Process of obtaining afikamten

Abstract

FIELD: medicine.SUBSTANCE: method for producing intermediate compounds (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, which provides treatment for cardiac diseases and conditions, is proposed.EFFECT: method for producing a compound of formula (5) comprises reacting a compound of formula (7) with (R)-tert-butanesulfinamide to produce a compound of formula (6) and subsequently converting it into a compound of formula (5) by reaction with a reducing agent.26 cl, 15 ex

Description

Cross-reference to a related application

[0001] This application claims the benefit of 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.TECHNICAL FIELD

[0002] The present document provides a method for producing (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, its intermediate compounds and salts thereof.BACKGROUND ART

[0003] The cardiac sarcomere consists of a network of contractile and structural proteins that regulate cardiac muscle function. Components of the cardiac sarcomere represent a target for the treatment of various diseases and pathological conditions of the heart, for example, by increasing contractility or promoting complete relaxation to modulate systolic and diastolic functions, respectively. The force and velocity of cardiac muscle contraction are the main determinants of organ function and are modulated by cyclic interactions between actin and myosin. Regulation of actin and myosin binding is determined by a network of myofilament regulatory proteins and intracellular Ca levels. 2+ The troponin complex and tropomyosin are thin filament proteins that regulate the availability of actin binding sites, while essential and regulatory light chains and myosin binding protein C modulate the position and mechanical properties of myosin.

[0004] Cardiac sarcomere abnormalities have been identified as a primary cause of various cardiac diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomere proteins cause disease by making the heart muscle hyper- or hypo-contractile. Cardiac sarcomere modulators can be used to restore contractility and halt or reverse the disease.

[0005] Current cardiac sarcomere-targeting agents, such as inotropes (drugs that increase cardiac contractility), are poorly selective for cardiac tissue, leading to known adverse effects that limit their use. These adverse effects include cellular damage caused by increased energy expenditure, exacerbation of relaxation impairments, and potential arrhythmogenic side effects that may arise from increased cytosolic Ca++ and cyclic AMP concentrations in inotropically stimulated myocardium. Given the limitations of current agents, new approaches are needed to improve cardiac function in HCM and HFpEF.

[0006] U.S. Patent No. 10836755 discloses (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, a selective allosteric inhibitor of cardiac myosin that has little or no effect on smooth muscle myosin. The advantages of this compound include a broader therapeutic index, lesser effect on cardiac relaxation, better pharmacokinetics, and improved safety, and therefore, it provides potential treatment for cardiac diseases and conditions.

[0007] There is a need for improved methods for producing such a compound at low cost and high overall yield and purity. SUMMARY OF THE INVENTION

[0008] In one aspect, the present document provides a method for producing a compound of formula (1): or a salt thereof, comprising(i) converting a compound of formula (7) or its salt into a compound of formula (6) or a salt thereof;(ii) converting a compound of formula (6) or a salt thereof into a compound of formula (5) or a salt thereof; and(iii) converting a compound of formula (5) or a salt thereof to a compound of formula (1) or a salt thereof. In some embodiments, converting a compound of formula (7) or a salt thereof to a compound of formula (6) or a salt thereof comprises reacting a compound of formula (7) with (R)-tert-butanesulfinamide. In some embodiments, reacting a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of a Lewis acid. In some embodiments, reacting a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of a water neutralizer. In some embodiments, reacting a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of titanium ethoxide. In some embodiments, reacting a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of toluene at a temperature of from about 75°C to about 85°C.

[0009] In some embodiments, converting a compound of formula (6) or a salt thereof to a compound of formula (5) or a salt thereof comprises reacting the compound of formula (6) with a reducing agent. In some embodiments, reacting the compound of formula (6) with a reducing agent is carried out in the presence of tetrahydrofuran at a temperature of about -15°C to about -5°C. In some embodiments, the reducing agent is sodium borohydride. In some embodiments, the compound of formula (6) is used without processing or purification.

[0010] In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (1) or a salt thereof comprises converting a compound of formula (5) or a salt thereof to a compound of formula (4) or a salt thereof. In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (4) or a salt thereof comprises hydrolyzing a sulfinamide of the compound of formula (5) or a salt thereof. In some embodiments, hydrolyzing a sulfinamide of the compound of formula (5) or a salt thereof is carried out in the presence of aqueous acid. In some embodiments, a salt of the compound of formula (4) is (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride. In some embodiments, a salt of the compound of formula (4) is (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile-4-methylbenzenesulfonate. In some embodiments, the method further comprises producing a compound of formula (4) by reacting a salt of the compound of formula (4) with a base.

[0011] In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (1) further comprises converting a compound of formula (4) or a salt thereof to a compound of formula (3) or a salt thereof. In some embodiments, converting a compound of formula (4) or a salt thereof to a compound of formula (3) or a salt thereof comprises: (i) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a carboxylic acid activating agent 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 activating agent is oxalyl chloride. In some embodiments, the carboxylic acid activating agent comprises a carbodiimide reagent. In some embodiments, the carboxylic acid activating agent comprises a carbodiimide reagent and hydroxybenzotriazole.

