Process for preparing aficamten

Abstract

This article provides a method for preparing (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methamide, its intermediates, and salts thereof.

Description

Technical Field

[0001] This article provides a method for preparing (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methamide, its intermediates, and salts thereof. Prior Technology

[0002] Cardiac sarcomeres are composed of a network of contractile and structural proteins that regulate cardiac function. Components of the cardiac sarcomere serve as targets for the treatment of various cardiac diseases and disorders, such as by increasing contractility or promoting complete relaxation to regulate systolic and diastolic functions, respectively. The strength and velocity of myocardial contraction are major determinants of organ function and are regulated by the periodic interactions of actin and myosin. Regulation of actin and myosin binding is determined by a network of myofilament regulatory proteins and intracellular Ca²⁺ levels. The troponin complex and tropomyosin are filamentous proteins that control actin binding sites and are essential for regulating the availability of light chains, while myosin-binding protein C regulates the position and mechanical properties of myosin.

[0003] Cardiac sarcomere abnormalities have been identified as a driving force behind various heart diseases and disorders, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomere proteins lead to disease by causing the myocardium to contract "too much" or "too little." Regulators of cardiac sarcomere function can be used to rebalance contractility and halt or reverse disease progression.

[0004] Current medications targeting cardiac sarcomas, such as cardiotonics (drugs that increase cardiac contractility), have poor selectivity for cardiac tissue, leading to recognized adverse reactions that limit their use. These adverse reactions include cell damage due to increased energy expenditure, exacerbation of diastolic abnormalities, and potential arrhythmogenic side effects, possibly caused by increased concentrations of cytosolic solutes Ca++ and circulating AMP in the heart, which may be inotropically stimulated by cardiotonics. Given the limitations of current medications, new approaches are needed to improve cardiac function in HCM and HFpEF.

[0005] U.S. Patent No. 10,836,755 discloses (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methamide, a selective cardiac myosin allosite inhibitor with minimal effect on smooth muscle myosin. The benefits of this compound include a broader therapeutic index, less effect on diastole, better pharmacokinetics, and improved safety, thus offering potential treatment for heart diseases and disorders.

[0006] An improved method is needed to prepare such compounds at low cost and with high overall yield and purity. Summary of the Invention

[0007] In one state sample, this paper provides a method for preparing a compound of formula (1) or a salt thereof: (1), It contains (i) Compound of formula (7) (7), Or its salt is converted into a compound of formula (6) (6), or its salt; (ii) Convert the compound of formula (6) or its salt into the compound of formula (5). (5), or its salt; and (iii) Converting the compound of formula (5) or a salt thereof into the compound of formula (1) or a salt thereof. In some embodiments, converting the compound of formula (7) or a salt thereof into the compound of formula (6) or a salt thereof comprises reacting the compound of formula (7) with (R)-tert-butanesulfinylamine. In some embodiments, the reaction of the compound of formula (7) with (R)-tert-butanesulfinylamine is carried out in the presence of a Lewis acid. In some embodiments, the reaction of the compound of formula (7) with (R)-tert-butanesulfinylamine is carried out in the presence of a water scavenger. In some embodiments, the reaction of the compound of formula (7) with (R)-tert-butanesulfinylamine is carried out in the presence of titanium ethoxide. In some embodiments, the reaction of the compound of formula (7) with (R)-tert-butanesulfinylamine is carried out in the presence of toluene at a temperature between about 75°C and about 85°C.

[0008] In some embodiments, converting a compound of formula (6) or a salt thereof into a compound of formula (5) or a salt thereof comprises reacting a compound of formula (6) with a reducing agent. In some embodiments, the reaction of a compound of formula (6) with a reducing agent is carried out in the presence of tetrahydrofuran at a temperature between about -15°C and about -5°C. In some embodiments, the reducing agent is sodium borohydride. In some embodiments, the compound of formula (6) is used directly without post-treatment or purification.

[0009] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) or a salt thereof includes converting a compound of formula (5) or a salt thereof into a compound of formula (4) or a salt thereof. (4) In some embodiments, the conversion of a compound of formula (5) or a salt thereof to a compound of formula (4) or a salt thereof comprises hydrolyzing a sulfinamide of compound (5) or a salt thereof. In some embodiments, the hydrolysis of a sulfinamide of compound (5) or a salt thereof is carried out in the presence of an aqueous solution of an acid. In some embodiments, the salt of compound (4) is (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride. In some embodiments, the salt of compound (4) is (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile 4-methylbenzenesulfonate. In some embodiments, the method further comprises obtaining compound (4) by reacting a salt of compound (4) with a base.

[0010] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) further comprises converting a compound of formula (4) or a salt thereof into a compound of formula (3) or a salt thereof. (3) In some embodiments, converting a compound of formula (4) or a salt thereof into a compound of formula (3) or a salt thereof comprises: (i) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and (ii) reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid with a compound of formula (4) or a salt thereof to form a compound of formula (3) or a salt thereof. In some embodiments, the carboxylic acid activator is oxalic acid chlorine. In some embodiments, the carboxylic acid activator comprises a carbodiimide reagent. In some embodiments, the carboxylic acid activator comprises a carbodiimide reagent and hydroxybenzotriazole.

[0011] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) or a salt thereof further comprises converting a compound of formula (3) or a salt thereof into a compound of formula (2) or a salt thereof. (2) In some embodiments, converting a compound of formula (3) or a salt thereof into a compound of formula (2) or a salt thereof comprises reacting hydroxylamine with a compound of formula (3) or a salt thereof. In some embodiments, the reaction of a compound of formula (3) or a salt thereof with hydroxylamine is carried out at a temperature of 25°C or lower. In some embodiments, the reaction of a compound of formula (3) or a salt thereof with hydroxylamine is carried out in the presence of N-methylpyrrolidone.

[0012] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) further comprises converting a compound of formula (2) or a salt thereof into a compound of formula (1) or a salt thereof. In some embodiments, converting a compound of formula (2) or a salt thereof into a compound of formula (1) or a salt thereof comprises: (i) reacting propionic acid with a second carboxylic acid activator to form activated propionic acid, and (ii) reacting the activated propionic acid with a compound of formula (2) or a salt thereof. In some embodiments, the second carboxylic acid activator is carbonyl diimidazole.

[0013] In another embodiment, a method for obtaining a compound of formula (4) or a salt thereof is provided, which is achieved by taking a compound of formula (5): (5), Or its salt is converted into a compound of formula (4) or its salt.

[0014] In some embodiments, the method of obtaining the compound of formula (4) further comprises reacting a reducing agent with the compound of formula (6): (6), The compound of formula (5) or its salt reacts with its salt to form a compound of formula (5) or its salt, thereby obtaining a compound of formula (5) or its salt.

[0015] In some embodiments, the reducing agent is a borohydride reducing agent.

[0016] In some embodiments, the method for obtaining the compound of formula (4) further comprises reacting (R)-tert-butanesulfinamide with the compound of formula (7): (7), To obtain a compound of formula (6) or a salt thereof by forming a compound of formula (6) or a salt thereof. Implementation

[0017] Cross-referencing of related applications

[0018] This application claims priority to U.S. Provisional Application No. 63 / 203,888, filed August 3, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes. definition

[0019] As used herein and unless the context otherwise indicates or implies, the terms used herein have the following meanings as defined. Unless otherwise prohibited or implied (e.g., by including mutually exclusive elements or options), the term "an" means one or more (types) in those definitions and throughout the specification, and the term "or" means and / or where the context permits. Thus, as used in the specification and the appended claims, the singular forms "an," "a," and "the" include a plurality of indicators unless the context clearly indicates otherwise.

[0020] Throughout this disclosure, such as in any of the disclosed embodiments or claims, the term "comprised of" a compound, composition, or method is used. Embodiments also specifically include compounds, compositions, or methods that are, constitute, or substantially constitute those specified components, elements, or steps. The term "comprised of" is used interchangeably with the term "comprising" and is expressed as equivalent. For example, disclosed compositions, apparatus, articles, or methods that "comprised" components or steps are open-ended and include or contain additional components or steps to those compositions or methods. However, these terms do not cover unlisted elements that would impair the function of the disclosed composition, apparatus, article, or method for its intended purpose. Similarly, disclosed compositions, apparatus, articles, or methods that "consist of components or steps" are closed-ended and would not include or contain those compositions or methods with a considerable amount of additional components or steps. Furthermore, the term "consistently of..." allows for the inclusion of unlisted elements that do not materially affect the function of the disclosed composition, apparatus, article, or method for its intended purpose, as further defined herein. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0021] As used herein, "about" when used in conjunction with a numerical value or range of values ​​provided to describe a particular property of a compound or composition indicates that the value or range of values ​​may deviate from what would be reasonable to a person generally skilled in the art, while still describing the particular property. Reasonable deviation includes deviations within the accuracy or precision range of the instruments used to measure, determine, or derive the particular property. Specifically, the term "about" in the context indicates that the numerical value or range of values ​​may vary by 10% of the listed value or range of values, while still describing the particular property.

[0022] Unless the context otherwise indicates or implies, as used herein, a "protecting group" means a portion that prevents or substantially reduces the ability of the atom or functional group to which it is attached to to participate in an undesirable reaction. Typical protecting groups for atoms or functional groups are given in Greene (2014), "Protective groups in organic synthesis, 5th edition," Wiley Interscience. Protecting groups for heteroatoms such as oxygen, sulfur, and nitrogen are sometimes used to minimize or avoid their undesirable reactions with electrophilic compounds. At other times, protecting groups are used to reduce or eliminate the nucleophilicity and / or basicity of unprotected heteroatoms. A non-limiting example of protected oxygen is given by -OR PR, where R PR is a protecting group for a hydroxyl group, wherein the hydroxyl group is protected in some embodiments as an ester (e.g., acetate, propionate, or benzoate). Other protecting groups on the hydroxyl group prevent interference with the nucleophilicity of organometallic reagents or other strongly basic reagents. For this purpose, the hydroxyl group is protected in some embodiments in the form of ethers, including but not limited to alkyl or heterocyclic ethers (e.g., methyl or tetrahydropiperanyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), aryl ethers substituted as appropriate, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tributyldiphenylsilyl (TBDPS), tributyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)). Nitrogen protecting groups include those used for primary or secondary amines such as -NHR PR or -N(R PR) 2, wherein at least one of R PR is a nitrogen protecting group or both R PR together define a nitrogen protecting group.

[0023] A protecting group is suitable for protection when it prevents or substantially avoids undesirable side reactions and / or premature loss of the protecting group under the reaction conditions required to achieve the desired chemical transformation at other sites of the molecule and during the purification of the newly formed molecule, if necessary. It can be removed without adversely affecting the structural or stereochemical integrity of the newly formed molecule. In some cases, suitable protecting groups are those previously described for protecting functional groups. For example, suitable protecting groups for the basic nitrogen atom of an acyclic or cyclic basic group are acid-instable carbamate protecting groups, such as tertiary butyryloxycarbonyl (Boc).

