ruxolitinib is ruxolitinibulinate.

[0477] 282. The method according to Embodiment 281, wherein ruxolitinibulinate is prepared by a method comprising reacting ruxolitinib with phosphoric acid.

[0478] 283. The method according to Embodiment 282, wherein approximately 1 to approximately 2 molar equivalents of phosphoric acid are used relative to ruxolitinib.

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

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

[0481] 286. Ruxolitinibrinate, (i) Adding the first solvent component to ruxolitinibrinate to produce the first solution, (ii) Concentrating the first solution to produce a second solution, (iii) Adding a second solvent component to the second solution to produce a third solution, (iv) Adding a third solvent to the third solution to produce a fourth solution, (v) Concentrating the fourth solution to produce a fifth solution, (vi) Isolating ruxolitinibrinate from the fifth solution, The method according to any one of embodiments 281 to 285, which is purified by a method including the following.

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

[0483] 288. The method according to Embodiment 286 or 287, wherein the first solvent component comprises methanol.

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

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

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

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

[0488] 293. The method according to any one of Embodiments 286 to 292, wherein the third solvent component comprises a nonpolar solvent.

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

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

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

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

[0493] 298. A method for preparing ruxolitinibrinate, (a) Compound of formula 1a or a salt thereof: [ka] This is reacted with the Vilsmeyer reagent formed from dimethylformamide to form the compound of formula 2c: [ka] To cause, (b) The compound of formula 2c above is the compound of formula 3: [ka] Reacting it with L-tartrate yields ruxolitinib, (c) Reacting ruxolitinib with phosphate to produce ruxolitinibrate, The method, including the method described above.

[0494] 299. The compound of formula 1a or a salt thereof, (a) Compound of formula 12a: [ka] Reacting with t-butyldimethylsilyl chloride yields the compound of formula 12b: [ka] To cause, (b) The compound of formula 12b is reacted with MeMgBr in the presence of a Grignard catalyst to obtain the compound of formula 12c: [ka] To cause, (c) Deprotecting the compound of formula 12c to produce the compound of formula 1a or a salt thereof, The method according to Embodiment 298, which is prepared by a method including the following.

[0495] 300. The compound of formula 1a or a salt thereof, (a) Compound of formula 22a: [ka] The compound of formula 23a is obtained by reacting t-butyldimethylsilyl chloride and MeMgBr in the presence of a Grignard catalyst: [ka] To cause, (b) Reacting the compound of formula 23a with hydrogen and palladium carbon to produce the compound of formula 1a or a salt thereof, The method according to Embodiment 298, which is prepared by a method including the following.

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

[0497] 302. The compound or a salt thereof [ka] A compound selected from the compounds described in Embodiment 301.

[0498] 303. The following compounds: [ka] or its salt.

[0499] 304. The following compounds: [ka] or its salt.

[0500] 305. The following compounds: [ka] or its salt.

[0501] 306. The following compounds: [ka] or its salt.

[0502] 307. The following compounds: [ka] or its salt.

[0503] 308. Salt of Equation 2a: [ka] And, In the formula, X - However, Cl -A compound that is a counter anion other than the one specified.

[0504] 309. The compound is [ka] A compound selected from the compound described in Embodiment 308.

[0505] 310. Salts of Equation 2d: [ka] The crystalline form.

[0506] 311. The crystal morphology according to Embodiment 310, having morphology I.

[0507] 312. The crystal morphology according to Embodiment 311, having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1.

[0508] 313. The crystal morphology according to embodiment 311 or 312, having a differential scanning calorimetry (DSC) thermogram substantially as illustrated in Figure 2.

[0509] 314. A crystalline morphology according to any one of embodiments 311 to 313, having a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3.

[0510] A crystalline morphology according to any one of embodiments 311 to 314, having a theta of 315.2 degrees (±0.2 degrees) and 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.

[0511] A crystalline morphology according to any one of embodiments 311 to 314, having a theta of 316.2 degrees (±0.2 degrees) and 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.

[0512] A crystalline morphology according to any one of embodiments 311 to 314, having a theta of 317.2 degrees (±0.2 degrees) and 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.

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

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

[0515] 320. A crystal morphology according to any one of embodiments 311 to 319, wherein the DSC thermogram has an endothermic peak with a starting temperature (±3°C) of 56°C and a maximum of 101°C.

[0516] 321. The crystal morphology according to embodiment 310, having morphology II.

[0517] 322. The crystal morphology according to embodiment 321, having substantially the XRPD pattern shown in Figure 4.

[0518] 323. The crystalline morphology according to embodiment 321 or 322, having a DSC thermogram substantially as illustrated in Figure 5.

[0519] 324. A crystalline form according to any one of embodiments 321 to 323, having a TGA thermogram substantially as illustrated in Figure 6.

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

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

[0522] A crystalline morphology according to any one of embodiments 321 to 324, having a theta of 327.2 degrees (±0.2 degrees) and 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.

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

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

[0525] 330. A crystal morphology according to any one of embodiments 321 to 329, wherein the DSC thermogram has an endothermic peak with an onset temperature (±3°C) of 47°C and a maximum of 99°C.

[0526] 331. Hexafluorophosphate of compound 2: [ka] The crystalline form.

[0527] 332. The crystal morphology according to embodiment 331, having substantially the XRPD pattern shown in Figure 7.

[0528] 333. The crystalline morphology according to embodiment 331 or 332, having a DSC thermogram substantially as illustrated in Figure 8.

[0529] 334. A crystalline form according to any one of embodiments 331 to 333, having a TGA thermogram substantially as illustrated in Figure 9.

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

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

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

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

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

[0535] 340. A crystal morphology according to any one of embodiments 331 to 339, wherein the DSC thermogram has a first endothermic peak with an initial temperature (±3°C) of 232°C and a maximum of 233°C, and a second endothermic peak with an initial temperature (±3°C) of 241°C and a maximum of 242°C.

[0536] 341.Compound 3a: [ka] The crystalline form.

[0537] 342. The crystal morphology according to embodiment 341, having substantially the XRPD pattern shown in Figure 11.

[0538] 343. The crystalline morphology according to embodiment 341 or 342, having a DSC thermogram substantially as illustrated in Figure 12.

[0539] 344. A crystalline form according to any one of embodiments 341 to 343, having a TGA thermogram substantially as illustrated in Figure 13.