[0012] In some embodiments, converting the compound of formula (5) or a salt thereof to the compound of formula (1) or a salt thereof further comprises converting the compound of formula (3) or a salt thereof to the compound of formula (2) or a salt thereof. In some embodiments, converting a compound of formula (3) or a salt thereof to a compound of formula (2) or a salt thereof comprises reacting hydroxylamine with the compound of formula (3) or a salt thereof. In some embodiments, reacting the compound of formula (3) or a salt thereof with hydroxylamine is carried out at a temperature of 25°C or below. In some embodiments, reacting the compound of formula (3) or a salt thereof with hydroxylamine is carried out in the presence of N-methylpyrrolidone.

[0013] In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (1) further comprises converting a compound of formula (2) or a salt thereof to a compound of formula (1) or a salt thereof. In some embodiments, converting a compound of formula (2) or a salt thereof to a compound of formula (1) or a salt thereof comprises: (i) reacting propionic acid with a second carboxylic acid activating agent 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 activating agent is carbonyldiimidazole.

[0014] In another aspect, a method for producing a compound of formula (4) or a salt thereof by converting a compound of formula (5): or its salt into a compound of formula (4) or its salt.

[0015] In some embodiments, the method for producing a compound of formula (4) further comprises producing a compound of formula (5) or a salt thereof by reacting a reducing agent with a compound of formula (6): or a salt thereof to form a compound of formula (5) or a salt thereof.

[0016] In some embodiments, the reducing agent is a borohydride reducing agent.

[0017] In some embodiments, the method for producing a compound of formula (4) further comprises producing a compound of formula (6) or a salt thereof by reacting (R)-tert-butanesulfinamide with a compound of formula (7): to form a compound of formula (6) or a salt thereof.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0018] As used herein, and unless otherwise stated or required by context, the terms used herein have the meanings defined below. Unless otherwise stated or implied, for example by the inclusion of mutually exclusive elements or variants, in these definitions and throughout the description, the singular means one or more, and the term "or" means "and / or" if the context so permits. Thus, when used in the context of the description of the present invention and in the appended claims of the present invention, the singular includes plural references unless the context clearly requires otherwise.

[0019] In various places of the present invention, for example, in any of the described embodiments or in the claims, reference is made to compounds, compositions, or methods that "comprise / include" one or more of the stated components, elements, or steps. The embodiments also expressly include those compounds, compositions, or methods that are, or that consist of, or that consist essentially of these stated components, elements, or steps. The term "consisting of" is used interchangeably with the term "comprising," and they are equivalent terms. For example, described compositions, devices, articles, or methods that "comprise" a component or step are not limiting and include these compositions or methods plus additional component(s) or step(s).However, these terms do not include unlisted elements that would impair the functionality of the described compositions, devices, articles, or methods with respect to their intended purpose. Similarly, described compositions, devices, articles, or methods that "consist of" a component or step are limiting and do not include compositions or methods having significant amounts of additional component(s) or additional step(s). Furthermore, the term "consisting essentially of" allows for the inclusion of unlisted elements that do not significantly affect the functionality of the described compositions, devices, articles, or methods with respect to their intended purpose, as further defined herein. Section headings used in this document are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0020] As used in this document, the term "about" when used in connection with a numerical value or range of values ​​intended to describe a specific property of a compound or composition indicates that the value or range of values ​​may vary to an extent considered reasonable by one skilled in the art and still describe the specific property. Reasonable deviations include those that are within the accuracy or permissible error of the instrument(s) used in measuring that determines or establishes the specific property. In particular, the term "about," when used in this context, indicates that the numerical value or range of values ​​may vary by 10% from the stated value or range of values ​​and still describe the specific property.

[0021] As used herein, "protecting group," unless otherwise stated or implied by the context, refers to a moiety that prevents or substantially reduces the ability of the atom or functional group to which it is attached to participate in unwanted reactions. Typical protecting groups are given in Greene (2014), "Protective groups in organic synthesis, 5 th ed., Wiley Interscience. Protecting groups for heteroatoms such as oxygen, sulfur, and nitrogen are sometimes used to minimize unwanted reactions with electrophilic compounds. Alternatively, a protecting group is used to reduce or eliminate the nucleophilicity and / or basicity of the unprotected heteroatom. Non-limiting examples of protected oxygen are illustrated by -OR PR , where R PRis a hydroxyl protecting group, wherein the hydroxyl is, in some embodiments, protected as an ester (e.g., acetate, propionate, or benzoate). Other hydroxyl protecting groups allow the hydroxyl to avoid its influence on the nucleophilicity of organometallic reagents or other highly basic reagents by protecting the hydroxyl as an ester in some embodiments, including, but not limited to, alkyl or heterocyclyl ethers (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methylsilyl (SEM)). Nitrogen protecting groups include groups for primary or secondary amines as in -NHR PR or -N(R PR)2, where at least one R PR represents a protecting group of the nitrogen atom or both R PR together they define the protecting group of the nitrogen atom.