[0024] The compounds disclosed herein may be in salt form. Each compound may contain at least one amino group, and thus may form an acid addition salt with that amino group. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleate, gentisinates, fumarates, gluconates, glucurons, gluconates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and papoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarbamate)).

[0025] Salts may involve another molecule, such as acetate ions, succinate ions, or other relative ions. The relative ion can be any organic or inorganic part that stabilizes the charge of the symphilic compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In cases where multiple charged atoms are part of a pharmaceutically acceptable salt, multiple relative ions may exist. Therefore, a salt may have one or more charged atoms and / or one or more relative ions.

[0026] "Pharmaceutically acceptable salts" refers to salts with toxicity characteristics within the range that provide utility in a pharmaceutical application. In some embodiments, pharmaceutically acceptable salts are selected from those described in PH Stahl and CG Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. The selection of salts depends on the characteristics that the pharmaceutical product must exhibit, including: sufficient water solubility at various pH values, depending on the intended route of administration; crystallinity suitable for sale with flow characteristics and low hygroscopicity (i.e., water absorption relative to relative humidity); and the required shelf life by determining chemical and solid-state stability under accelerated conditions (i.e., for determining degradation or solid-state changes when stored at 40°C and 75% relative humidity). method

[0027] In one state sample, this paper provides a preparative compound of formula (1): (1), or the method of salting it, which includes (i) Compound of formula (7) (7), Or its salt is converted into a compound of formula (6) (6), or its salt; (ii) Convert the compound of formula (6) or its salt into the compound of formula (5). (5), or its salt; and (iii) Convert the compound of formula (5) or its salt into the compound of formula (1) or its salt.

[0028] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) or a salt thereof includes converting a compound of formula (5) or a salt thereof into a compound of formula (4) or a salt thereof. (4)

[0029] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) further comprises converting a compound of formula (4) or a salt thereof into a compound of formula (3) or a salt thereof. (3)

[0030] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) or a salt thereof further comprises converting a compound of formula (3) or a salt thereof into a compound of formula (2) or a salt thereof. (2)

[0031] In some embodiments, converting a compound of formula (5) or a salt thereof into a compound of formula (1) further comprises converting a compound of formula (2) or a salt thereof into a compound of formula (1) or a salt thereof.

[0032] In some of the foregoing embodiments, this document provides a method for preparing compound of formula (1) according to the following procedure: General preparation of compounds of formula (1) Preparation of compound of formula (1)

[0033] In one state sample, this paper provides a preparative compound of formula (1): (1), Or a salt thereof, comprising taking a compound of formula (2): (2), Or a salt thereof, to be converted into a compound of formula (1) or a salt thereof. In some embodiments, a method for preparing a compound of formula (1) is provided, comprising converting a compound of formula (2) into a compound of formula (1).

[0034] In some embodiments, a method of converting a compound of formula (2) or a salt thereof into a compound of formula (1) or a salt thereof comprises reacting a compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or an acrylonitrile equivalent such as acryl chloride or acryl bromide. In some embodiments, activated propionic acid includes, but is not limited to, propionic anhydride, 1H-imidazol-1-carboxylic acid propionic anhydride, propionic esters such as methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate, and tert-butyl propionate.

[0035] In some embodiments, the reaction of the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or acrylamide equivalent is carried out in the presence of an organic solvent. In some embodiments, the organic solvent includes, but is not limited to, acetonitrile (ACN or MeCN), benzene, chloroform, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, and the like. In some embodiments, the organic solvent is anhydrous or substantially anhydrous. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those given herein as examples. In some embodiments, the organic solvent is a mixture of DMF and toluene. In some embodiments, the organic solvent is DMF. In some embodiments, the organic solvent is 1,4-dioxane. In some embodiments, the organic solvent is acetonitrile. It should be understood that each description of an organic solvent can be combined with each description of propionic acid, activated propionic acid, or acrylamide equivalent, as if each and every combination were specifically and individually listed.

[0036] In some embodiments, the reaction of the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or an acetylated equivalent further comprises a base. In some embodiments, the reaction of the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or an acetylated equivalent is carried out in the presence of a base. In some embodiments, a base is added after the reaction of the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or an acetylated equivalent. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base includes, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and the like. In some embodiments, the base is a carbonate base. In some embodiments, the base is potassium carbonate. In some embodiments, the base is an organic base. In some embodiments, organic bases include, but are not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, colinine, dimethylpyridine, pyridine, methylpyridine, dicyclohexylamine, morpholine, 1,8-diazabicyclo[5.4.0]undecyl-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nonyl-5-ene (DBN), imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is DBU. It should be understood that each description of a base may be combined with each description of an organic solvent and each description of propionic acid, activated propionic acid, or acrylamide equivalent, as if each and every combination were specifically and individually listed.

[0037] In some embodiments, the reaction of the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or an acrylamide equivalent is carried out at a temperature of about 153°C, about 150°C, about 140°C, about 130°C, about 120°C, about 111°C, about 110°C, about 100°C, about 90°C, about 82°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, about 20°C, about 10°C, about 0°C, about -10°C, about -20°C, about -30°C, about -40°C, about -50°C, or about -60°C. In some embodiments, the reaction is carried out at a temperature of about 130°C, about 120°C, about 110°C, about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, or about 40°C. In some embodiments, the reaction is carried out at a temperature between about 0°C and about 153°C, between about 0°C and about 150°C, between about 0°C and about 100°C, between about 20°C and about 100°C, between about 20°C and about 80°C, between about 30°C and about 70°C, between about 40°C and about 60°C, or between about 45°C and about 55°C. In some embodiments, the reaction is carried out at a temperature between about 110°C and about 130°C. In some embodiments, the reaction is carried out at a temperature between about 90°C and about 110°C. In some embodiments, the reaction is carried out at a temperature between about 50°C and about 70°C. In some embodiments, the reaction is carried out in the presence of DMF and toluene at a temperature of about 120°C, about 110°C, about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, or about 50°C. In some embodiments, the reaction is carried out in the presence of DMF and toluene at a temperature of about 120°C, about 110°C, or about 100°C. In some embodiments, the reaction is carried out in the presence of DMF and toluene at a temperature of about 120°C. In some embodiments, the reaction is carried out in the presence of 1,4-dioxane at a temperature of about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, or about 50°C. In some embodiments, the reaction is carried out in the presence of 1,4-dioxane at a temperature of about 100°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 80°C, about 70°C, about 60°C, or about 50°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 70°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature between about 40°C and about 80°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature between about 50°C and about 70°C. It should be understood that each description of temperature or temperature range may be combined with each description of propionic acid, activated propionic acid, or acrylamide equivalent, each description of organic solvent, and / or base, as if each and every combination were specifically and individually listed.

[0038] In some embodiments, the reaction is carried out in the presence of a solvent selected from acetonitrile, DMF, toluene, and 1,4-dioxane, or a mixture thereof, at a temperature of about 100°C or lower, about 90°C or lower, about 80°C or lower, about 70°C or lower, about 60°C or lower, about 50°C or lower, about 40°C or lower, or about 30°C or lower, followed by the addition of a base selected from DBU, DBN, potassium carbonate, and DIEA, with the temperature increased by about 5°C, about 10°C, about 20°C, about 30°C, or about 40°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50°C or lower, followed by the addition of a base such as DBU, with the temperature increased by about 20°C or higher. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50°C or lower, followed by the addition of a base such as DBU, with the temperature increased by about 20°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50°C or lower, followed by the addition of a base such as DBU, with the temperature increased to about 70°C. It should be understood that each description of a solvent may be combined with each description of propionic acid, activated propionic acid, or acrylonitrile equivalents and / or each description of a base, as if each and every combination were specifically and individually listed.

[0039] In another sample, this paper provides a preparative compound of formula (1): (1), or a method of salting it, comprising: (i) Reacting propionic acid with a primary carboxylic acid activator to form activated propionic acid, and (ii) React the activated propionic acid from step (i) with the compound of formula (2): (2) The method involves reacting the activated propionic acid from step (i) with a compound of formula (2) to form a compound of formula (1) or a salt thereof. In some embodiments, the method comprises reacting the activated propionic acid from step (i) with a compound of formula (2) to form a compound of formula (1).

[0040] In some embodiments, the carboxylic acid activator includes: acetic acid chloride, such as thionyl chloride, oxalyl chloride, or methanesulfonyl chloride; acid anhydride, such as acetic anhydride; carbodiimide, such as N,N'-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI), in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole (HOBt); or other acetic acid coupling agents, such as azabenzotriazole tetramethylurea hexafluorophosphate (HATU), benzotriazole tetramethylurea hexafluorophosphate (HBTU), O-(1 H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (7-azabenzotriazol-1-yloxy)tripyridine phosphonium hexafluorophosphate (PyAOP), benzotriazol-1-yloxytripyridine phosphonium hexafluorophosphate (PyBOP), brominatedtripyridine phosphonium hexafluorophosphate (PyBroP); and carbonyl diimidazole. In some embodiments, the first carboxylic acid activator in step (i) (the step of reacting propionic acid with a first carboxylic acid activator to form activated propionic acid) is carbonyl diimidazole.

[0041] In some embodiments, steps (i) (reacting propionic acid with a first carboxylic acid activator to form activated propionic acid) and (ii) (reacting the activated propionic acid from step (i) with the compound of formula (2)) are both carried out in an organic solvent. In some embodiments, steps (i) and (ii) are each carried out in the same organic solvent. In some embodiments, the organic solvent includes, but is not limited to, acetonitrile (ACN or MeCN), benzene, chloroform, dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, N-methylpyrrolidone (DMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those given herein as examples. In some embodiments, the organic solvent is free of or substantially free of water. In some embodiments, the organic solvent contains water. In some embodiments, the organic solvent used in step (i) contains acetonitrile. In some embodiments, the organic solvent used in step (ii) contains acetonitrile. In some embodiments, the organic solvent used in steps (i) and (ii) comprises acetonitrile. In some embodiments, the organic solvent used in step (ii) comprises 1,4-dioxane. In some embodiments, the organic solvent used in steps (i) and (ii) comprises 1,4-dioxane.

[0042] In some embodiments, step (ii) (reacting the activated propionic acid of step (i) with the compound of formula (2)) further comprises a base. In some embodiments, step (ii) is carried out in the presence of a base. In some embodiments, a base is added after step (ii). In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base includes, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and the like. In some embodiments, the base is a carbonate base. In some embodiments, the base is potassium carbonate. In some embodiments, the base is an organic base. In some embodiments, the organic base includes, but is not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, colinine, dimethylpyridine, pyridine, methylpyridine, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is DBU. It should be understood that each description of a base can be combined with each description of a solvent, as if each and every combination were specifically and individually listed.