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

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

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

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

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

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

[0546] 351. The crystal morphology according to Embodiment 341, characterized by having a monoclinic P21 space group and having 4 compositional units (Z) in the cell, as determined by single-crystal X-ray diffraction.

[0547] 352. The crystal morphology according to Embodiment 351, having unit cell parameters such that the space group a is approximately 7.68 Å, b is approximately 7.60 Å, c is approximately 13.72 Å, and beta is approximately 96.94°.

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

[0549] Example 1. 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) [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. During the addition of DMF, the internal temperature was controlled to below 10°C. 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)arylidene)-N-methylmethaneaminium chloride hydrochloride (2d, 24.38 g, 23.72 g (theoretical yield), 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. Regarding compound 2d: 1H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19 Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LC MS (EI) m / e 244.2 (M + (Base peak).

[0550] The crystal morphology I of compound 2d was characterized by XRPD, DSC, and TGA.

[0551] 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.

[0552] 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]

[0553] 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 shown in Figure 2.

[0554] 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 rate of 25 mL / min, and a platinum sample holder. TGA analysis of compound 2d, crystalline form I, revealed a weight loss of 8.0% below 100°C and a significant weight loss above 175°C, due to decomposition. A TGA thermogram of compound 2d, crystalline form I, is provided in Figure 3.

[0555] Example 2: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]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. During the addition of DMF, the internal temperature was controlled to below 10°C. 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 (25.44 g, 150 mmol, hydrochloride of compound 1a) was added in situ to the Vilsmeier reagent as a solid at ambient temperature, 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, 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, 47.43 g (theoretical yield), 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. Regarding compound 2d: 1 H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LC MS (EI) m / e 244.2 (M + (Base peak).

[0556] The crystalline form II of compound 2d was characterized by XRPD, DSC, and TGA.

[0557] 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.

[0558] 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]

[0559] 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.

[0560] 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 rate of 25 mL / min, and a 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.

[0561] Example 3: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-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. During the addition of DMF, the internal temperature was controlled to below 10°C. 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 situ as a solid all at once at ambient temperature to the Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, and then 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, 23.72 g (theoretical yield), 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. Regarding compound 2d: 1 H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LC MS (EI) m / e 244.2 (M + (Base peak).

[0562] Example 4: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile (Compound 1) A solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium chloride hydrochloride (compound 2d, 20.0 g, 55.8 mmol) in water (22.7 mL) was treated with 50% NaOH aqueous solution at 0-5°C until the pH reached 7-8. 3.6 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 moistened charcoal cake was washed with water (20 mL). Next, the resulting aqueous solution containing (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium chloride (compound 2c) was treated with ethanol (160 mL) and (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a, 18.91 g, 55.8 mmol, 1.0 equivalent) at ambient temperature. The resulting mixture was then stirred at ambient temperature for 12 to 24 hours. When the reaction was complete, the reaction mixture was filtered to remove the solid (L-tartaric acid). The cake was washed with ethanol (2 × 25 mL). The filtrate and washings were combined, and the combined solution was concentrated under reduced pressure at 40 to 50°C to remove most of the ethanol. Then, H2O (70 mL) and dichloromethane (DCM, 200 mL) were added to the residue. The two layers were separated, and the aqueous layer was extracted with DCM (80 mL). The combined organic extract was washed with an aqueous sodium bicarbonate solution (4% NaHCO3 aqueous solution, 112 mL) and water (2 × 100 mL). The resulting solution containing the desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile (compound 1), was concentrated under reduced pressure, and the residue (18.7 g, 17.1 g (theoretical yield)) was used in the subsequent phosphate formation reaction without further purification. The free base of compound 1 obtained by the current synthesis method is identical in all comparable aspects to the compound obtained by the previously reported synthesis method (US8,410,265B2). About compound 1: 1H NMR(DMSO-d6,400MHz)δ12.10(br.s,1H),8.78(s,1H),8.67(s,1H),8.36(s,1H),7.58(dd,1H,J=2.3,3.4Hz),6.97(dd,1H,J=1.5,3.6Hz), C 17 H 18 N6(MW,306.37),LCMS(EI)m / e 307(M + +H).

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

[0564] To a solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2, 200.0 mg, 0.582 mmol) in ethanol (EtOH, 2.0 mL), (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a, 217.2 mg, 0.64 mmol, 1.1 equivalents) was added at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours. When the reaction was complete, the reaction mixture was filtered to remove the solid (L-tartaric acid). The cake was washed with ethanol (2.0 mL). The filtrate and washing solution were combined, and the combined solution was concentrated under reduced pressure at 40-50°C to remove most of the ethanol. Next, H2O (4.0 mL) and dichloromethane (DCM, 5.0 mL) were added to the residue. The two layers were separated, and the aqueous layer was extracted with DCM (2 × 4.0 mL). The combined organic extract was washed with brine (4.0 mL) and water (4.0 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile (Compound 1, 174 mg, 178.3 mg (theoretical yield), yield 97.6%), as a yellow oil, which was identical in all comparable aspects to the compound obtained by Example 4 and the previously reported synthesis method (US8,410,265B2), and was used in the subsequent phosphate formation reaction without further purification.

[0565] Example 6: Alternative preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile (Compound 1). [ka] (E)-3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acrylaldehyde (compound 2b, 5.0 g, 26.4 mmol) slurry in DMF (70.4 mL) was mixed with (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a, 9.4 g, 27.7 mmol, 1.05 equivalents). The resulting reaction mixture was stirred at ambient temperature for 22 hours. When the reaction was complete, water (80 mL) and sodium bicarbonate (NaHCO3, 5.0 g, 59.5 mmol, 2.25 equivalents) were added, and the resulting mixture was stirred at ambient temperature for 30 minutes. The mixture was extracted with dichloromethane (DCM, 3 × 40 mL), and the combined organic extract was washed with aqueous sodium bicarbonate solution (20 mL) and water (2 × 20 mL). The solution obtained by DCM containing the crude desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile (Compound 1), was concentrated under reduced pressure, and the residue (7.88 g, 8.09 g (theoretical yield)) was used in the subsequent phosphate formation reaction without further purification. The free base of Compound 1 obtained by the current synthesis method is identical in all comparable aspects to the product obtained by the procedures listed under Examples 4-5 and by the previously reported synthesis method (US8,410,265B2). Regarding Compound 1: 1 H NMR(DMSO-d6,400MHz)δ12.10(br.s,1H),8.78(s,1H),8.67(s,1H),8.36(s,1H),7.58(dd,1H,J=2.3,3.4Hz),6.97(dd,1H,J=1.5,3.6Hz), C 17 H 18 N6(MW,306.37),LCMS(EI)m / e 307(M + +H).