[0022] A protecting group is suitable for protection when it is capable of preventing or substantially preventing unwanted side reactions and / or premature loss of the protecting group under reaction conditions required to effect the necessary chemical transformations at a certain location in the molecule and during purification of the newly formed molecule, if necessary, and can be removed under conditions that do not adversely affect the structure or stereochemical integrity of the newly formed molecule. In some aspects, suitable protecting groups are those described above for the protection of functional groups. For example, a suitable protecting group for the basic nitrogen atom of an acyclic or cyclic basic group is an acid-labile carbamate protecting group, such as tert-butyloxycarbonyl (Boc).

[0023] Each compound disclosed herein may be in salt form. The compound may contain at least one amino group, and accordingly, acid addition salts can be formed with the amino group. Exemplary salts include, but are not limited to, salts such as sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, lactate, salicylate, hydrogen citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene bis-(2-hydroxy-3-naphthoate)).

[0024] A salt may include another molecule, such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge of the parent 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 counterions may be present. Therefore, a salt may have one or more charged atoms and / or one or more counterions.

[0025] “Pharmaceutically acceptable salt” refers to salts that have toxicity profiles in the range that allow pharmaceutical use. In some embodiments, the pharmaceutically acceptable salt is selected from those described in P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. The choice of salt depends on the properties that the drug product must exhibit, including adequate solubility in water at different pH values, depending on the intended route(s) of administration, crystallinity with flow characteristics and low hygroscopicity (i.e., water absorption depending on relative humidity), suitable for processing and the required shelf life as determined by chemical and solid-phase stability under accelerated conditions (i.e., to determine disintegration or solid-phase changes upon storage at 40 °C and 75% relative humidity). Methods

[0026] In one aspect, the present document provides a method for producing a compound of formula (1): or a salt thereof, comprising(i) converting a compound of formula (7) or its salt into a compound of formula (6) (6), or a salt thereof; (ii) converting a compound of formula (6) or a salt thereof into a compound of formula (5) (5), or a salt thereof; and(iii) converting the compound of formula (5) or a salt thereof into a compound of formula (1) or a salt thereof.

[0027] In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (1) or a salt thereof comprises converting a compound of formula (5) or a salt thereof to a compound of formula (4) or a salt thereof.

[0028] In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (1) further comprises converting a compound of formula (4) or a salt thereof to a compound of formula (3) or a salt thereof.

[0029] In some embodiments, converting a compound of formula (5) or a salt thereof to a compound of formula (1) or a salt thereof further comprises converting a compound of formula (3) or a salt thereof to a compound of formula (2) or a salt thereof.

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

[0031] In some embodiments of the above, provided herein is a method for preparing a compound of formula (1) according to the scheme below: General Preparation of Compound of Formula (1) Obtaining a compound of formula (1)

[0032] In one aspect, the present document provides a method for producing a compound of formula (1): (1), or its salt, involving the transformation of a compound of formula (2): (2), or a salt thereof, into a compound of formula (1) or a salt thereof. In some embodiments, a method for producing a compound of formula (1) is provided, comprising converting a compound of formula (2) into a compound of formula (1).

[0033] In some embodiments, the method of converting a compound of formula (2) or a salt thereof into a compound of formula (1) or a salt thereof comprises reacting the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid or a propionyl equivalent, such as propionyl chloride or propionyl bromide. In some embodiments, activated propionic acids include, but are not limited to, propionic anhydride, 1H-imidazole-1-carboxylic propionic anhydride, propionic acid esters such as methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate and tert-butyl propionate.

[0034] In some embodiments, the reaction of a compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or a propionyl equivalent is carried out in the presence of an organic solvent. In some embodiments, organic solvents include, but are not limited to, acetonitrile (ACN or MeCN), benzene, chloroform, dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, and the like. In some embodiments, the organic solvent is free of or substantially free of water. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those provided as embodiments herein. 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 is understood that each description of the organic solvent can be combined with each description of propionic acid, activated propionic acid, or propionyl equivalent, just as if each combination were specifically and individually stated.

[0035] In some embodiments, the reaction of a compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or a propionyl equivalent further comprises a base. In some embodiments, the reaction of a compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or a propionyl equivalent is carried out in the presence of a base. In some embodiments, after the reaction of a compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or a propionyl equivalent, a base is added. In some embodiments, the base is an inorganic base. In some embodiments, inorganic bases include, but are 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, collidine, lutidine, pyridine, picoline, dicyclohexylamine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is DBU.It is understood that each description of the base may be combined with each description of the organic solvent and with each description of propionic acid, activated propionic acid, or propionyl equivalent, just as if each combination were specifically and individually stated.

[0036] In some embodiments, the reaction of a compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or a propionyl 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 of from about 0°C to about 153°C, from about 0°C to about 150°C, from about 0°C to about 100°C, from about 20°C to about 100°C, from about 20°C to about 80°C, from about 30°C to about 70°C, from about 40°C to about 60°C, or from about 45°C to about 55°C. In some embodiments, the reaction is carried out at a temperature of from about 110°C to about 130°C. In some embodiments, the reaction is carried out at a temperature of from about 90°C to about 110°C. In some embodiments, the reaction is carried out at a temperature of from about 50°C to 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 of from about 40°C to about 80°C.In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of from about 50°C to about 70°C. It is understood that each description of a temperature or temperature range can be combined with each description of propionic acid, activated propionic acid, or propionyl equivalent, each description of an organic solvent, and / or each description of a base, just as if each combination were specifically and individually recited.