[0043] In some embodiments, step (i) (reacting propionic acid with a first carboxylic acid activator to form activated propionic acid) is performed at a temperature of about 82°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, about 25°C, about 20°C, about 10°C, about 0°C, about -10°C, or about -20°C. In some embodiments, step (i) is performed at a temperature between about 0°C and about 80°C. In some embodiments, step (i) is performed at a temperature between about 0°C and about 50°C. In some embodiments, step (i) is performed at a temperature between about 10°C and about 40°C. In some embodiments, step (i) is performed at a temperature between about 15°C and about 35°C. In some embodiments, step (i) is performed at a temperature of about 25°C. In some embodiments, step (i) is performed at a temperature less than about 80°C, less than about 70°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 35°C, less than about 30°C, or less than about 25°C. In some embodiments, step (i) is performed at a temperature less than about 35°C, less than about 30°C, or less than about 25°C. In some embodiments, step (i) is performed at a temperature less than about 25°C. In some embodiments, step (ii) (reacting the activated propionic acid of step (i) with the compound of formula (2)) is performed at a temperature of about 82°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, about 25°C, about 20°C, about 10°C, about 0°C, about -10°C, or about -20°C. In some embodiments, step (ii) is performed at a temperature of about 50°C. In some embodiments, step (ii) is performed at a temperature between about 0°C and about 80°C. In some embodiments, step (ii) is carried out at a temperature between about 30°C and about 80°C. In some embodiments, step (ii) is carried out at a temperature between about 45°C and about 75°C. In some embodiments, step (ii) is carried out at a temperature between about 50°C and about 70°C. In some embodiments, step (ii) is carried out at a temperature between about 45°C and about 55°C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50°C or lower, followed by the addition of a base and an increase in temperature to about 70°C or higher. It should be understood that each description of temperature may be combined with each description of base and / or organic solvent, as if each and every combination has been specifically and individually listed. For example, in some embodiments, step (i) is carried out in acetonitrile at a temperature of about 25°C or lower, and step (ii) is carried out in acetonitrile at a temperature of about 50°C, followed by the addition of DBU and an increase in temperature to about 70°C. It should be understood that each description of temperature or temperature range may be combined with each description of carboxylic acid activators, each description of organic solvents, and / or each description of bases, as if each and every combination were specifically and individually listed.

[0044] In some embodiments, water is added to the reaction mixture after step (ii) (reacting the activated propionic acid of step (i) with the compound of formula (2)). In some embodiments, the diluted reaction mixture is filtered and the filtrate is concentrated into a slurry. In some embodiments, the diluted reaction mixture is filtered and the filtrate is concentrated into a slurry at a temperature between about 10°C and about 50°C. In some embodiments, the slurry is further diluted with water to form a mixture. In some embodiments, the slurry is heated to a temperature between 70°C and about 80°C and then diluted with water to form a mixture while maintaining the temperature of the mixture at at least about 70°C. In some embodiments, the mixture is filtered to provide the compound of formula (1) in solid form. In some embodiments, the mixture is cooled to a temperature between about 15°C and about 25°C and then filtered to provide the compound of formula (1) in solid form. In some embodiments, the compound of formula (1) in the form of a wet filter cake solid is separated. In some embodiments, the wet filter cake solid of formula (1) is washed with water and dried under vacuum to form a dry solid. In some embodiments, the dry solid of formula (1) is de-lumped.

[0045] It should be understood that each description of the conditions for step (i) (reacting propionic acid with a first carboxylic acid activator to form activated propionic acid) and step (ii) (reacting the activated propionic acid of step (i) with the compound of formula (2)) can be combined, as each and every combination is specifically and individually listed. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyl diimidazole in acetonitrile to prepare activated propionic acid, and step (ii) comprises reacting the activated propionic acid with the compound of formula (2) and subsequently reacting it with DBU. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyl diimidazole in acetonitrile at a temperature of 25°C or lower to prepare activated propionic acid, and step (ii) comprises reacting the activated propionic acid with the compound of formula (2) in acetonitrile at a temperature of about 50 ± 5°C, and subsequently reacting it with DBU in acetonitrile at a temperature of about 70 ± 5°C. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyl diimidazole in acetonitrile at a temperature of 25°C or lower to prepare activated propionic acid, and step (ii) comprises reacting the activated propionic acid with a compound of formula (2) in acetonitrile at a temperature of about 50 ± 5°C, followed by reacting it with DBU in acetonitrile at a temperature of about 70 ± 5°C, followed by the addition of water. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyl diimidazole in acetonitrile at a temperature of 25°C or lower to prepare activated propionic acid, and step (ii) comprises reacting the activated propionic acid with a compound of formula (2) in acetonitrile at a temperature of about 50 ± 5°C, followed by reacting with DBU in acetonitrile at a temperature of about 70 ± 5°C, followed by the addition of water, fine filtration, concentration into a slurry at a temperature between about 10°C and about 50°C, heating to a temperature between 70°C and about 80°C, then diluting with water to form a mixture, cooling to a temperature between about 15°C and about 25°C, and filtering the mixture to provide a compound of formula (1) in solid form. Preparation of compound (2)

[0046] In some embodiments, the compound of formula (2) or a salt thereof is obtained by using the compound of formula (3): (3), The method is prepared by converting a compound of formula (2) or a salt thereof into a compound of formula (3). In some embodiments, the method comprises converting a compound of formula (2) into a compound of formula (3). In some embodiments, the method comprises reacting hydroxylamine with a compound of formula (3) or a salt thereof. In some embodiments, hydroxylamine is provided in the form of an aqueous solution of hydroxylamine. In some embodiments, the reaction of hydroxylamine with a compound of formula (3) is carried out in an organic solvent. In some embodiments, the organic solvent includes, but is not limited to, acetonitrile, dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl-tetrahydrofuran, methanol, ethanol, isopropanol, and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those given by way of example herein. In some embodiments, the organic solvent comprises water. In some embodiments, the organic solvent comprises ethanol. In some embodiments, the organic solvent comprises NMP.

[0047] In some embodiments, the reaction of hydroxylamine with the compound of formula (3) is carried out at a temperature of about 80°C, about 70°C, about 60°C, about 58°C, about 50°C, about 40°C, about 30°C, about 20°C, about 10°C, about 0°C, about -10°C, or about -20°C. In some embodiments, the reaction is carried out at a temperature of about 50°C, about 40°C, about 30°C, about 25°C, about 20°C, about 10°C, about 0°C, about -10°C, or about -20°C. In some embodiments, the reaction is carried out at a temperature of about 50°C or lower, about 40°C or lower, about 30°C or lower, about 25°C or lower, about 20°C or lower, about 10°C or lower, or about 0°C or lower. In some embodiments, the reaction is carried out at a temperature between about -20°C and about 50°C. In some embodiments, the reaction is carried out at a temperature between about -10°C and about 50°C. In some embodiments, the reaction is carried out at a temperature between about 0°C and about 50°C. In some embodiments, the reaction is carried out at a temperature between about 0°C and about 40°C. In some embodiments, the reaction is carried out at a temperature between about 0°C and about 30°C. In some embodiments, the reaction is carried out at a temperature between about 5°C and about 25°C. In some embodiments, the reaction is carried out at a temperature between about 10°C and about 25°C. It should be understood that each description of temperature or temperature range may be combined with each description of organic solvent, as each and every combination is specifically and individually listed. For example, in some embodiments, the method comprises reacting a compound of formula (3) with an aqueous hydroxylamine solution in NMP at a temperature of about 10°C or lower, followed by heating to a temperature between about 15°C and about 25°C. For example, in some embodiments, the method comprises reacting a compound of formula (3) with an aqueous hydroxylamine solution in NMP at a temperature of room temperature or about 25°C.

[0048] In some embodiments, after the reaction of hydroxylamine with the compound of formula (3) is completed, the compound of formula (2) is precipitated by adding a co-solvent. In some embodiments, the co-solvent is water. In some embodiments, after the reaction of hydroxylamine with the compound of formula (3) is completed, the compound of formula (2) is precipitated by adding an organic co-solvent. In some embodiments, the co-solvent is an organic acetate. In some embodiments, the co-solvent is ethyl acetate (EtOAc), isopropyl acetate (IPAc), or tributyl acetate. In some embodiments, the co-solvent is isopropyl acetate. In some embodiments, the co-solvent is added at a temperature of at least about 30°C, at least about 40°C, at least about 50°C, or at least about 60°C. In some embodiments, the co-solvent is added at a temperature between about 50°C and about 80°C. In some embodiments, the co-solvent is added at a temperature between about 50°C and about 75°C. In some embodiments, the co-solvent is added at a temperature of about 65°C. In some embodiments, the precipitated compound of formula (2) is separated in the form of a wet filter cake by vacuum filtration. In some embodiments, the compound of formula (2) is dried under vacuum. It should be understood that each description of the precipitation step can be combined with each description of the reaction conditions, as if each and every combination were specifically and individually listed. For example, in some embodiments, the method comprises reacting the compound of formula (3) with an aqueous hydroxylamine solution in NMP at a temperature of about 10°C or lower, followed by heating to a temperature between about 15°C and about 25°C, and then heating to a temperature between about 60°C and 70°C and adding IPAc. For example, in some embodiments, the method comprises reacting the compound of formula (3) with an aqueous hydroxylamine solution in NMP at a temperature of room temperature or about 25°C, followed by adding water at a temperature of room temperature or about 25°C. Preparation of compound (3)

[0049] In some embodiments, the compound of formula (3) or a salt thereof is prepared by means of: (iii) Reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and (iv) The activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) is reacted with the compound of formula (4): (4), or its salt, to form a compound of formula (3) or its salt. In some embodiments, step (iv) comprises reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid of step (iii) with a compound of formula (4) to form a compound of formula (3).

[0050] In some embodiments, the carboxylic acid activator includes: acetic acid, such as thionyl chloride, oxadiazine, or methanesulfonyl chloride; acid anhydride, such as acetic anhydride; carbodiimide, such as DCC, DIC, or EDC, in the presence of HOAt or HOBt, if applicable; or other acetylamine coupling agents, such as HATU, HBTU, HCTU, BOP, PyAOP, PyBOP, PyBroP; and carbonyl diimidazole. In some embodiments, the second carboxylic acid activator in step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with the second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) is oxadiazine. In some embodiments, the second carboxylic acid activator in step (iii) comprises a carbodiimide reagent. In some embodiments, the carbodiimide reagent comprises EDC. In some embodiments, step (iii) is carried out in the presence of the carbodiimide reagent and HOAt or HOBt.