[0566] Example 7: Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium chloride (chloride of compound 2) 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. During the addition of DMF, the internal temperature was controlled to below 10°C. 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 situ as a solid all at once at ambient temperature to the Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, and then 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. The wet cake was then dissolved in water (120 mL), and the pH of the resulting aqueous solution was adjusted to 7-8 by treatment with 50% sodium hydroxide aqueous solution (NaOH, 19.06 g) at 0-5°C. The neutralized aqueous solution was treated with charcoal (5.5 g) and stirred at ambient temperature for 12 hours. The char 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, ultrapure to 99.0% by HPLC area%), was used in the subsequent reaction without further treatment.

[0567] Example 8: Synthesis of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]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. During the addition of DMF, the internal temperature was controlled to below 10°C. 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 situ as a solid all at once at ambient temperature to the Vilsmeier reagent, and the resulting slurry was stirred at ambient temperature for 5–10 minutes to ensure complete mixing, and then 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, 23.5 g (theoretical yield), 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. Regarding compound 2c: 1H NMR(500MHz,DMSO-d6)δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99-7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR(DMSO-d6,125MHz)δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm;C 13 H 19 Cl2N5 (MW, 279.77 for compound 2c and 244.32 for compound 2 without anion) LC MS (EI) m / e 244.2 (M + (Base peak).

[0568] 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 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), as a white solid, which was used in subsequent reactions 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 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0569] (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 vacuum-dried to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium tetrafluoroborate (tetrafluoroborate of compound 2, 1.80 g, 3.49 g (theoretical yield), 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 tetrafluoroborate of compound 2 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0570] (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium hexafluorophosphate (hexafluorophosphate of compound 2): To 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) in water (80 mL), which was produced from 4-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene) in water (80 mL), aqueous sodium hydroxide (NaOH) was added at 0-5°C to adjust the pH of the solution to 7-8. 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 moistened 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 vacuum-dried 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, 35.81 g (theoretical yield), 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 obtain a pure product as a white crystalline solid. Regarding the 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 and 244.32 for compound 2 without anion) LCMS(EI) m / e 244.2(M + (Base peak). The crystallinity of the hexafluorophosphate of compound 2 was characterized by XRPD, DSC, and TGA.

[0571] 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 the peak data is provided in Table 3. [Table 3]

[0572] 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 the melting point, and a second endothermic peak at an onset temperature of 241.1°C and a maximum of 242.1°C, attributed to decomposition. A DSC thermogram of compound 2 hexafluorophosphate is provided in Figure 8.

[0573] Thermogravimetric Analysis (TGA): TGA was 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 rate of 25 mL / min, and platinum sample holder. TGA analysis of crystalline samples of compound 2 hexafluorophosphate revealed a significant weight loss above 250°C due to decomposition. The TGA thermogram of compound 2 hexafluorophosphate is provided in Figure 9.

[0574] (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 vacuum-dried to obtain the crude desired product, (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)alilidene)-N-methylmethaneaminium hexafluoroarsenate (hexafluoroarsenate of compound 2, 4.51 g, 4.56 g (theoretical yield), 99% yield), as a white solid, which was used in subsequent reactions without further purification. Regarding 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 the hexafluoroarsenate of compound 2 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0575] (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 vacuum-dried 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, 5.05 g (theoretical yield), yield 51.7%), as a white solid, which was used in subsequent reactions without further purification. Regarding 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 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0576] Example 10: Alternative preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)arylidene)-N-methylmethaneaminium perchlorate (perchlorate of compound 2) Method 1 [ka] Oxalyl chloride (20.0 mL, 228 mmol, 3.04 equivalents) was slowly added to DMF (107 mL, 1378 mmol, 18.4 equivalents) over 15 minutes while maintaining the internal temperature below 50°C. After addition, the resulting slurry was cooled to ambient temperature and stirred at ambient temperature for 2 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, then at 50°C for 5.5 hours. The reaction mixture was cooled to ambient temperature and the reaction was stopped with ice (60 g). The reaction mixture residue was vacuum concentrated and then dissolved in water (50 mL). Sodium perchlorate (NaClO4, 20.23 g, 165 mmol, 2.2 equivalents) was then added to the aqueous solution at ambient temperature. The resulting mixture was cooled in an ice bath, and then sodium hydroxide (NaOH, 7.5 g, 188 mmol, 2.5 equivalents) was slowly added. The solid was collected 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, 25.78 g (theoretical yield), 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 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0577] Method 2 [ka] To a solution of 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)acetic acid (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. The resulting reaction mixture was then heated to 80-90°C and stirred at 80-90°C for 30 minutes. When the reaction was complete, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was stopped by pouring it into ice (10 g). The solution was then concentrated under reduced pressure, and the resulting residue was treated with water (3 mL). The aqueous solution was neutralized to pH 7-8 with 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). Next, the combined filtrate and washing solution were 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 1 hour at 0-5°C. 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, 688 mg (theoretical yield), yield 48%, as a gray solid, which was used in subsequent reactions without further purification. Regarding the perchlorate of compound 2: 1 H NMR(400MHz,DMSO-d6)δ12.50-12.17(s,1H),8.94-8.73(s,1H),8.08-7.87(s,2H),7.77-7.57(dd C 13 H 18 ClN5O4(MW, 343.77 for perchlorate of compound 2 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0578] Method 3 [ka] To a solution of 2-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)sodium acetate (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. The resulting reaction mixture was then heated to 80-90°C and stirred at 80-90°C for 30 minutes. When the reaction was complete, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was stopped by pouring it into ice (40 g). The solution was then concentrated under reduced pressure, and the resulting residue was treated with water (10 mL). The aqueous solution was neutralized to pH 7-8 with 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). The combined filtrate and washing solution were then 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 1 hour at 0-5°C. The solid was then collected 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, 2.94 g (theoretical yield), yield 44.3%), as a grayish-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 and 244.32 for compound 2 without anion)LCMS(EI)m / e 244.2(M + (Base peak).