[0037] 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 of the above; 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; and followed by adding a base selected from DBU, DBN, potassium carbonate and DIEA, with an increase in temperature 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 adding a base, such as DBU, and increasing the temperature 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 below, followed by the addition of a base, such as DBU, and increasing the temperature 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 below, followed by the addition of a base, such as DBU, and increasing the temperature to about 70°C. It is understood that each solvent description may be combined with each propionic acid, activated propionic acid, or propionyl equivalent description and / or each base description, just as if each combination were specifically and individually recited.

[0038] In another aspect, the present document provides a method for producing a compound of formula (1): (1), or a salt thereof, comprising: (i) reacting propionic acid with a first carboxylic acid activating agent to form activated propionic acid, and (ii) reacting the activated propionic acid from step (i) with a compound of formula (2): (2), or a salt thereof 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 the compound of formula (2) to form a compound of formula (1).

[0039] In some embodiments, carboxylic acid activating agents include acid chlorides such as thionyl chloride, oxalyl chloride, or methanesulfonyl chloride; acid anhydrides such as acetic anhydride; carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI), optionally in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) or hydroxybenzotriazole (HOBt);or other amide coupling reagents such as azabenzotriazoletetramethyluronium hexafluorophosphate (HATU), benzotriazoletetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), and carbonyldiimidazole. In some embodiments, the first carboxylic acid activating agent of step (i) (the step of reacting propionic acid with the first carboxylic acid activating agent to form activated propionic acid) is carbonyldiimidazole.

[0040] In some embodiments, each of step (i) (reacting propionic acid with a first carboxylic acid activating agent to form activated propionic acid) and step (ii) (reacting the activated propionic acid from step (i) with a compound of formula (2)) is carried out in an organic solvent. In some embodiments, each of step (i) and step (ii) is carried out in the same organic solvent. In some embodiments, organic solvents include, but are 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 described as embodiments herein.In some embodiments, the organic solvent does not contain or is substantially free of water. In some embodiments, the organic solvent includes water. In some embodiments, the organic solvent for step (i) includes acetonitrile. In some embodiments, the organic solvent for step (ii) includes acetonitrile. In some embodiments, the organic solvent for both step (i) and step (ii) includes acetonitrile. In some embodiments, the organic solvent for step (ii) includes 1,4-dioxane. In some embodiments, the organic solvent for both step (i) and step (ii) includes 1,4-dioxane.

[0041] In some embodiments, step (ii) (reacting the activated propionic acid from 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, step (ii) is followed by the addition of a base. In some embodiments, the base is an inorganic base. In some embodiments, inorganic bases include, but are 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, collidine, lutidine, pyridine, picoline, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is DBU. It is understood that each description of the base can be combined with each description of the solvent, just as if each combination were specifically and individually recited.

[0042] In some embodiments, step (i) (reacting propionic acid with a first carboxylic acid activating agent to form activated propionic acid) is conducted 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 conducted at a temperature of from about 0°C to about 80°C. In some embodiments, step (i) is conducted at a temperature of from about 0°C to about 50°C. In some embodiments, step (i) is conducted at a temperature of from about 10°C to about 40°C. In some embodiments, step (i) is carried out at a temperature of about 15°C to about 35°C. In some embodiments, step (i) is carried out at a temperature of about 25°C.In some embodiments, step (i) is carried out at a temperature of 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 carried out at a temperature of less than about 35°C, less than about 30°C, or less than about 25°C. In some embodiments, step (i) is carried out at a temperature of less than about 25°C. In some embodiments, step (ii) (reacting the activated propionic acid from step (i) with the compound of formula (2)) is conducted 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 conducted at a temperature of about 50°C. In some embodiments, step (ii) is conducted at a temperature of from about 0°C to about 80°C.In some embodiments, step (ii) is carried out at a temperature of about 30°C to about 80°C. In some embodiments, step (ii) is carried out at a temperature of about 45°C to about 75°C. In some embodiments, step (ii) is carried out at a temperature of about 50°C to about 70°C. In some embodiments, step (ii) is carried out at a temperature of about 45°C to 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 the temperature to about 70°C or higher. It is understood that each description of temperature can be combined with each description of base and / or organic solvent, just as if each combination were specifically and individually recited.For example, in some embodiments, step (i) is carried out in acetonitrile at a temperature of about 25°C or below, 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 is understood that each description of temperature or temperature range can be combined with each description of a carboxyl activating agent, each description of an organic solvent, and / or each description of a base, just as if each combination were specifically and individually recited.