[0051] In some embodiments, step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) further comprises a base. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base includes, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and the like. In some embodiments, the base is an organic base. In some embodiments, the organic base includes, but is not limited to, N,N-diisopropylethylamine (DIEA or DIPEA), methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, colinine, dimethylpyridine, pyridine, methylpyridine, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is an amine base. In some embodiments, the base is selected from N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, and tributylamine. In some embodiments, the base is diisopropylethylamine. It should be understood that each description of a base can be combined with each description of a carboxylic acid activator, as if each and every combination were specifically and individually listed. For example, in some embodiments, the reaction is carried out in the presence of EDC, HOBt, and DIEA. In other embodiments, the reaction is carried out in the presence of EDC, HOAt, and DIEA.

[0052] In some embodiments, step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) is performed at a temperature of about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, about 20°C, or about 10°C. In some embodiments, step (iii) is performed at a temperature below about 80°C. In some embodiments, step (iii) is performed at a temperature below about 61°C. In some embodiments, step (iii) is performed at a temperature below about 55°C. In some embodiments, step (iii) is performed at a temperature below about 50°C. In some embodiments, step (iii) is performed at a temperature below about 40°C. In some embodiments, step (iii) is performed at a temperature below about 35°C. In some embodiments, step (iii) is performed at a temperature between about 0°C and about 80°C. In some embodiments, step (iii) is performed at a temperature between about 0°C and about 60°C. In some embodiments, step (iii) is performed at a temperature between about 10°C and about 40°C. In some embodiments, step (iii) is performed at a temperature between about 20°C and about 40°C. In some embodiments, step (iii) is performed at a temperature between about 20°C and about 35°C. In some embodiments, step (iii) is performed at a temperature between about 25°C and about 35°C. It should be understood that each description of temperature or temperature range may be combined with each description of carboxylic acid activator and / or each description of base, as if each and every combination were specifically and individually listed.

[0053] In some embodiments, step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) is carried out in an organic solvent as described herein. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the organic solvent further comprises water. In some embodiments, the solvent comprises a mixture of solvents as described herein. In some embodiments, the solvent comprises a mixture of DMF and 2-MeTHF. It should be understood that the solvent may be combined with each description of the carboxylic acid activator, each description of the base, and / or each description of the temperature or temperature range, as each and every combination is specifically and individually listed. For example, in some embodiments, step (iii) is carried out in the presence of EDC, HOBt, DIEA, and DMF at a temperature between about 40°C and about 20°C. In other embodiments, step (iii) is carried out in the presence of EDC, HOBt, DIEA, and DMF at a temperature between about 40°C and about 20°C. In other embodiments, step (iii) is carried out in the presence of acetaminophen and DMF at a temperature between about 40°C and about 20°C. In other embodiments, step (iii) is carried out in the presence of acetaminophen and DMF at a temperature below about 35°C. In other embodiments, the reaction is carried out in the presence of acetaminophen, 2-MeTHF, and DMF at a temperature between about 20°C and about 40°C, between about 20°C and about 35°C, or between about 25°C and about 35°C. In other embodiments, the reaction is carried out in the presence of acetaminophen, 2-MeTHF, and DMF at a temperature below about 35°C.

[0054] In some embodiments, the crude product of step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) can be used without further treatment. In some embodiments, the crude product of step (iii) can be used without purification.

[0055] In some embodiments, step (iv) (reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid of step (iii) with the compound of formula (4)) is carried out in the presence of a base. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base includes, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, sodium tributoxide, potassium carbonate, sodium bis(trimethylsilyl)acetate, and the like. In some embodiments, the base is a hydroxide base, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is an organic base. In some embodiments, the organic base includes, but is not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, pyridine, or morpholine. In some embodiments, the base is an aqueous solution. In some embodiments, the base is an aqueous solution of sodium hydroxide.

[0056] In some embodiments, step (iv) (reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid of step (iii) with the compound of formula (4)) is carried out in an organic solvent as described herein. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the organic solvent further comprises water. In some embodiments, the solvent comprises a mixture of solvents as described herein. In some embodiments, the solvent comprises a mixture of DMF and 2-MeTHF. It should be understood that each description of the organic solvent in step (iv) may be combined with each description of step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid), each description of the base in step (iv), and / or each description of the temperature or temperature range in step (iv), as if each and every combination were specifically and individually listed. For example, in some embodiments, step (iii) comprises reacting 1-methyl-1H-pyrazole-4-carboxylic acid with oxalic acid to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and step (iv) comprises reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) with the compound of formula (4) in the presence of NaOH. For example, in some embodiments, step (iii) comprises reacting 1-methyl-1H-pyrazole-4-carboxylic acid with oxalic acid in DMF and 2-MeTHF to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and step (iv) comprises reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) with the compound of formula (4) in the presence of aqueous NaOH. For example, in some embodiments, step (iii) comprises reacting 1-methyl-1H-pyrazole-4-carboxylic acid with oxalic acid in DMF and 2-MeTHF at a temperature below about 35°C to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and step (iv) comprises reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) with the compound of formula (4) in the presence of an aqueous solution of NaOH at a temperature below about 30°C. For example, in some embodiments, steps (iii) and (iv) comprise reacting 1-methyl-1H-pyrazole-4-carboxylic acid with the compound of formula (4) in the presence of HOBt, EDC, and DIEA. For example, in some embodiments, steps (iii) and (iv) comprise reacting 1-methyl-1H-pyrazole-4-carboxylic acid with the compound of formula (4) in DMF in the presence of HOBt, EDC, and DIEA.

[0057] In some embodiments, the compound of formula (3) is separated by filtration to provide a wet filter cake solid. In some embodiments, the wet filter cake solid is washed with a solvent such as 2-MeTHF or water. In some embodiments, the compound of formula (3) is dried under vacuum.

[0058] Procedure 1 describes the process for synthesizing compound (1). Process 1:

[0059] Process 2 illustrates the alternative process for synthesizing compound (2). Process 2: Preparation of polymorphs of compound (1)

[0060] In some of the foregoing embodiments, the method for preparing the compound of formula (1) further includes preparing a polymorph of the compound of formula (1). The method for preparing a polymorph of the compound of formula (1) is disclosed in WO2021 / 011807, the contents of which are incorporated herein by reference in their entirety.

[0061] In some embodiments, the polymorphic system of the compound of formula (1) is polymorphic form I. In some embodiments, the polymorphic form is characterized by having an XRPD pattern containing peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern containing peaks at 2-θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees.

[0062] In some embodiments, the polymorphic system of the compound of formula (1) is polymorphic form II. In some embodiments, the polymorphic form is characterized by having an XRPD pattern containing peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern containing peaks at 2-θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees.

[0063] In some embodiments, the polymorphic system of the compound of formula (1) is polymorphic form III. In some embodiments, the polymorphic form is characterized by having an XRPD pattern containing peaks at 2-θ angles of 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees.

[0064] In some embodiments, the polymorphic system of the compound of formula (1) is in polymorphic form IV. In some embodiments, the polymorphic form is characterized by having an XRPD pattern containing peaks at 2-θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern containing peaks at 2-θ angles of 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24.8±0.2 degrees.

[0065] In some embodiments, the polymorphic system of the compound of formula (1) is in polymorphic form V. In some embodiments, the polymorphic form is characterized by having an XRPD pattern containing peaks at 2-θ angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern containing peaks at 2-θ angles of 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern containing peaks at 2-θ angles of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees.

[0066] In some embodiments, the polymorphic system of the compound of formula (1) is polymorphic form VI. In some embodiments, the polymorphic form is characterized by having an XRPD pattern containing peaks at 2-θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern containing peaks at 2-θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. Preparation of compound (4)

[0067] In another sample, this paper provides a preparative compound of formula (4): (4), Or the method of salting it, which is by taking a compound of formula (5): (5), The method involves converting a compound of formula (4) or a salt thereof into a compound of formula (4) or a salt thereof. In some embodiments, the method comprises converting a compound of formula (5) into a compound of formula (4) or a salt thereof. In some embodiments, the method for preparing a compound of formula (4) or a salt thereof comprises hydrolyzing a sulfinamide of a compound of formula (5) or a salt thereof.

[0068] In some embodiments, the sulfinamide of formula (5) is hydrolyzed in the presence of an aqueous acid. In some embodiments, the aqueous acid is an inorganic acid. In some embodiments, the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. In some embodiments, the aqueous acid is an organic acid. In some embodiments, the organic acid includes acetic acid, propionic acid, ascorbic acid, citric acid, trifluoroacetic acid, toluenesulfonic acid, and the like. In some embodiments, the aqueous acid is any compatible mixture of acids, such as those given herein as examples. In some embodiments, the aqueous acid is hydrochloric acid.

[0069] In some embodiments, the sulfinamide of formula (5) is hydrolyzed in the presence of an alkaline solution. In some embodiments, the sulfinamide is hydrolyzed in the presence of an alkaline aqueous solution. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base includes, but is not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and the like. In some embodiments, the base is an organic base. In some embodiments, the organic base includes, but is not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, trimethylolamine, ethanolamine, colinine, dimethylpyridine, pyridine, methylpyridine, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like.

[0070] In some embodiments, the hydrolysis of sulfinamide is carried out in an organic solvent. In some embodiments, the organic solvent includes, but is not limited to, acetonitrile, dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tributyl acetate, and the like. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those given herein as examples. In some embodiments, the organic solvent comprises water. It should be understood that each description of an acid or base may be combined with each description of an organic solvent, as each and every combination has been specifically and individually listed. For example, in some embodiments, the hydrolysis of sulfinamide is carried out in the presence of an aqueous HCl solution. For example, in some embodiments, the hydrolysis of sulfinamide is carried out in the presence of IPAc. For example, in some embodiments, the hydrolysis of sulfinamide is carried out in the presence of an aqueous HCl solution and IPAc.

[0071] In some embodiments, the compound of formula (4) is collected by filtration. In some embodiments, filtration provides the compound of formula (4) as a wet filter cake. In some embodiments, the wet filter cake solid compound of formula (4) is washed with IPAc. In some embodiments, the compound of formula (4) is dried under vacuum. Preparation of compound (5)

[0072] In some embodiments, the compound of formula (5) or its salt is reacted with the reducing agent and the compound of formula (6): (6), The method is prepared by reacting a reducing agent with a compound of formula (6) or a salt thereof to form a compound of formula (5). In some embodiments, the method comprises reacting a reducing agent with a compound of formula (6) to form a compound of formula (5). In some embodiments, the reducing agent includes, but is not limited to, hydrogen, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, tin chloride, and the like in the presence of a catalyst such as a palladium catalyst. In some embodiments, the reducing agent is a borohydride reducing agent. In some embodiments, the reducing agent is sodium borohydride.