[0579] 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) [ka] Oxalyl chloride (12.00 ml, 137 mmol, 3.64 equivalents) was added dropwise to DMF (50 mL, 646 mmol, 17.18 equivalents) while maintaining the internal temperature below 50°C. The resulting mixture was stirred at ambient temperature for 30 minutes. 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 5.00 g, 37.6 mmol) was added all at once as a solid, and the resulting reaction mixture was stirred at room temperature for 3 days and at 50°C for 4 hours. Once the reaction was complete, the reaction mixture was cooled to room temperature and stopped with ice (30 g). Sodium hydroxide (NaOH, 16.1 g, 403 mmol, 10.72 equivalents) was added to the reaction mixture that had been stopped, 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 a batch of ice, and then concentrated HCl solution was added to adjust the pH to 5-6. The mixture was gradually warmed to ambient temperature and stirred at ambient temperature for 2 hours. The solid was collected 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, 7.113 g (theoretical yield), yield 89%), as a gray powder, which was used directly in subsequent reactions without further purification. Regarding compound 2b: 1H NMR(400MHz,DMSO-d6)δ13.74(br s,2H),9.52(s,2H),8.73(s,1H),7.53(dd,J=3.4,2.3Hz,1H),7.46(dd,J=3.5,1.7Hz,1H)ppm;C9H7N3O2(MW,189.17)LCMS(EI)m / e 190.1(M + (Base peak).

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

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

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

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

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

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

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

[0587] The crystallinity of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a) was characterized by XRPD, DSC, and TGA. X-ray powder diffraction (XRPD): X-ray powder diffraction (XRPD) 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.

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

[0589] 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 (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (compound 3a) revealed one endothermic peak with an onset temperature of 55.3°C and a maximum of 79.1°C, and a second exothermic peak with an onset temperature of 121.0°C and a maximum of 123.5°C, attributed to dehydration. A DSC thermogram of a crystalline sample of compound 3a is provided in Figure 12.

[0590] Thermogravimetric Analysis (TGA): TGAs 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 rate of 25 mL / min, and a platinum sample holder. TGA analysis of a crystalline sample of (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dehydrated product (compound 3a) revealed a 10.3% weight loss below 100°C, attributed to dehydration decomposition above 120°C. A TGA thermogram of the crystalline sample of compound 3a is provided in Figure 13.

[0591] Example 13: Preparation of phosphate of compound 1 Crude (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)pyrazole-1-yl]propionitrile phosphate (phosphate of crude compound 1): [ka] The crude (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)pyrazole-1-yl]propionitrile (free base of compound 1, 18.7 g, 17.1 g (theoretical yield), 55.8 mmol) solution in dichloromethane (DCM, 294 mL) and isopropanol (IPA, 12.8 mL), prepared in the previous step, was heated to 36°C, and then a solution of phosphoric acid in isopropanol (IPA, 12.7 mL) (85% H3PO4 aqueous solution, 7.40 g, 64.2 mmol, 1.15 equivalents) was added at 36°C. A precipitate formed almost immediately. The resulting mixture was then heated at 36°C for 1 hour, then gradually cooled to ambient temperature, and stirred at room temperature for 1 hour. The solid was collected by filtration, washed with DCM (2 × 50.8 mL) and n-heptane (22.6 mL), and dried to constant weight in a vacuum oven at 40-45°C to obtain (3R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)pyrazole-1-yl]propionitrile phosphate (23.04 g, 22.56 g (theoretical yield), 102% yield of crude compound 1) as a white to grayish-white crystalline powder containing some residual phosphate, which was then purified in the subsequent step by recrystallization in a mixture of methanol (MeOH), isopropanol (IPA), and n-heptane. Regarding the phosphate of compound 1: 1 H NMR(DMSO-d6,500MHz)d ppm 12.10(s,1H),8.78(s,1H),8.68(s,1H),8.36(s 1H),7.58(dd,1H,J=1.9,3.5Hz),6.97(d,1H,J=3.6Hz),4.52(td,1H,J=3.9,9.7Hz),3.25(dd,1H,J=9.8,17.2Hz),3.1 6(dd,1H,J=4.0,17.0Hz),2.41,(m,1H),1.79(m,1H),1.59(m,1H),1.51(m,2H),1.42(m,1H),1.29(m,2H),1.18(m,1H); 13C NMR(DMSO-d6,125MHz)d ppm 152.1,150.8,149.8,139.2,131.0,126.8,120.4,118.1,112.8,99.8,62.5,44.3,29.1,29.0,24.9,24.3,22.5;C 17 H 18 N6 (MW, free base 306.37) LC-MS (EI) m / e 307 (M + +H, base peak), 329.1(M + +Na).

[0592] Purification of the phosphate of crude compound 1: [ka] (3R)-Cyclopentyl-3-[4-(7H-Pyrrolo[2,3-d]pyrimidine-4-yl)pyrazole-1-yl]propionitrile phosphate (phosphate of compound 1) A suspension of crude compound 1 phosphate (40.0 g, 100 mmol) in methanol (MeOH, 520 mL) is heated to 50-60°C to produce a homogeneous solution. The solution is polish-filtered at 50-60°C. Methanol (287 mL) is partially distilled at atmospheric pressure at 60-70°C, and then IPA (320 mL) is added to the mixture at the same temperature to initiate crystallization of the final product (compound 1 phosphate). Next, n-heptane (1000 mL) is added to the mixture at 60-70°C, and distillation is continued at atmospheric pressure at 60-70°C. Once distillation is complete, the mixture is stirred at 60-70°C for 10-60 minutes, then gradually cooled to room temperature and stirred at room temperature for 3-6 hours. The solid was collected by filtration, sequentially washed with a mixture of IPA and n-heptane, and then with n-heptane, and vacuum-dried at 40-50°C to obtain the final product (phosphate of compound 1, 39.4 g, 98.5%) as a white crystalline powder. For phosphate of compound 1: mp. 197.6°C; 1H NMR(DMSO-d6,500MHz)δ ppm 12.10(s,1H),8.78(s,1H),8.68(s,1H),8.36(s1H),7.58(dd,1H,J=1.9,3.5Hz),6.97(d,1H,J=3.6Hz),4.52(td,1H,J=3.9,9.7Hz),3.25(dd, 1H,J=9.8,17.2Hz),3.16(dd,1H,J=4.0,17.0Hz),2.41,(m,1H),1.79(m ,1H),1.59(m,1H),1.51(m,2H),1.42(m,1H),1.29(m,2H),1.18(m,1H); 13 C NMR(DMSO-d6,125MHz)δ ppm 152.1,150.8,149.8,139.2,131.0,126.8,120.4,118.1,112.8,99.8,62.5,44.3,29.1,29.0,24.9,24.3,22.5;C 17 H 18 N6 (MW, free base 306.37) LC-MS (EI) m / e 307 (M + +H, base peak), 329.1(M + +Na).