[0043] In some embodiments, step (ii) (reacting the activated propionic acid from step (i) with the compound of formula (2)) is followed by adding water to the reaction mixture. In some embodiments, the diluted reaction mixture is subjected to a control filtration and the filtrate is concentrated to a slurry. In some embodiments, the diluted reaction mixture is subjected to a control filtration and the filtrate is concentrated to a slurry at a temperature of about 10°C to 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 of about 70°C to about 80°C before diluting with water to form a mixture, while maintaining the temperature of the mixture at least about 70°C. In some embodiments, the mixture is filtered to obtain the compound of formula (1) as a solid.In some embodiments, the mixture is cooled to a temperature of about 15°C to about 25°C before filtering the mixture to obtain the compound of Formula (1) as a solid. In some embodiments, the compound of Formula (1) is isolated as a wet solid. In some embodiments, the wet cake 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 triturated.

[0044] It should be understood that each description of the conditions for step (i) (reacting propionic acid with a first carboxylic acid activating agent to form activated propionic acid) and step (ii) (reacting the activated propionic acid from step (i) with a compound of formula (2)) can be combined, just as if each combination were specifically and individually stated. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyldiimidazole in acetonitrile to form activated propionic acid, and step (ii) comprises reacting the activated propionic acid with a compound of formula (2), then reacting with DBU.For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyldiimidazole in acetonitrile at a temperature of 25°C or below to produce 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, then reacting with DBU in acetonitrile at a temperature of about 70±5°C. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyldiimidazole in acetonitrile at a temperature of 25°C or below to produce 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, then reacting with DBU in acetonitrile at a temperature of about 70±5°C, then adding water.For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyldiimidazole in acetonitrile at a temperature of 25°C or below to produce 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, then reacting with DBU in acetonitrile at a temperature of about 70±5°C, then adding water, checking by filtration, concentrating to a slurry at a temperature of about 10°C to about 50°C, heating to a temperature of 70°C to about 80°C before diluting with water to form a mixture, cooling to a temperature of about 15°C to about 25°C, and filtering the mixture to obtain a compound of formula (1) as a solid. Obtaining a compound of formula (2).

[0045] In some embodiments, a compound of formula (2) or a salt thereof is prepared by converting a compound of formula (3): or a salt thereof into a compound of formula (2) or a salt thereof. 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, the hydroxylamine is provided as aqueous hydroxylamine. In some embodiments, the reaction of hydroxylamine with a compound of formula (3) is carried out in an organic solvent. In some embodiments, organic solvents include, but are not limited to, acetonitrile, dimethylformamide, dimethylsulfoxide, 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 exemplified 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.

[0046] In some embodiments, the reaction of hydroxylamine with a 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 of about -20°C to about 50°C. In some embodiments, the reaction is carried out at a temperature of about -10°C to about 50°C. In some embodiments, the reaction is carried out at a temperature of about 0°C to about 50°C.In some embodiments, the reaction is carried out at a temperature of about 0°C to about 40°C. In some embodiments, the reaction is carried out at a temperature of about 0°C to about 30°C. In some embodiments, the reaction is carried out at a temperature of about 5°C to about 25°C. In some embodiments, the reaction is carried out at a temperature of about 10°C to about 25°C. It is understood that each description of a temperature or temperature range can be combined with each description of an organic solvent, just as if each combination were specifically and individually recited. For example, in some embodiments, the method comprises reacting a compound of formula (3) with aqueous hydroxylamine in NMP at a temperature of about 10°C or lower, followed by heating to a temperature of about 15°C to about 25°C.For example, in some embodiments, the method comprises reacting a compound of formula (3) with aqueous hydroxylamine in NMP at room temperature or a temperature of about 25°C.

[0047] 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 tert-butyl acetate. In some embodiments, the co-solvent is isopropyl acetate. In some embodiments, the addition of the co-solvent is conducted 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 addition of the cosolvent is conducted at a temperature of about 50°C to about 80°C. In some embodiments, the addition of the cosolvent is conducted at a temperature of about 50°C to about 75°C. In some embodiments, the addition of the cosolvent is conducted at a temperature of about 65°C. In some embodiments, the precipitated compound of formula (2) is isolated by vacuum filtration as a wet cake. In some embodiments, the compound of formula (2) is dried under vacuum. It is understood that each description of the precipitation step can be combined with each description of the reaction conditions, just as if each combination were specifically and individually stated.For example, in some embodiments, the method comprises reacting a compound of formula (3) with aqueous hydroxylamine in NMP at a temperature of about 10°C or lower, followed by heating to a temperature of about 15°C to about 25°C, followed by heating to a temperature of about 60°C to 70°C and adding IPAc. For example, in some embodiments, the method comprises reacting a compound of formula (3) with aqueous hydroxylamine in NMP at room temperature or a temperature of about 25°C, followed by adding water at room temperature or a temperature of about 25°C. Obtaining a compound of formula (3).

[0048] In some embodiments, a compound of formula (3) or a salt thereof is prepared by(iii) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activating agent to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and(iv) reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) with a compound of formula (4): or a salt thereof to form a compound of formula (3) or a salt thereof. In some embodiments, step (iv) comprises reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) with a compound of formula (4) to form a compound of formula (3).