[0073] In some embodiments, the reaction of the compound of formula (6) with the reducing agent is carried out in the presence of a solvent. In some embodiments, the organic solvent includes, but is not limited to, dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and the like. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises THF. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those given herein as examples, such as a mixture of toluene and THF. In some embodiments, the reaction is carried out at a temperature between about -15°C and about -5°C. It should be understood that, taking into account any combination of the foregoing conditions, for example, the reaction of the reducing agent with the compound of formula (6) can be carried out in the presence of toluene, tetrahydrofuran, or toluene and tetrahydrofuran. For example, the reaction of the reducing agent with the compound of formula (6) can be carried out in the presence of toluene, tetrahydrofuran, or toluene and tetrahydrofuran at a temperature between about -15°C and about -5°C. In some such embodiments, the reducing agent is sodium borohydride.

[0074] In some embodiments, the compound of formula (5) in solid form is isolated. In some embodiments, the compound of formula (5) is isolated by precipitation or recrystallization. In some embodiments, the compound of formula (5) is isolated from a mixture of ethyl acetate and n-heptane. Preparation of compound (6)

[0075] In some embodiments, the compound of formula (6) is obtained by reacting (R)-tert-butanesulfinamide with the compound of formula (7): (7), The reaction is prepared to form a compound of formula (6) or a salt thereof. In some embodiments, the reaction is carried out in the presence of a Lewis acid and a water scavenger. In some embodiments, the reagents acting as Lewis acids and water scavengers include, but are not limited to, CuSO₄, GaCl₃, Ti(OEt)₄, and the like. In some embodiments, the reaction is carried out in the presence of Ti(OEt)₄. In some embodiments, the reaction is carried out in toluene. In some embodiments, the reaction is carried out at a temperature between about 75°C and about 85°C. In some embodiments, the compound of formula (6) is used without post-treatment. In some embodiments, the compound of formula (6) is used without purification. In some embodiments, the compound of formula (6) is not isolated. In some embodiments, the compound of formula (6) is formed in situ. It should be understood that, considering any combination of the foregoing conditions, for example, the reaction of (R)-tert-butanesulfinamide with the compound of formula (7) can be carried out in toluene in the presence of Ti(OEt)₄. For example, the reaction of (R)-tert-butanesulfinamide with the compound of formula (7) can be carried out in toluene in the presence of Ti(OEt)4 at a temperature between about 75°C and about 85°C. Preparation of compound (7)

[0076] In some embodiments, the compound of formula (7) or a salt thereof is obtained by using the compound of formula (8): (8) The compound is prepared by conversion to compound (7). In some embodiments, conversion of compound (8) to compound (7) comprises reacting compound (8) with a cyaniding agent via a palladium-catalyzed cyanidation reaction. In some embodiments, the cyaniding agent includes, but is not limited to, KCN, NaCN, Zn(CN)₂, CuCN, trimethylsilyl cyanide, and ferricyanide. In some embodiments, the reaction comprises reacting compound (8) with Zn(CN)₂ in the presence of a palladium catalyst. In some embodiments, the reaction comprises reacting compound (8) with Zn(CN)₂ in the presence of XPhos and Pd₂(dba)₃. In some embodiments, the reaction is carried out at a temperature between about 85°C and about 95°C.

[0077] In some embodiments, the compound of formula (7) is purified by hot filtration and / or recrystallization. In some embodiments, the compound of formula (7) is purified by hot filtration in ethanol. In some embodiments, the compound of formula (7) is purified by hot filtration at a temperature greater than about 60°C. In some embodiments, the compound of formula (7) is purified by hot filtration at a temperature of about 70°C, about 75°C, about 78°C, or about 80°C. In some embodiments, the compound of formula (7) is purified by recrystallization. In some embodiments, the solvent for recrystallization comprises ethanol. In some embodiments, the solvent for recrystallization comprises water. In some embodiments, the solvent for recrystallization comprises a mixture of ethanol and water. In some embodiments, recrystallization is carried out at a temperature between about 0°C and about 78°C. In some embodiments, recrystallization is carried out at a temperature between about 0°C and about 70°C. In some embodiments, recrystallization is carried out at a temperature between about 0°C and about 60°C. In some embodiments, recrystallization is initiated at a temperature between about 50°C and about 60°C and then cooled to a temperature between about 0°C and about 10°C.

[0078] It should be understood that, considering any combination of the foregoing conditions, for example, in some embodiments, the reaction comprises reacting the compound of formula (8) with XPhos, Pd 2(dba) 3, and Zn(CN) 2 in the presence of DMF and 2-MeTHF. For example, in some embodiments, the reaction comprises reacting the compound of formula (8) with XPhos, Pd 2(dba) 3, and Zn(CN) 2 in the presence of DMF and 2-MeTHF at a temperature between about 85°C and about 95°C, followed by hot filtration in ethanol, and then recrystallization in a mixture of ethanol and water.

[0079] Process 3 describes the process for synthesizing the hydrochloride salt of compound (4). Process 3:

[0080] The aforementioned method for preparing compound (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile or its salts (e.g., (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride) shows an improvement over previous synthetic methods in this art. For example, the method described herein requires fewer synthetic steps, avoids the separation and / or purification of certain intermediates, requires fewer separated intermediates, and provides a greater overall yield compared to the methods described in U.S. Publications No. US2006 / 0173183A1 and WO 2006 / 083454 for the preparation of (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride from 5-bromo-dihydroindene-1-ylamine. For example, compared to the method described in U.S. Patent No. 10,836,755, which describes the preparation of (R)-(5-cyano-2,3-dihydro-1H-inden-1-one)carbamate tributyl ester from 5-bromo-2,3-dihydro-1H-inden-1-one, the method described herein requires fewer synthetic steps, provides a greater overall yield, and eliminates the need for a protecting group, as well as the need for tin or azide reagents. Alternative preparation of compound (4)

[0081] In another sample, this paper provides a preparative compound of formula (4): (4), Or the method of salting it, which involves using a compound of formula (A) (A), The method involves converting a compound of formula (A) or its salt into a compound of formula (4) or its salt. In some embodiments, the method comprises converting a compound of formula (A) into a compound of formula (4) or its salt. In some embodiments, converting a compound of formula (A) into a compound of formula (4) comprises reacting a compound of formula (A) with an acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. In some embodiments, the aqueous solution of the acid is an organic acid. In some embodiments, the organic acid includes acetic acid, propionic acid, ascorbic acid, citric acid, trifluoroacetic acid, toluenesulfonic acid, and the like. In some embodiments, the acid is toluenesulfonic acid. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the compound of formula (4) or its salt is separated by vacuum filtration. In some embodiments, the compound of formula (4) or its salt is purified by washing the solid with an organic solvent. In some embodiments, the compound of formula (4) or its salt is purified by washing the solid with petroleum ether.

[0082] In some embodiments, a compound of formula (A) or a salt thereof is disposed of by a compound of formula (B). (B) The method prepares the compound by converting a salt of formula (B) to a compound of formula (A). In some embodiments, the method includes converting a compound of formula (B) to a compound of formula (A). In some embodiments, converting a compound of formula (B) or a salt of formula (A) to a compound of formula (B) or a salt of formula (A) includes reacting the compound of formula (B) or a salt of formula (A) via a palladium-catalyzed cyanidation reaction. In some embodiments, the reaction includes reacting the compound of formula (B) or a salt of formula (B) with potassium ferricyanide in the presence of XPhos Pd G2 and / or XPhos. In some embodiments, the reaction is carried out in the presence of a base. In some embodiments, a base acetate is used. In some embodiments, a base potassium acetate is used.

[0083] In some embodiments, the compound of formula (A) is purified by grinding in ethyl acetate in hexane. In some embodiments, the compound of formula (A) is purified by grinding in 10% by volume ethyl acetate in hexane. In some embodiments, the compound of formula (A) is purified by column chromatography. In some embodiments, the column chromatography comprises a silicone column. In some embodiments, the compound of formula (A) is dissociated from the column in ethyl acetate in petroleum ether. In some embodiments, the compound of formula (D) is dissociated from the column in 15% by volume ethyl acetate in petroleum ether.

[0084] In some embodiments, a compound of formula (B) or a salt thereof is disposed of by a compound of formula (C). (C) The method is prepared by converting a compound of formula (C) or a salt thereof into a compound of formula (B). In some embodiments, the method comprises converting a compound of formula (C) or a salt thereof into a compound of formula (B). In some embodiments, a compound of formula (B) is prepared by reacting a compound of formula (C) or a salt thereof with di(tertiary butyl) dicarbonate. In some embodiments, converting a compound of formula (C) into a compound of formula (B) further comprises reacting a compound of formula (C) with di(tertiary butyl) dicarbonate in the presence of a base. In some embodiments, the base includes, but is not limited to, N,N-diisopropylethylamine, trimethylamine, diethylamine, triethylamine, tributylamine, colinine, dimethylpyridine, pyridine, methylpyridine, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is triethylamine. In some embodiments, a compound of formula (B) is purified by grinding in hexane.

[0085] In some embodiments, a compound of formula (C) or a salt thereof is disposed of by means of a compound of formula (D): (D) The method involves converting a compound of formula (C) or a salt thereof to prepare the compound. In some embodiments, the method includes converting a compound of formula (D) to a compound of formula (C). In some embodiments, converting a compound of formula (D) to a compound of formula (C) or a salt thereof involves reacting the compound of formula (D) with a reducing agent. In some embodiments, the reducing agent includes, but is not limited to, triphenylphosphine, zinc, sodium borohydride, tin chloride, lithium aluminum hydride, sodium borohydride, hydrogen in the presence of a catalyst such as a palladium catalyst, and the like. In some embodiments, the reducing agent is tin chloride. In some embodiments, the compound of formula (C) is used without purification. In some embodiments, the compound of formula (C) is purified by acid-base extraction.

[0086] In some embodiments, a compound of formula (D) or a salt thereof is disposed of by a compound of formula (E). (E) The compound is prepared by converting a salt of formula (E) or a compound of formula (D). In some embodiments, the method includes converting a compound of formula (E) into a compound of formula (D). In some embodiments, converting a compound of formula (E) or a salt of formula (D) into a compound of formula (D) includes reacting the compound of formula (E) or a salt of formula (D) with an azide reagent. In some embodiments, the azide reagent includes, but is not limited to, sodium azide, diphenylphosphohydrazide, trimethylsilyl azide, azidoic acid, and the like. In some embodiments, the reaction of the compound of formula (E) or a salt of formula (D) with the azide reagent further includes a base. In some embodiments, the base is DBU. In some embodiments, the compound of formula (D) is purified by column chromatography. In some embodiments, the column chromatography includes a silicone column packed with 1% triethylamine in petroleum ether. In some embodiments, the compound of formula (D) is dissolved from the column with petroleum ether.