[0593] Example 14: Preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) [ka] Step 1. 4,6-Dichloropyrimidine-5-carbaldehyde (Compound 9a): A 5 L four-necked flask equipped with a mechanical stirrer, addition funnel, condenser, thermocouple, and N2 sweep for 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. Then, 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 approximately 0.5 hours, crystallization occurred and the reaction temperature increased from 0 to 10°C. The addition was stopped and the mixture was cooled again to approximately 2°C. The remaining DMF was added over 2.5 hours at below 8°C. The suspension became very concentrated and difficult to stir. When 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 in small amounts 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 increased to approximately 12°C over 0.5 hours. The remaining 4,6-dihydroxypyrimidine was added in small amounts over 0.25 hours, and the reaction temperature increased from 12°C to 27°C. The reaction temperature was maintained at 25-27°C by 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 approximately 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 increase to approximately 63°C, remained at this temperature for several minutes, and then decreased. When heating of the mixture was resumed, a mild reflux (approximately 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 dark in color. After about 0.5 hours, the solution developed into a clear brown color, and the reflux temperature slowly increased to 115°C over 1.25 hours. After a total of 2.5 hours under 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 remaining thick brown oil was very slowly poured into cold H2O (5 L) using a 20 L separatory funnel, with ice added as needed to maintain the aqueous mixture at 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 NaHCO3 aqueous solution (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, 395 g (theoretical yield), 68.4%) as a yellow-orange solid. Twenty g of this crude substance was purified by Kugelrohr 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. Regarding 4,6-dichloropyrimidine-5-carbaldehyde: 1 H NMR(300MHz,CDCl3)δ10.46(s,1H),8.89(s,1H)ppm.

[0594] Step 2.4-Amino-6-chloropyrimidine-5-carbaldehyde (compound 10a): A solution of 7 M 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 slowly increased from 20°C 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 collected by filtration. The solid was washed with ELISA (1 L). The filtrate was concentrated under reduced pressure, the solid was triturated 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, then stirring in THF (750 mL) for 1 hour, and filtering. Both filtrates in HCl and THF were concentrated under reduced pressure, and the resulting solid was triturated with toluene and n-heptane (2:1 v / v, 450 mL), filtered, and dried to 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, 146.5 g (theoretical yield)) was 78.6%. Regarding 4-amino-6-chloropyrimidine-5-carbaldehyde: 1 HNMR(300MHz,DMSO-d6)δ10.23(s,1H),8.71(bs,1H),8.55(bs,1H),8.39(s,1H)ppm;C5H4ClN3O(MW,157.56),LCMS(EI)m / e 158(M + +H).

[0595] Step 3. 6-Chloro-5-(2-methoxyvinyl)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 resulting mixture, a deep reddish-orange color, was stirred at -2 to -3°C for 1 hour. Then, 4-amino-6-chloropyrimidine-5-carbaldehyde (compound 10a, 115.2 g, 0.7338 mol, 1.0 equivalent) was added to the reaction mixture in solid form in small amounts, after rinsing the container and funnel with THF (200 mL). During the addition, the reaction temperature increased from -3°C to 13°C and turned brown. When the reaction temperature dropped to 10°C, the cooling bath was removed, and the reaction mixture was heated to ambient temperature and stirred at ambient temperature for 42 hours. The reaction mixture was cooled to -2°C, and the reaction was stopped by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between 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 with Na2SO4, and stirred with charcoal (10 g) and silica gel (10 g) for 1 hour. The mixture was filtered through Celite, washing the Celite pad with HCl (1 L). The filtrate was concentrated, and the residual HCl was co-evaporated with n-heptane (500 mL). The resulting brownish solid was evacuated under high vacuum for 2 hours to obtain crude 6-chloro-5-(2-methoxyvinyl)pyrimidine-4-ylamine (compound 11a, 72.3 g, 136.2 g (theoretical yield), 53.1%). The crude compound 11a, the desired product, was used in the subsequent reaction without further purification. A sample of the crude compound 11a (2.3 g) was purified by silica gel column chromatography while eluting with 0% to 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.Regarding 6-chloro-5-(2-methoxyvinyl)pyrimidine-4-ylamine: 1 ¹H NMR (300MHz, DMSO-d6) 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 and 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).

[0596] 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 with 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 for 1 hour. The mixture was then 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, 58.1 g (theoretical yield), 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 left at ambient temperature overnight. The suspension was then cooled to 0-5°C for 2 hours, and the solid was collected by filtration. The solid was dried to obtain pure 4-chloro-7H-[pyrrolo[2,3-d]pyrimidine (compound 12a, 54.5 g, 58.1 g (theoretical yield), 94%) as yellowish-brown crystals. Regarding compound 12a: 1 H NMR(400MHz,DMSO-d6)δ12.58(bs,1H),8.58(s,1H),7.69(d,1H,J=3.5Hz),6.59(d,1H,J=3.5Hz)ppm;LCMS(EI)m / e 154 / 156(M + +H).

[0597] Example 15: Alternative preparation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) [ka] Step 1. Ethyl 2-cyano-4,4-diethoxybutanoate (compound 14a): A mixture of ethyl cyanoacetate (compound 13a, 182 kg, 1609 mol) and DMSO (325 kg) is mixed with sodium tert-amyloxide ( t AmONa (158.8 kg) was added in small amounts at 5°C. 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, and then 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, and then 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, 152.5 kg (theoretical yield), 96.1%) as a yellow to brown oil, which was used directly in subsequent reactions without further purification.