[0049] In some embodiments, the carboxylic acid activating agents include acid chlorides such as thionyl chloride, oxalyl chloride, or methanesulfonyl chloride; acid anhydrides such as acetic anhydride; carbodiimides such as DCC, DIC, or EDC, optionally in the presence of HOAt or HOBt; or other amide coupling reagents such as HATU, HBTU, HCTU, BOP, PyAOP, PyBOP, PyBroP; and carbonyldiimidazole. In some embodiments, the second carboxylic acid activating agent of step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with the second carboxylic acid activating agent to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) is oxalyl chloride. In some embodiments, the second carboxylic acid activating agent of 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 a carbodiimide reagent and HOAt or HOBt.

[0050] In some embodiments, step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activating agent 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, inorganic bases include, but are 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, organic bases include, but are not limited to, N,N-diisopropylethylamine (DIEA or DIPEA), methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, collidine, lutidine, pyridine, picoline, 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 is understood that each description of the base may be combined with each description of the carboxyl activating agent, just as if each combination were specifically and individually specified.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.

[0051] In some embodiments, step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activating agent to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) is conducted 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 conducted at a temperature below about 80°C. In some embodiments, step (iii) is conducted at a temperature below about 61°C. In some embodiments, step (iii) is conducted at a temperature below about 55°C. In some embodiments, step (iii) is conducted at a temperature below about 50°C. In some embodiments, step (iii) is conducted at a temperature below about 40°C. In some embodiments, step (iii) is carried out at a temperature below about 35°C.In some embodiments, step (iii) is carried out at a temperature of about 0°C to about 80°C. In some embodiments, step (iii) is carried out at a temperature of about 0°C to about 60°C. In some embodiments, step (iii) is carried out at a temperature of about 10°C to about 40°C. In some embodiments, step (iii) is carried out at a temperature of about 20°C to about 40°C. In some embodiments, step (iii) is carried out at a temperature of about 20°C to about 35°C. In some embodiments, step (iii) is carried out at a temperature of about 25°C to about 35°C. It is understood that each description of temperature or temperature range can be combined with each description of a carboxyl activating agent and / or each description of a base, just as if each combination were specifically and individually recited.

[0052] In some embodiments, step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activating agent 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 is understood that the solvent can be combined with each description of the carboxylic activating agent, each description of the base, and / or each description of the temperature or temperature range, just as if each combination were specifically and individually recited.For example, in some embodiments, step (iii) is carried out in the presence of EDC, HOBt, DIEA, and DMF at a temperature of about 40°C to about 20°C. In other embodiments, step (iii) is carried out in the presence of EDC, HOAt, DIEA, and DMF at a temperature of about 40°C to about 20°C. In other embodiments, step (iii) is carried out in the presence of oxalyl chloride and DMF at a temperature of about 40°C to about 20°C. In other embodiments, step (iii) is carried out in the presence of oxalyl chloride and DMF at a temperature below about 35°C. In other embodiments, the reaction is carried out in the presence of oxalyl chloride, 2-MeTHF, and DMF at a temperature of about 20°C to about 40°C, about 20°C to about 35°C, or about 25°C to about 35°C. In other embodiments, the reaction is carried out in the presence of oxalyl chloride, 2-MeTHF and DMF at a temperature below about 35°C.

[0053] In some embodiments, the crude product from step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activating agent to form activated 1-methyl-1H-pyrazole-4-carboxylic acid) is used without processing. In some embodiments, the crude product from step (iii) is used without purification.

[0054] In some embodiments, step (iv) (reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from 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, inorganic bases include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium carbonate, sodium bis(trimethylsilyl)amide, 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, organic bases include, but are not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, pyridine, or morpholine. In some embodiments, the base is aqueous. In some embodiments, the base is aqueous sodium hydroxide.

[0055] In some embodiments, step (iv) (reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid from step (iii) with a 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 is understood that each description of the organic solvent of step (iv) can be combined with each description of step (iii) (reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a second carboxylic acid activating agent to form activated 1-methyl-1H-pyrazole-4-carboxylic acid), each description of the base of step (iv), and / or each description of the temperature or temperature range of step (iv), just as if each combination were specifically and individually recited. For example, in some embodiments, step (iii) comprises reacting 1-methyl-1H-pyrazole-4-carboxylic acid with oxalyl chloride to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and step (iv) comprises reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid of step (iii) with a 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 oxalyl chloride 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 a 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 oxalyl chloride 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 a compound of formula (4)) in the presence of aqueous NaOH at a temperature below about 30°C.For example, in some embodiments, step (iii) and step (iv) comprise reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a compound of formula (4) in the presence of HOBt, EDC, and DIEA. For example, in some embodiments, step (iii) and step (iv) comprise reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a compound of formula (4) in the presence of HOBt, EDC, and DIEA in DMF.

[0056] In some embodiments, the compound of formula (3) is isolated by filtration to obtain a wet solid precipitate. In some embodiments, the wet solid precipitate is washed with a solvent such as 2-MeTHF or water. In some embodiments, the compound of formula (3) is dried under vacuum.

[0057] Scheme 1 shows the synthesis scheme of the compound of formula (1).

[0058] Scheme 2 shows an alternative scheme for the synthesis of the compound of formula (2). Obtaining a polymorph of the compound of formula (1)

[0059] In some embodiments of the above, the method for producing a compound of formula (1) further comprises producing a polymorph of the compound of formula (1). Methods for producing polymorphs of the compound of formula (1) are disclosed in WO 2021 / 011807, the contents of which are incorporated herein by reference in their entirety.