[0087] In some embodiments, a compound of formula (E) or a salt thereof is disposed of by a compound of formula (F). (F) The compound is prepared by conversion to a compound of formula (E) or a salt thereof. In some embodiments, conversion of a compound of formula (F) to a compound of formula (E) or a salt thereof comprises subjecting the compound of formula (F) to reducing conditions to form the compound of formula (E). In some embodiments, the reducing conditions comprise a reducing agent. In some embodiments, the reducing agent includes, but is not limited to, hydrogen, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, borane, and the like in the presence of a catalyst such as a palladium catalyst. In some embodiments, the reducing conditions comprise a reducing agent and a counteracting agent. In some embodiments, the palmitic reagent includes, but is not limited to, palmitic oxazaborolidine, such as (3R)-1-methyl-3,3-biphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborone (Corey-Bakshi-Shibata catalyst), (S)-3,3-biphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborone, (S)-1-butyl-3,3-biphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborone, and the like. In some embodiments, the reduction conditions comprise borane. In some embodiments, the reduction conditions comprise (3R)-1-methyl-3,3-biphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborone and borane. In some embodiments, the reduction conditions comprise (3R)-1-methyl-3,3-bis(3,5-dimethylphenyl)-hexahydropyrrolo[1,2-c][1,3,2]oxazoloboronide and borane. In some embodiments, the compound of formula (E) is purified by column chromatography. In some embodiments, the column chromatography comprises a silicone column packed with 1% triethylamine in petroleum ether. In some embodiments, the compound of formula (D) is dissociated from the column with ethyl acetate in petroleum ether. In some embodiments, the compound of formula (D) is dissociated from the column with 30% by volume ethyl acetate in petroleum ether. In some embodiments, the compound of formula (D) is further purified by grinding in hexane.

[0088] Procedure 4 describes an alternative procedure for synthesizing the hydrochloride salt of compound (4). Process 4:

[0089] In another sample, this paper provides a preparative compound of formula (4): (4), The method for separating compound (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile or its salts is carried out by reductive purification of 1-amino-2,3-dihydro-1H-indene-5-carboxynitrile or its salts. In some embodiments, 1-amino-2,3-dihydro-1H-indene-5-carboxynitrile or its salts are prepared by reductive amination of compound (F) by methods known in this art.

[0090] In some embodiments, the method of preparing a compound of formula (1) or a salt thereof further comprises obtaining a compound of formula (4) or a salt thereof by any of the methods described herein.

[0091] When it is desired to obtain a specific isomer of the compound or to purify the reaction product in other ways, chromatography, recrystallization, and other known separation procedures can also be used on the intermediates or the final product.

[0092] Some of the methods described herein are illustrated with reference to the illustrative synthetic procedures and subsequent specific examples. Some of the reactions and transformations described herein can be carried out using methods known in this art. For example, U.S. Patent No. 10,836,755 describes methods and reagents that can be used to synthesize some of the compounds disclosed herein. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, starting materials can be suitably selected such that the desired final substituent is carried out in the reaction process with or without protection to obtain the desired product. Alternatively, it may be necessary or desirable to use suitable groups to replace the desired final substituent, which can be carried out through the reaction process and, as appropriate, by substitution of the desired substituent. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amine, carboxyl, or side chain groups) from the effects of reaction conditions, and that such groups are removed under standard conditions when appropriate.

[0093] When it is desired to obtain a specific mirror-image isomer of a compound, this can be achieved from the corresponding mixture of mirror-image isomers using any suitable conventional procedure for separating or resolving mirror-image isomers. Thus, for example, a non-mirror-image isomer derivative can be generated by reacting a mixture of mirror-image isomers (e.g., a racemic mixture) with a suitable opposing compound. The non-mirror-image isomer can then be separated by any conventional method (e.g., by crystallization), and the desired mirror-image isomer can be recovered. In another resolution process, opposing high-performance liquid chromatography can be used to separate the racemic mixture. Alternatively, if desired, a specific mirror-image isomer can be obtained by using a suitable opposing intermediate in one of the described processes. Example

[0094] The abbreviations used in this article are explained in the table below. [abbreviation] [meaning] ACN Acetonitrile Aq. Aqueous solution CDI carbonyl diimidazole DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DMF N,N-Dimethylformamide EtOAc Ethyl acetate EtOH ethanol HPLC High performance liquid chromatography IPAc Isopropyl acetate LOD Detection Limits IPC Process control NMP N-methylpyrrolidone THF Tetrahydrofuran 2-MeTHF 2-Methyltetrahydrofuran Example 1. Synthesis of 1-Side-oxy-2,3-dihydro-1H-inden-5-formonitrile

[0095] 5-Chloro-1-dihydroindanone (70.0 kg, 420.17 mol, 1.00 equivalent) was dissolved in a mixture of dimethylformamide (DMF, 280 kg, 296.6 L) and 2-methyltetrahydrofuran (2-MeTHF, 280 kg, 327.9 L) and completely degassed. XPhos (2.2 kg, 4.61 mol, 0.011 equivalent) and Pd₂(dba)₃ (2.1 kg, 2.29 mol, 0.0055 equivalent) were then added to the reaction solution, and the mixture was heated to 85–95 °C. In a separate flask, 2-MeTHF (140 kg, 163.9 L) was added to zinc cyanide (Zn(CN)₂, 27.3 kg, 232.5 mol, 0.55 equivalents); the heterogeneous mixture was degassed and the slurry was added to the above hot reaction mixture. Stirring was continued at 85–95 °C until process control (IPC) was met, with an acceptable limit of ≤5% area of ​​5-chloro-1-dihydroindanone. The mixture was then cooled to 20–30 °C and dichloromethane (DCM, 500 kg, 375.9 L) was added to the reaction mixture.

[0096] In a separate container, potassium carbonate (116.9 kg, 845.9 mol, 2.0 equivalents) and water (630 kg, 630 L) were stirred at 20–30 °C to obtain a homogeneous solution, which was then added to the crude reaction mixture above. The quenched reaction mixture was filtered through a diatomaceous earth mat (20.3 kg) and washed with DCM (690 kg, 518.8 L). The two-phase filtrates were separated, and the upper aqueous layer was extracted with another portion of DCM (210 kg, 157.9 L). The combined lower organic phase was washed with water (350 kg, 350 L), filtered through a silicone mat (21 kg), and washed with DCM (140 kg, 105.3 L). The reaction mixture was concentrated, and the solvent was exchanged for ethanol (EtOH, 2 x 70 kg, 2 x 88.7 L), and the solution was concentrated to dryness. Ethanol (700 kg, 887.2 L) was added to the residue, and the mixture was heated to 70–80 °C, hot filtered, and cooled to 60 °C. The filtrate was concentrated under vacuum at <60 °C to give a solid. Ethanol (180 kg, 228.1 L) was added to the crude product, and the mixture was heated to 50–60 °C to dissolve it. Water (28 kg, 28 L) was added, and the reaction mixture was subsequently cooled to 0–10 °C. The recrystallized product was separated by filtration and dried at <60 °C to give 1-sideoxy-2,3-dihydro-1H-inden-5-carboxynitrile as a yellow solid in 70.2% yield. Example 2. Synthesis of (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide

[0097] (R)-tert-butanesulfinamide (66.7 kg, 550.3 mol, 2.22 equivalents) and titanium ethoxide (Ti(OEt)4, 113.3 kg, 496.7 mol, 2.00 equivalents) were stirred in toluene (135.3 kg, 156.1 L) and the mixture was heated to 75-85 °C over 3 hours. Then, a solution of 1-sideoxy-2,3-dihydro-1H-indene-5-carboxynitrile (39.0 kg, 248.1 mol, 1.00 equivalents) in toluene (286 kg) was added to the reaction mixture while maintaining the temperature at 75-85 °C. The mixture was stirred at this temperature for 3-4 hours. When the acceptable limit of ≤ 0.5% residual 1-sideoxy-2,3-dihydro-1H-indene-5-carboxynitrile (IPC-1) is met, the preparation of intermediate (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-ylidene)-2-methylpropane-2-sulfinamide is considered complete.

[0098] The reaction mixture was cooled to 20–30 °C, and THF (172.8 kg, 194.4 L) was added, followed by the addition of sodium borohydride (NaBH4, 4.7 kg, 124.2 mol, 0.5 equivalents) in portions, maintaining the temperature of the reaction mixture between -15 °C and -10 °C. The reaction mixture was stirred at -10 to -5 °C for 14–20 hours until IPC-2 met the specification limit of ≤ 2% residual (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-ylene)-2-methylpropane-2-sulfinamide.

[0099] The reaction mixture was heated to 20–30 °C and added to a 2.5 M potassium glycolate solution (483.8 kg). The reactor was rinsed with toluene (182.1 kg, 210.0 L) and the wash solution was added to the quenching solution. The concentrated slurry was stirred for 20–40 min, and then the layers were separated over 1–3 h. The lower aqueous layer was separated, and the solids were retained together with the organic layer. The organic layer was washed twice with 2.5 M potassium glycolate (2 × 132.6 kg) and twice with 10% sodium chloride (2 × 124.8 kg). The organic layer was then filtered through a diatomaceous earth mat (4.6 kg) and washed with toluene (2 x 39 kg, 2 x 45 L).