[0598] Step 2.7H-pyrrolo[2,3-d]pyrimidine-4-ol (compound 15a): A solution of 18% sodium ethoxide (EtONa) in ethanol (1558 kg) and formamidine acetate (153.5 kg, 1474.4 mol) were added to the reactor. 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 an aqueous solution of 21% ammonium chloride (NH4Cl, 783 kg) 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 filtered. The cake was again slurryed with water (493 kg) and filtered. The solid was suspended in water (474 ​​kg) and concentrated hydrochloric acid (HCl, 89.2 kg) was added. The mixture was stirred at 20°C for 1 hour, then heated to 30°C until the cyclization reaction was complete. The mixture was then cooled to 5°C and an aqueous solution of ammonium hydroxide (NH4OH, 72 kg) was added. After the addition, the mixture was stirred at 5°C for 1 hour and then filtered. The wet cake was washed with water and dried in a vacuum oven to obtain 7H-pyrrolo[2,3-d]pyrimidine-4-ol (compound 15a, 99.6 kg, 159 kg (theoretical yield), 62.6%) as a grayish-white to yellow solid, which was used in subsequent reactions without further purification.

[0599] 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. Next, 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. Next, 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 filtered. The filtrate was concentrated into a thick slurry, cooled to 0°C, and filtered. The cake was dried under reduced pressure to obtain pure 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a, 71.9 kg, 113.2 kg (theoretical yield), 63.5%) as yellow to brown crystals. The 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (compound 12a) produced by this synthesis method is identical in all comparable aspects to the compound obtained by Example 14. 1 H NMR(400MHz,DMSO-d6)δ12.58(bs,1H),8.58(s,1H),7.69(d,1H,J=3.5Hz),6.59(d,1H,J=3.5Hz)ppm;LCMS(EI)m / e 154 / 156(M + +H).

[0600] Example 16. Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a) [ka] A suspension of sodium hydride (NaH, 60% suspension in mineral oil, 309 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 below 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 the reaction mixture to stop the reaction, and the internal temperature was controlled to below 10°C during the stopping treatment. Methyl tert-butyl ether (MTBE, 5.0 L) was added to the stopped 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 an aqueous solution of 26-28% ammonium hydroxide (NH4OH, 1.0 L), and the resulting mixture was stirred at 15-40°C for 16 hours. When 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 collected 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, 849.6 g (theoretical yield), 98.9%), as a brown powder, which was purified by recrystallization in a mixture of ethyl acetate and n-heptane.

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

[0602] Example 17. Alternative preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a) [ka] Step 1. 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a): A 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 heated to room temperature and stirred at ambient temperature for 3 hours. The in situ-formed 2-acetyl-4,4-dimethoxybutanenitrile was then 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 into a residue under reduced pressure. 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). The 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 into the residue, which was then triturated with THF (170 mL, 2 × 150 mL).The filtrates were combined and concentrated into a residue, which was dissolved in DCM (30 mL). The residue was then purified by column chromatography using silica gel (SiO2, 120 g) while eluting with 0% to 100% siRNA in the DCM to obtain the desired product, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 1a, 5.1 g, 10.25 g (theoretical yield), 49.8% in 3 steps), as a grayish-white crystalline solid, which is identical in all comparable aspects to the compound obtained in Example 16.

[0603] Step 2. 2-Acetyl-4,4-dimethoxybutanamide (compound 20a): A solution of 3-oxobutanamide (compound 19a, 5.0 g, 49.5 mmol) in DMF (15 mL) was treated with cesium carbonate (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 for 5-8 hours. The reaction mixture was cooled to ambient temperature, and then stopped with water (20 mL). The stopped reaction mixture was then 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, 9.37 g (theoretical yield), 61.9%) as a concentrated oil containing some residual DMF. Regarding 2-acetyl-4,4-dimethoxybutanamide: 1 C8H 15 NO4(MW,189.21),LCMS(EI)m / e 190.2(M + +H).

[0604] Step 3. 2-Acetyl-4,4-dimethoxybutanenitrile (Compound 17a): A solution of 2-acetyl-4,4-dimethoxybutanamide (compound 20a, 1.0 g, 4.23 mmol) in DMF (4 mL) was treated with cyanuric acid chloride (compound 21a, 0.39 g, 2.11 mmol, 0.5 equivalents). The resulting reaction mixture was stirred at ambient temperature for 1 hour. Once the reaction was complete, the reaction mixture was stopped with water (10 mL), and the stopped 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, 724 mg (theoretical yield), 38.7%) as a concentrated oil. Regarding 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 -OH group of the enol form), 4.38 (m, 1H), 3.25 (m, 6H for the two OMe groups and 1 / 2H for the -CH- group of the ketone form), 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 16 described above.

[0605] Example 18. Preparation of 4-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl) hydrochloride (hydrochloride of compound 1a) [ka] Under nitrogen, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (compound 22a, 200 g, 1.064 mol) and THF (1.2 L) were added to the reactor. After cooling the contents of the reactor to below -5°C, 60% NaH in mineral oil (51 g, 1.28 mol, 1.2 equivalents) was added in small amounts. 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, 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 coupling reaction was indicated as complete by HPLC IPC. Subsequently, the reaction mixture was 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 placed 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, 300 g), as an oily residue, which was used directly in subsequent reactions without further purification.

[0606] A mixture of crude 7-(tert-butyldimethylsilyl)-2-chloro-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (compound 22a, 300 g, 1.064 mol) and 5% palladium-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 cake 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, 180.5 g (theoretical yield), 84% yield in 2 steps) as a pale yellow crystalline powder. Regarding 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 (base peak).

[0607] Example 19.2 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 to be 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. When the reaction was complete, the reaction mixture was filtered, the solid was washed with acetone, and discarded. The filtrate was then concentrated under reduced pressure, and the residue was treated with methyl tert-butyl ether (MTBE, 180 mL) and n-heptane (180 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with n-heptane (180 mL), and dried to constant weight in a vacuum oven to obtain the desired product, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (compound 24a, 32.1 g, 36.0 g (theoretical yield), yield 89.2%), as a grayish-white powder, which was used in subsequent reactions without further purification. Regarding 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine: 1 H NMR(DMSO-d6,400MHz)δ8.78(s,1H),8.10(d,2H),7.79(d,1H),7.34(d,2H),6.72(d,1H),2.41(s,3H)ppm; 13 H 10 ClN3O2S(MW,307.75),LCMS(EI)m / e 308.1(M + +H).