[0060] In some embodiments, the polymorph of the compound of formula (1) is polymorphic form I. In some embodiments, the polymorphic form is characterized by an diffraction pattern having peaks at 2-theta 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 a diffraction pattern having peaks at 2-theta 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.

[0061] In some embodiments, the polymorph of the compound of formula (1) is polymorphic form II. In some embodiments, the polymorphic form is characterized by an diffraction pattern having peaks at 2-theta 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 a diffraction pattern having peaks at 2-theta 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.

[0062] In some embodiments, the polymorph of the compound of formula (1) is polymorphic form III. In some embodiments, the polymorphic form is characterized by an diffraction pattern having peaks at 2-theta angles of 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees.

[0063] In some embodiments, the polymorph of the compound of formula (1) is polymorphic form IV. In some embodiments, the polymorphic form is characterized by an diffraction pattern having peaks at 2-theta 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 a diffraction pattern having peaks at 2-theta 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.

[0064] In some embodiments, the polymorph of the compound of formula (1) is polymorphic form V. In some embodiments, the polymorphic form is characterized by an diffraction pattern having peaks at 2-theta 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 a diffraction pattern having peaks at 2-theta 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 an diffraction pattern having peaks at 2-theta 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.

[0065] In some embodiments, the polymorph of the compound of formula (1) is polymorphic form VI. In some embodiments, the polymorphic form is characterized by an diffraction pattern having peaks at 2-theta 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 an diffraction pattern having peaks at 2-theta 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 the compound of formula (4)

[0066] In another aspect, the present document provides a method for producing a compound of formula (4): (4), or its salts by converting the compound of formula (5): (5), 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 producing a compound of formula (4) or a salt thereof comprises hydrolyzing the sulfinamide of a compound of formula (5) or a salt thereof.

[0067] In some embodiments, the sulfinamide of the compound of formula (5) is hydrolyzed in the presence of an aqueous acid. In some embodiments, the aqueous acid of the step is an inorganic acid. In some embodiments, inorganic acids include, but are 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, organic acids include 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 provided as embodiments herein. In some embodiments, the aqueous acid is hydrochloric acid.

[0068] In some embodiments, the sulfinamide of the compound of formula (5) is hydrolyzed in the presence of a base. In some embodiments, the sulfinamide is hydrolyzed in the presence of an aqueous base. In some embodiments, the base is an inorganic base. In some embodiments, inorganic bases include, but are 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, organic bases include, but are not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, collidine, lutidine, pyridine, picoline, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like.

[0069] In some embodiments, the hydrolysis of the sulfinamide is carried out in an organic solvent. In some embodiments, organic solvents include, but are not limited to, acetonitrile, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl-tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tert-butyl 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 described as embodiments herein. In some embodiments, the organic solvent includes water. It should be understood that each description of an acid or base can be combined with each description of an organic solvent, just as if each combination were specifically and individually recited.For example, in some embodiments, the hydrolysis of the sulfinamide is carried out in the presence of aqueous HCl. For example, in some embodiments, the hydrolysis of the sulfinamide is carried out in the presence of IPAc. For example, in some embodiments, the hydrolysis of the sulfinamide is carried out in the presence of aqueous HCl and IPAc.

[0070] In some embodiments, the compound of formula (4) is collected by filtration. In some embodiments, the filtration provides the compound of formula (4) as a wet cake. In some embodiments, the wet solid compound of formula (4) is washed with IPAc. In some embodiments, the compound of formula (4) is dried under vacuum. Preparation of the compound of formula (5)

[0071] In some embodiments, a compound of formula (5) or a salt thereof is prepared by reacting a reducing agent with a compound of formula (6): (6), or a salt thereof to form a compound of formula (5) or a salt thereof. 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, reducing agents include, but are not limited to, hydrogen in the presence of a catalyst such as a palladium catalyst, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, tin chloride, and the like. In some embodiments, the reducing agent is a borohydride reducing agent. In some embodiments, the reducing agent is sodium borohydride.

[0072] In some embodiments, the reaction of the compound of formula (6) with a reducing agent is carried out in the presence of a solvent. In some embodiments, organic solvents include, but are not limited to, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl-tetrahydrofuran, toluene, and the like. In some embodiments, the solvent includes toluene. In some embodiments, the solvent includes THF. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those provided as embodiments herein, for example, a mixture of toluene and THF. In some embodiments, the reaction is carried out at a temperature of from about -15°C to about -5°C.It should be understood that any combination of the above conditions is intended, 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 of from about -15°C to about -5°C. In some such embodiments, the reducing agent is sodium borohydride.