[0100] The combined toluene layers were concentrated to dryness and solvent-exchanged with ethyl acetate (EtOAc, 2 x 117 kg, 2 x 129.7 L), and the solution was concentrated to dryness. The residue was dissolved in EtOAc (117 kg, 129.7 L) at 60–70 °C, and the solution was stirred at this temperature for 1 hour. Then, n-heptane (234 kg, 242.1 L) was slowly added, and the temperature was maintained at 60–70 °C for 1–2 hours. The reaction mixture was cooled to 0–5 °C over a period of 4–5 hours and stirred at this temperature for another 2–3 hours. The solids were separated by centrifugation, and the filter cake was washed with a solution of cooled (0–5 °C) EtOAc (26 kg, 28.8 L) and n-heptane (51.8 kg, 75.7 L). The crude product was dried at 20-30°C for 8-10 hours to obtain 42.2 kg (64.8%) (R)-N-((R)-5-cyano-2,3-dihydro-1H-indene-1-yl)-2-methylpropane-2-sulfinamide. Example 3: Synthesis of (R)-1-amino-2,3-dihydro-1H-indene-5-formonitrile hydrochloride

[0101] Isopropyl acetate (IPAc, 942 kg, 1082.8 L) was added to (R)-N-((R)-5-cyano-2,3-dihydro-1H-indene-1-yl)-2-methylpropane-2-sulfinamide (42.2 kg, 1608 mol, 1.00 equivalent), and the solution was treated with 6 M HCl (39 kg, 197.7 mol, 1.23 equivalent) for 16–20 hours until IPC-3 was met; the residual (R)-N-((R)-5-cyano-2,3-dihydro-1H-indene-1-yl)-2-methylpropane-2-sulfinamide ≤ 0.5%. The crude product (R)-1-amino-2,3-dihydro-1H-indene-5-formonitrile hydrochloride was separated by centrifugation. The wet filter cake was washed with IPAc (130 kg 149.4 L) and dried at 30–40 °C for 16–24 hours, and the LOD was measured (report, result: 0.28 % w / w). The purity (specification: ≥98.0% area, result: 99.7% area), piezoresistive purity (specification: ≥99.0%, result: 99.7% area), and Karl Fischer titration of the (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride product were analyzed (report, result: 0.45 % w / w). The title compound was isolated in 91.1% yield. Example 4: Synthesis of (S)-5-bromo-2,3-dihydro-1H-inden-1-ol

[0102] Under a nitrogen atmosphere, (3R)-1-methyl-3,3-biphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazoloboronoxane (37 mL in toluene, 1 M, 0.15 equivalents) was added to a solution of 5-bromo-2,3-dihydro-1H-indone (50 g, 237 mmol, 1.0 equivalents) in THF (400 mL). The mixture was cooled to -10 °C and borane dimethyl sulfide (10 M in THF, 32.2 g, 1.4 equivalents) was added dropwise over 1 h with stirring. After stirring at -10 °C for 3 h, the reactants were quenched by the slow addition of water (200 mL). The resulting solution was extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silicone column packed with 1% TEA (30% ethyl acetate / petroleum ether) in petroleum ether to obtain a solid, which was ground with hexane (300 mL) to give 38.0 g (75%) of (1S)-5-bromo-2,3-dihydro-1H-indene-1-ol as a pale yellow solid. LRMS (ES): C 9H 9BrO Calculated value 212.0 Da, measured value 195 m / z [M+H-18]+. Example 5: Synthesis of (R)-1-azido-5-bromo-2,3-dihydro-1H-indene

[0103] Diphenylphosphine azide (74.3 g, 270.0 mmol, 1.4 equivalents) was added to a solution of (S)-5-bromo-2,3-dihydro-1H-indene-1-ol (42 g, 197 mmol, 1.0 equivalents) in toluene (500 mL) under nitrogen atmosphere. DBU (45 g, 295 mmol, 1.5 equivalents) was added dropwise to the mixture over 1 h with stirring at 0 °C. After stirring for 3 h between 0 and 15 °C, the mixture was diluted with ethyl acetate (400 mL) and washed three times with water (400 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with 1% TEA (dissolved in petroleum ether) to give 44.4 g (95%) of (R)-1-azido-5-bromo-2,3-dihydro-1H-indene as a dark brown oil. The dark brown oily substance was used in the next step without further purification. LRMS (ES): C 9H 8BrN 3 Calculated value 237.0 Da, measured value 195, 197 m / z [M+H-42]+. Example 6: Synthesis of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine

[0104] SnCl₂·2H₂O (76 g, 337 mmol, 1.81 equivalents) was slowly added to a solution of (R)-1-azido-5-bromo-2,3-dihydro-1H-indene (44.3 g, 186 mmol, 1.0 equivalents) in methanol (600 mL). After stirring overnight at room temperature, the mixture was diluted with ethyl acetate (500 mL) and NaOH (2 N, 700 mL), stirred at room temperature for 1 h, and filtered. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were extracted twice with HCl (1 N, 500 mL), and the aqueous layers were combined. The pH of the aqueous layer was adjusted to 11 with saturated sodium hydroxide, and the aqueous layer was extracted three times with ethyl acetate (300 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 31.8 g (80%) of (R)-5-bromo-2,3-dihydro-1H-indene-1-amine as a yellow oil. LRMS (ES): C 9H 10BrN Calculated value 211.0 Da, measured value 195, 197 m / z [M+H-16]+. Example 7: Synthesis of (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate tert-butyl ester

[0105] At -5°C, over a 45-minute period, a solution of TEA (22.7 g, 224.8 mmol, 1.5 equivalents) and (Boc)₂O (39.2 g, 180 mmol, 1.2 equivalents) in CH₂Cl₂ (150 mL) was added to a solution of (R)-5-bromo-2,3-dihydro-1H-indene-1-amine (31.8 g, 150 mmol, 1.2 equivalents). The mixture was then heated to room temperature, stirred for 2 h, diluted with CH₂Cl₂ (200 mL), washed twice with water (500 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The solid was ground with hexane (300 mL) to give 38.7 g (83%) of (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate tributyl ester as a white solid. LRMS (ES): C 14H 18BrNO 2 Calculated value 311.1 Da, measured value 256, 258 m / z [M+H-56]+. Example 8: Synthesis of (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate tert-butyl ester

[0106] Under a nitrogen atmosphere, K₄Fe(CN)₆·3H₂O (17.3 g, 41 mmol, 0.5 equivalent), K₄Fe(CN)₆·3H₂O (17.3 g, 41 mmol, 0.5 equivalent), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (second-generation XPhos precatalyst, 965 mg, 1.2 mmol, 0.02 equivalent), X-phos (584 mg, 1.2 mmol, 0.01 equivalent), and KOAc (16.0 g, 163 mmol, 2.0 equivalent) were added to a solution of (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate in dioxane (270 mL) in water (270 mL). The solution was stirred at 105 °C for 5 hours, and then diluted with ethyl acetate (500 mL). The solid was removed by filtration. The filtrate was separated, and the aqueous layer was extracted twice with ethyl acetate (300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (15% ethyl acetate / petroleum ether) to give 20.0 g (94%) (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate tributyl ester. LRMS (ES): C 15H 18N 2O 2 Calculated value 258.1 Da, measured value 259 m / z [M+H]+. Example 9: Synthesis of (R)-1-amino-2,3-dihydro-1H-indene-5-formonitrile hydrochloride

[0107] To a solution of (R)-(5-cyano-2,3-dihydro-1H-indene-1-yl)carbamate tributyl ester (20.0 g, 77 mmol, 1.0 equivalent) in CH₂Cl₂, 4 M HCl in dioxane (192.5 mL, 770 mmol, 10 equivalent) was added. The mixture was stirred overnight and diluted with ethyl acetate (500 mL). The precipitate was collected by filtration, washed twice with petroleum ether (200 mL), and dried to give (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride (13.0 g, 86%) as a white solid. LRMS (ES): C₁₀H₁₀O₂ Calculated value 158.1 Da, measured value 159 m / z [M + H]⁺. Example 10: Synthesis of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine

[0108] 1-Methyl-1H-pyrazole-4-carboxylic acid (12.2 kg, 96.73 mol, 1.00 equivalent), 2-MeTHF (76.9 kg, 89.4 L), and DMF (62.9 g, 66.6 mL, 0.861 mol, 0.0089 equivalent) were charged into the reactor. Oxalic acid chloride (11.7 kg, 91.89 mol, 0.95 equivalent) was slowly added over a period of at least 45 minutes while maintaining the temperature below 35°C. The transfer line was flushed with 2-MeTHF (6.1 kg), and the flushing solution was sent to the reactor. The resulting mixture was stirred at 30 ± 5°C. After stirring at 30 ± 5°C for at least 8 hours (actual reaction time: 19.3 h), the IPC sample was collected and analyzed by HPLC. The reaction was considered complete when the IPC (specification: 1-methyl-1H-pyrazole-4-carboxylic acid ≤ 15% area; result: 9.6% 1-methyl-1H-pyrazole-4-carboxylic acid) was met. This reaction mixture could be used directly for the synthesis of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide without further treatment.

[0109] Solid NaOH (14.6 kg, 366.0 mol, 3.78 equivalents) was dissolved in 78.3 kg of water.

[0110] (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride (17.9 kg, 91.89 mol, 0.95 equivalents) and 2-MeTHF (63.9 kg, 74.3 L) were charged into a separate reactor. A prepared 4N NaOH solution (92.9 kg) was added to the mixture while maintaining the temperature < 30 °C. The drum containing the NaOH solution was rinsed with water (12.2 kg), and the rinse solution was transferred to a reaction vessel. The mixture was stirred at 20 °C for 30 min to obtain a clear two-phase solution. Over a period of at least 20 min, a prepared solution of 1-methyl-1H-pyrazole-4-carboxylic acid and acetic acid in 2-MeTHF was slowly transferred to an amine-free solution while maintaining the internal temperature < 30 °C. The reactor used for acetic acid was rinsed with 2-MeTHF (12.2 kg, 14.2 L), and the rinse solution was added to the reaction mixture. After the addition of chlorophenyl chloride, a large amount of solid was formed. The resulting mixture was stirred at 20±5°C for at least 5 hours (actual reaction time: 17.8 hours), and the reaction was considered complete when the IPC (specification: (R)-1-amino-2,3-dihydro-1H-indene-5-nitrile ≤ 5%; result 0.7%) was met.

[0111] The solid product (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine was collected by filtration, and the wet filter cake was washed with 2-MeTHF (24.4 kg, 28.4 L) and water (3 × 211.5 kg, 1 x 36.6 kg). The pH of the filtrate after the final water wash was measured (specification: pH 8.5 ± 1.5; result: pH 8.7).

[0112] The material was dried in a disc dryer at <45°C under vacuum with slow nitrogen evacuation for at least 20 hours until the LOD was met (specification: ≤3% w / w; result: 0.8% w / w). The product was dried for 64.7 hours to obtain 21.5 kg (87.8% yield) of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine, and its purity was analyzed (specification: ≥97.0% area; result: 99.4% area). Example 11: Synthesis of (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine

[0113] A solution of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methamide (21.0 kg, 78.86 mol, 1.00 equivalent) in NMP (108.2 kg, 105.3 L, 5.0 volume) was cooled to 5 ± 5 °C, and a 50% aqueous solution of hydroxylamine (15.6 kg, 236.58 mol, 3.00 equivalent) was slowly added over a period of at least 10 min, while maintaining the internal temperature ≤ 10 °C. The mixture was then slowly heated to 20 ± 5 °C over a period of at least 2 h and stirred at 20 ± 5 °C for at least 16 h (actual reaction time: 19.7 h). Obtain the IPC of the reaction completion (specification: ≤ 2% CK-3834025, result: 0.05% CK-3834025, 0.65% byproduct acetylamine).