[0608] Step 2.2-(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. The resulting reaction mixture was then heated to 50-60°C and stirred at 50-60°C for 2-3 hours. When the reaction was complete, the reaction mixture was cooled to ambient temperature and then treated with water (H2O, 80 mL). The reaction-terminating reaction mixture was then stirred at ambient temperature for 1 hour, followed by 1 hour at 0-5°C. The solid was collected by filtration, washed with water (50 mL), followed by n-heptane (50 mL), and dried to constant weight in a vacuum oven at 40°C to obtain the desired product, 2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)malonate diethyl (compound 25a, 6.2 g, 9.81 g (theoretical yield), yield 63.2%), as a grayish-white powder, which was used in subsequent reactions without further purification. Regarding 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).

[0609] 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 with a solution of 21% sodium ethoxide (NaOEt, 21% by weight, 0.30 g, 0.927 mmol, 0.10 equivalents) in ethanol at ambient temperature, and the resulting reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was stopped 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, 3.33 g (theoretical yield), yield 62.6%), as a grayish-white powder, which was used in subsequent reactions without further purification. Regarding 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).

[0610] 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 stopped with a 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, 1.9 g (theoretical yield), yield 68.3%), as a grayish-white powder, which was used in subsequent reactions without further purification. Regarding 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).

[0611] 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 with an aqueous solution of 6N sodium hydroxide (6N NaOH, 1.462 mL, 8.77 mmol, 1.5 equivalents) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours. The solid was collected by filtration, and the isolated solid was suspended in methanol (MeOH, 4.0 mL). Then, acetone (15 mL) was added to the resulting suspension, and the mixture was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with acetone (2 × 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, 1.164 g (theoretical yield), yield 94.5%), as a grayish-white powder, which was used in subsequent reactions without further purification. Regarding 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).

[0612] 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 with an aqueous solution of 6N sodium hydroxide (6N NaOH, 1.462 mL, 8.77 mmol, 1.5 equivalents) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then treated with an aqueous solution of 1N hydrochloric acid (1N HCl, 9.0 mL) and concentrated under reduced pressure. The residue was then 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, 1.04 g (theoretical yield), yield 79.8%), as a grayish-white solid, which was used in subsequent reactions without further purification. Regarding 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).

[0613] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references, including all patents, patent applications, and publications cited herein, are incorporated herein by reference in their entirety.

Claims

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

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

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

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

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

6. The compound of formula 3 or the salt thereof is formula 3a: 【Transformation 5】 The method according to claim 3, having the following characteristics.

7. The L-tartrate in formula 3 above is Compound 7a: 【Transformation 6】 The method according to any one of claims 5 to 6, which is prepared by a method comprising reacting with L-tartaric acid.

8. The compound of formula 7a is The compound of formula 6a: 【Transformation 7】 The method according to claim 7, which is prepared by a method comprising reacting with hydrazine.

9. X － is Cl － , BF ４ － , PF ６ － , AsF ６ － , SbF ６ － , and ClO ４ － The method according to any one of claims 2 to 8, selected from

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

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

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

13. The salt of formula 2a or the compound of formula 2b, Compound of formula 1a: 【Transformation 8】 The method according to any one of claims 2 to 12, further comprising reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

14. The method according to claim 13, wherein the Vilsmeyer reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent.

15. The method according to claim 13, wherein the chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, and triphosgene.

16. The method according to claim 13, wherein the chlorinating agent is oxalyl chloride.

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

18. Salt of equation 2d: 【Chemistry 10】 When reacted with a base, the salt of formula 2c is obtained: 【Chemistry 11】 The method according to claim 17, further comprising forming a

19. The reaction with the aforementioned Vilsmeyer reagent yields the salt of formula 2c: 【Chemistry 12】 A method according to any one of claims 13 to 16, for generating a

20. Salt of formula 2c above: 【Chemistry 13】 Formula M ＋ X － Reacting with the salt of the above formula 2a － The further comprising forming a salt of, in the formula, M ＋ However, it is a counter-cation, X － However, Cl － Other anti-anion types, The method according to any one of claims 18 to 19.

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

22. The compound of formula 1a or the salt thereof, Compound of formula 1aP: 【Chemistry 14】 Prepared by a method that includes deprotecting, In the formula, P １ The method according to any one of claims 13 to 21, wherein the protecting group is an amino protecting group.

23. P １ However, (R １ ) ３ Selected from Si, in the formula, R １ However, C １－６ The method according to claim 22, wherein the alkyl group is alkyl.

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

25. The compound of formula 1aP is, Compound of formula 2P: 【Chemistry 15】 It is prepared by a method that includes reacting it with MeMgBr in the presence of a Grignard catalyst, In the formula, P １ However, the amino protecting group is The method according to any one of claims 22 to 24.

26. The compound of formula 2P is, Compound of formula 12a: 【Chemistry 16】 The method according to claim 25, prepared by a method comprising protecting and forming the compound of formula 2P.

27. The protection described above involves the compound of formula 12a being an alkali metal hydride and P １ The method according to claim 26, comprising reacting with Y, wherein Y is a halo.

28. P １ -Y is (R １ ) ３ Si - Y, where Y is halo and R １ However, C １－６ The method according to claim 27, wherein the alkyl group is used.

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

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

31. The compound of formula 10a or a salt thereof Compound of formula 9a: 【Chemistry 19】 The method according to claim 30, which is prepared by a method comprising reacting with ammonia.

32. The compound of formula 9a is, Compound of formula 8a: 【Chemistry 20】 The method according to claim 31, wherein the solution is prepared by a method comprising reacting the solution with a Vilsmeyer reagent formed from dimethylformamide.

33. The method according to claim 32, wherein the Vilsmeyer reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent.

34. The compound of formula 12a is, Compound of formula 15a: 【Chemistry 21】 The method according to any one of claims 26 to 28, which is prepared by a method comprising reacting with a chlorinating agent.

35. The compound of formula 15a is (i) Compound of formula 14a: 【Chemistry 22】 When reacted with formamidine acetate and alkali metal hydroxide, the compound of formula 14aa is obtained: 【Chemistry 23】 To cause, (ii) Reacting the compound of formula 14aa with a strong acid, The method according to claim 34, which is prepared by a method comprising:

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

37. The compound of formula 1a or the salt thereof, Compound of formula 23P: 【Chemistry 25】 Prepared by a method including the reduction of In the formula, P ２ The method according to any one of claims 13 to 21, wherein the protecting group is an amino protecting group.