[0114] After the reaction was complete, the mixture was heated to 65 ± 5 °C (clear solution). IPAc (182.8 kg, 209.6 L, 10.0 L / v) was slowly added over a period of at least 1 hour while maintaining an internal temperature ≥ 50 °C. Upon addition of IPAc, a large amount of solid was formed. The resulting mixture was stirred at 60 ± 5 °C for 1 hour. The mixture was slowly cooled to 20 ± 5 °C over a period of 4 hours and stirred at 20 ± 5 °C for at least 8 hours (actual duration: 15.3 hours of stirring). The solid was collected by filtration. The wet filter cake was washed with IPAc [2 × 98.8 kg (2 × 113.3 L, 2 × 5.4 L / v)]. The material was initially dried on a filter under vacuum for at least 1 hour. The wet filter cake sample of (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine was collected and analyzed by HPLC. Results: 99.49% product (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine, 0.27% byproduct pyramine. The starting material (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine was not detected. The material was dried in a vacuum disc dryer at ≤ 50°C for at least 24 h (actual drying time: 24.3 h) until the LOD specification was met (specification: LOD ≤ 1% w / w; result: 0.10% w / w).

[0115] The purity of (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed (specification: ≥ 95% area; result: 99.5% area (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, with 0.26 area% of pyrazole as a byproduct). A total of 21.8 kg of (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained (92.4% yield). Example 12: Synthesis of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine

[0116] CDI (11.9 kg, 73.67 mol, 1.05 equivalent) and CH3CN (131.4 kg, 167.2 L) were charged into reactor (vessel 1), and the resulting mixture was treated with propionic acid (5.7 kg, 77.18 mol, 1.10 equivalent) while maintaining the temperature < 25 °C. The transfer line was flushed with CH3CN (10.2 kg, 13.0 L), and the flushing solution was transferred to the main reaction mixture. The resulting clear solution was stirred at 20 ± 5 °C for at least 1 h. The reaction was considered complete when the IPC (specification: free propionic acid ≤ 20 mol%, by 1H NMR; result: 4.8% free propionic acid) was met.

[0117] (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine (21.0 kg, 70.16 mol, 1.00 equivalent) and CH3CN (40.4 kg, 51.4 L) were charged into a separate reactor (vessel 2). The freshly prepared active imidazole solution in vessel 1 was transferred to vessel 2. Vessel 1 was rinsed with CH3CN (20.2 kg, 25.7 L), and the rinse solution was transferred to vessel 2. The mixture was heated to 50 ± 5 °C. The reactants were stirred at this temperature for at least 12 hours (actual reaction time: 16.6 hours). The mixture was a readily stirable slurry. IPC sample obtained (specification: (R)-N-(5-(N'-hydroxyaminomethoxy)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methoxyamine ≤ 2%, result: 0.28%).

[0118] DBU (21.4 kg, 140.32 mol, 2.00 equivalents) was then added to the reactants. The transfer line was flushed with CH3CN (6.5 kg, 8.3 L), and the flushing solution was transferred to the bulk solution. The temperature was adjusted to 70 ± 5 °C, and the mixture was stirred at 70 ± 5 °C for at least 2 h until the IPC (specification: imidazole intermediate ≤ 2 area %; result: 0.16% imidazole intermediate) was met.

[0119] The reaction mixture was quenched by adding water (64.6 kg) while maintaining the temperature ≥ 50°C. The temperature was adjusted to 55 ± 5°C and the mixture was filtered. The solution was concentrated at a temperature ≤ 50°C but not lower than 10°C until the batch volume was approximately 200 L. The concentrated slurry was heated to 75 ± 5°C and diluted with water (417.3 kg) to obtain a clear solution while maintaining the temperature ≥ 70°C. The temperature was adjusted to 75 ± 5°C and the mixture was stirred at 75 ± 5°C for 2 h. The mixture was then slowly cooled to 20 ± 5°C over a period of at least 4 h. The mixture was stirred at 20 ± 5°C for at least 2 h (actual reaction time: 11.5 h).

[0120] The solids were collected by filtration and the wet filter cake was washed with water (3 × 161.5 kg). The solids were dried in a vacuum oven at ≤ 50 °C with slow nitrogen venting for at least 24 h (actual drying time: 48 h) and the LOD was analyzed (specification: LOD ≤ 1% w / w; result: LOD 0.05% w / w).

[0121] The purity of dried (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed (specification: ≥97% area; result: 100% area). A total of 22.0 kg of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained (92.8% yield). The product (22.0 kg) was then de-agglomerated to give 21.4 kg (97.3%). Example 13: Synthesis of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methamide

[0122] DIEA (7.5 mL, 45.4 mmol, 3.0 equivalent) was added to a mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (2.3 g, 18.2 mmol, 1.2 equivalent), HOBt (2.1 g, 15.1 mmol, 1.0 equivalent), and EDC (5.8 g, 30.3 mmol, 2.0 equivalent) in DMF (10 mL). The mixture was stirred for 10 min, followed by the addition of (R)-1-amino-2,3-dihydro-1H-indene-5-carboxynitrile hydrochloride (2.9 g, 15.1 mmol, 1.0 equivalent). The reaction mixture was stirred overnight and then diluted with water (60 mL). The solid was collected, washed with water (20 mL), and dried to give 3.5 g (86%) of (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine as a grayish-white solid. ¹H NMR (400 MHz, dichloromethane-d²) δ 7.86 (s, ¹H), 7.74 (d, J = 0.8 Hz, ¹H), 7.60 – 7.48 (m, 2H), 7.48 – 7.42 (m, 1H), 6.06 (d, J = 8.4 Hz, 1H), 5.69 (q, J = 8.3 Hz, 1H), 3.94 (s, 3H), 3.15 – 2.90 (m, 2H), 2.74–2.64 (m, 1H), 2.03–1.90 (m, 1H). LRMS (ES): C₁₅H₁₄NO calculated 266.1 Da, measured 267.1 m / z [M⁺H]⁺. Example 14: (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine

[0123] Hydroxylamine (50% w / w in water, 4.0 mL) was added to a suspension of (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine (3.0 g, 11.3 mmol, 1.0 equivalent) in EtOH (20 mL). The mixture was heated to 80 °C for 3 h and concentrated to give 3.3 g (98%) of (R,Z)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine as a grayish-white solid. LRMS (ES): C 15H 17N 5O 2 Calculated value 299.1 Da, measured value 300.1 m / z [M + H] +. Example 15: (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-methylamine

[0124] Hydroxylamine (50% w / w in water, 17.7 g, 3.0 equivalent) was added to a solution of (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine (24.0 g, 89.5 mmol, 1.0 equivalent) in NMP (120 mL). The mixture was stirred at room temperature for 18 hours and water (240 mL) was added. The reaction mixture yielded a thin slurry, which was filtered and washed with deionized water (120 mL x 3) for 2 hours to give 25.1 g (93.1%) of (R)-N-(5-(N'-hydroxyaminomethyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-methylamine as a grayish-white solid. LRMS (ES): C 15H 17N 5O 2 Calculated value 299.1 Da, measured value 300.1 m / z [M + H] +.

Claims

1. A method for preparing a compound of formula (5): (5), comprising: (i) converting a compound of formula (7) (7) into a compound of formula (6) (6) by reacting the compound of formula (7) with (R)-tert-butanesulfinamide; and (ii) converting the compound of formula (6) into the compound of formula (5) by reacting the compound of formula (6) with a reducing agent.

2. The method of claim 1, wherein the reaction of the compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of a Lewis acid.

3. The method of claim 1 or 2, wherein the reaction of the compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of a water scavenger.

4. The method of claim 1 or 2, wherein the reaction of the compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of titanium ethoxide.

5. The method of claim 1 or 2, wherein the reaction of the compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of toluene at a temperature between 75°C and 85°C.

6. The method of claim 1 or 2, wherein the reaction of the compound of formula (6) with the reducing agent is carried out in the presence of tetrahydrofuran at a temperature between -15°C and -5°C.

7. The method of claim 1 or 2, wherein the reducing agent is sodium borohydride.

8. The method of claim 1 or 2, wherein the compound of formula (6) can be used without post-treatment or purification.

9. The method of claim 1 or 2, further comprising converting the compound of formula (5) into the compound of formula (4), or a salt thereof, by hydrolyzing the sulfinamide of the compound of formula (5).

10. The method of claim 9, wherein the hydrolysis of the sulfinamide compound of formula (5) is carried out in the presence of an aqueous solution of acid.

11. The method of claim 9, wherein the compound of formula (4) is prepared as a hydrochloride.

12. The method of claim 9, wherein the compound of formula (4) is prepared as 4-methylbenzenesulfonate.

13. The method of claim 9 further comprises obtaining the compound of formula (4) by reacting a salt of the compound of formula (4) with a base.

14. The method of claim 9, further comprising converting the compound of formula (4) or a salt thereof into compound (3) of formula (3), or a salt thereof, by: (i) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and (ii) reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid with the compound of formula (4) or a salt thereof.

15. The method of claim 14, wherein the carboxylic acid activator is oxalic acid chloride.

16. The method of claim 14, wherein the carboxylic acid activator comprises a carbodiimide reagent.

17. The method of claim 14, wherein the carboxylic acid activator comprises a carbodiimide reagent and hydroxybenzotriazole.

18. The method of claim 14, further comprising converting the compound of formula (3) or a salt thereof into compound (2) of formula (2), or a salt thereof, by reacting hydroxylamine with the compound of formula (3) or a salt thereof.

19. The method of claim 18, wherein the reaction of the compound of formula (3) or its salt with hydroxylamine is carried out at a temperature of 25°C or lower.

20. The method of claim 18, wherein the reaction of the compound of formula (3) or a salt thereof with hydroxylamine is carried out in the presence of N-methylpyrrolidone.

21. The method of claim 18 further comprises converting the compound of formula (2) or a salt thereof into the compound of formula (1) or a salt thereof by: (i) reacting propionic acid with a second carboxylic acid activator to form activated propionic acid, and (ii) reacting the activated propionic acid with the compound of formula (2) or a salt thereof.

22. The method of claim 21, wherein the second carboxylic acid activator is carbonyl diimidazole.

23. A method (4) for preparing a compound of formula (4) or a salt thereof, comprising converting a compound of formula (5): (5), into a compound of formula (4) or a salt thereof by hydrolyzing a sulfinamide of the compound of formula (5).

24. The method of claim 23 further comprises obtaining the compound of formula (5) by reacting a reducing agent with the compound of formula (6): (6) to form the compound of formula (5).

25. The method of claim 24, wherein the reducing agent is a borohydride reducing agent.

26. The method of claim 24 or 25 further comprises obtaining the compound of formula (6) by reacting (R)-tert-butanesulfinamide with the compound of formula (7): (7), to form the compound of formula (6).