38. The method according to claim 37, wherein the reduction of the compound of formula 23P is carried out by a method comprising reacting the compound of formula 23P with hydrogen gas in the presence of a catalyst.

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

40. The compound of formula 22P is, Compound of formula 22a: 【Chemistry 27】 The method according to claim 39, which is prepared by a method comprising protecting and forming the compound of formula 22P.

41. The protection described above involves the compound of formula 22a being an alkali metal hydride and P ２ The method according to claim 40, comprising reacting with Y, wherein Y is a halo.

42. P ２ However, (R １ ) ３ It is Si, and in the formula, R １ However, C １－６ The method according to claim 41, wherein the alkyl group is used.

43. The compound of formula 1a or the salt thereof, Compound of formula 18a: 【Chemistry 28】 The method according to any one of claims 13 to 21, which is prepared by a method comprising reacting with an acid to form a compound of formula 1a.

44. The compound of formula 18a or a salt thereof, Compound of formula 17a: 【Chemistry 29】 The method according to claim 43, wherein the compound is prepared by reacting with formamidine acetate and triethyl orthoformate to form the compound of formula 17a.

45. The compound of formula 17a or a salt thereof, Compound of formula 20a: 【Transformation 30】 Compound of formula 21a: 【Chemistry 31】 The method according to claim 44, which is prepared by a method comprising reacting with to form the compound of formula 17a.

46. The compound of formula 20a or a salt thereof Compound of formula 19a: 【Chemistry 32】 The method according to claim 45, wherein the compound is prepared by a method comprising reacting with bromo-1,1-dimethoxyethane and a base to form the compound of formula 20a.

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

48. The compound of formula 17a or a salt thereof, Compound of formula 16a: 【Transformation 33】 The method according to claim 44, wherein the compound is prepared by a method comprising reacting with ethyl acetate and a base to form the compound of formula 17a.

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

50. The salt of formula 2a or the compound of formula 2b, Compound of formula 5a: 【Transformation 34】 The method according to any one of claims 2 to 12, further comprising reacting a salt thereof with a Vilsmeyer reagent formed from dimethylformamide.

51. The method according to claim 50, wherein the Vilsmeyer reagent is prepared by a method comprising reacting dimethylformamide with a chlorinating agent.

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

53. The method according to claim 51, wherein the chlorinating agent is oxalyl chloride.

54. The product of the reaction with the Vilsmeyer reagent is given by formula 2d: 【Chemistry 35】 The method according to any one of claims 50 to 53, comprising:

55. Salt of the above formula 2d: 【Transformation 36】 When reacted with a base, the salt of formula 2c is obtained: 【Chemistry 37】 The method according to claim 54, further comprising forming a

56. The reaction with the aforementioned Vilsmeyer reagent yields the salt of formula 2c: 【Transformation 38】 The method according to any one of claims 50 to 53, for generating a

57. Salt of formula 2c above: 【Chemistry 39】 Formula M ＋ X － Reacting with the salt of the above formula 2a － The further comprising forming a salt of, in the formula, M ＋ However, it is a counter-cation, X － However, Cl － Other anti-anion types, The method according to any one of claims 55 to 56.

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

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

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

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

62. The compound of formula 27a is Compound of formula 26P: 【Chemistry 41】 Prepared by a method including the reaction of a strong acid, in which P １ The method according to any one of claims 59 to 61, wherein the protecting group is an amino protecting group.

63. P １ The method according to claim 62, wherein the substance is p-toluenesulfonyl.

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

65. The compound of formula 25P is, Compound of formula 2P: 【Chemistry 43】 It is prepared by a method comprising reacting diethyl malonate and a base, wherein P １ The method according to claim 64, wherein the protecting group is an amino protecting group.

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

67. The method according to claim 66, wherein the ruxolitinibulinate is prepared by a method comprising reacting the ruxolitinib with phosphoric acid.

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

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

70. The salt of formula 2c is the salt of formula 2d: 【Chemistry 47】 The method according to claim 69, which is prepared by a method comprising reacting with a base to form a salt of formula 2c.

71. The salt of the above formula 2d is (a) Compound of formula 2P: 【Chemistry 48】 The compound of formula 1aP is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: 【Chemistry 49】 To form, (b) Deprotect the compound of formula 1aP to obtain the compound of formula 1a: [Transformation 50] or to form a salt thereof, (c) Reacting the compound of formula 1a or its salt with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, Prepared by a method including, In the formula, P １ The method according to claim 70, wherein the protecting group is an amino protecting group.

72. The salt of the above formula 2d is (a) Compound of formula 22P: 【Chemistry 51】 The compound of formula 23P is obtained by reacting it with MeMgBr in the presence of a Grignard catalyst: 【Chemistry 52】 To form, (b) The compound of formula 23P is reduced to the compound of formula 1a: 【Chemistry 53】 or to form a salt thereof, (c) Reacting the compound of formula 1a or its salt with a Vilsmeyer reagent and a chlorinating agent formed from dimethylformamide to form a salt of formula 2d, Prepared by a method including, In the formula, P ２ The method according to claim 70, wherein the protecting group is an amino protecting group.

73. The salt of formula 3a is (a) Compound of formula 6a: 【Chemistry 54】 When reacted with hydrazine, the compound of formula 7a is obtained: 【Transformation 55】 To form, (b) Reacting the compound of formula 6a with L-tartaric acid to form the salt of formula 3a, The method according to claims 69 to 72, which is prepared by a method comprising:

74. (a) 【Transformation 56】 Or the salt, or (b) 【Chemistry 57】 or (c) 【Transformation 58】 or (d) 【Chemistry 59】 Or the salt, or (e) 【Transformation 60】 Or the salt, or (f) 【Chemistry 61】 Or the salt, or (g) 【Transformation 62】 Or the salt, or (h) 【Transformation 63】 Or the salt, or (i) 【Chemistry 64】 (In the formula, X － Cl － (Other than the opposing anion), or (j) 【Transformation 65】 or (k) 【Chemical Formula 66】 or (l) 【Transformation 67】 or (m) 【Transformation 68】 or (n) 【Transformation 69】 or (o) 【Transformation 70】 A compound or salt selected from the following.

75. A salt of formula 2d, selected from form I and form II: 【Chemistry 71】 The crystalline form.

76. Salt of formula 3a: 【Chemistry 72】 The crystalline form.

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