[0073] In some embodiments, the compound of formula (5) is isolated as a solid. 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 of formula (6)

[0074] In some embodiments, the compound of formula (6) is prepared by reacting (R)-tert-butanesulfinamide with a compound of formula (7): (7), 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 neutralizer. In some embodiments, reactants that act as a Lewis acid and a water neutralizer 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 of from about 75°C to about 85°C. In some embodiments, the compound of formula (6) is used without workup. 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 any combination of the above conditions is contemplated, for example, the reaction of (R)-tert-butanesulfinamide with a compound of formula (7) can be carried out in the presence of Ti(OEt)4 in toluene. For example, the reaction of (R)-tert-butanesulfinamide with a compound of formula (7) can be carried out in the presence of Ti(OEt)4 in toluene at a temperature from about 75°C to about 85°C. Preparation of a compound of formula (7).

[0075] In some embodiments, the compound of formula (7) is prepared by converting the compound of formula (8) (8) into a compound of formula (7). In some embodiments, converting a compound of formula (8) to a compound of formula (7) comprises reacting a compound of formula (8) via a palladium-catalyzed cyanation reaction using a cyanation reagent. In some embodiments, cyanation reagents include, but are not limited to, KCN, NaCN, Zn(CN)2, CuCN, trimethylsilyl cyanide, and ferricyanide. In some embodiments, the reaction comprises reacting a compound of formula (8) with Zn(CN)2 in the presence of a palladium catalyst. In some embodiments, the reaction comprises reacting a compound of formula (8) with Zn(CN)2 in the presence of XPhos and Pd2(dba)3. In some embodiments, the reaction is conducted at a temperature of from about 85°C to about 95°C.

[0076] 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 recrystallization solvent comprises ethanol. In some embodiments, the recrystallization solvent comprises water. In some embodiments, the recrystallization solvent comprises a mixture of ethanol and water.In some embodiments, recrystallization is carried out at a temperature of about 0°C to about 78°C. In some embodiments, recrystallization is carried out at a temperature of about 0°C to about 70°C. In some embodiments, recrystallization is carried out at a temperature of about 0°C to about 60°C. In some embodiments, recrystallization is initiated at a temperature of about 50°C to about 60°C, followed by cooling to a temperature of about 0°C to about 10°C.

[0077] It should be understood that any combination of the above conditions is contemplated, for example, in some embodiments, the reaction comprises reacting a compound of formula (8) with XPhos, Pd2(dba)3, and Zn(CN)2 in the presence of DMF and 2-MeTHF. For example, in some embodiments, the reaction comprises reacting a compound of formula (8) with XPhos, Pd2(dba)3, and Zn(CN)2 in the presence of DMF and 2-MeTHF at a temperature of from about 85°C to about 95°C, followed by hot filtration in ethanol, followed by recrystallization from a mixture of ethanol and water.

[0078] Scheme 3 illustrates the synthesis scheme of the HCl salt of the compound of formula (4).

[0079] The above methods for producing a compound of formula (4), which is (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile, or a salt thereof (e.g., (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride), show improvements over previous synthetic methods in the art. For example, the methods described herein require fewer synthetic steps, avoid the isolation and / or purification of certain intermediates, require fewer isolated intermediates, and provide a higher overall yield compared to the methods presented in U.S. Publication No. US2006 / 0173183A1 and WO 2006 / 083454, which describes the preparation of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride from 5-bromoindan-1-ylamine.For example, the methods described herein require fewer synthetic steps, provide higher overall yields, and eliminate the need for protecting groups, as well as eliminate the need for tin or azide reagents, compared to the methods presented in U.S. Patent No. 10,836,755, which describes the preparation of tert-butyl (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate from 5-bromo-2,3-dihydro-1H-inden-1-one. Alternative preparation of compound of formula (4).

[0080] In another aspect, the present document provides a method for producing a compound of formula (4): (4), or its salts by converting the compound of formula (A) (A), 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 (A) into a compound of formula (4) or a salt thereof. In some embodiments, converting a compound of formula (A) into a compound of formula (4) comprises reacting the compound of formula (A) with an acid. In some embodiments, the acid is an inorganic acid. In some embodiments, inorganic acids include, but are 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, organic acids include 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 isolated by vacuum filtration. In some embodiments, the compound of formula (4) or its salt is purified by solids washing with an organic solvent. In some embodiments, the compound of formula (4) or its salt is purified by solids washing with petroleum ether.

[0081] In some embodiments, a compound of formula (A) or a salt thereof is prepared by converting a compound of formula (B) (B) or a salt thereof into a compound of formula (A). In some embodiments, the method comprises converting a compound of formula (B) into a compound of formula (A). In some embodiments, converting a compound of formula (B) or a salt thereof into a compound of formula (A) or a salt thereof comprises reacting the compound of formula (B) or a salt thereof via a palladium-catalyzed cyanation reaction. In some embodiments, the reaction comprises reacting the compound of formula (B) or a salt thereof with potassium ferricyanide in the presence of a palladium catalyst. In some embodiments, the reaction comprises reacting the compound of formula (B) or a salt thereof 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, the base is an acetate base. In some embodiments, the base is potassium acetate.

[0082] In some embodiments, the compound of formula (A) is purified by trituration in ethyl acetate hexanes. In some embodiments, the compound of formula (A) is purified by trituration in 10% by volume ethyl acetate in hexanes. In some embodiments, the compound of formula (A) is purified by column chromatography. In some embodiments, the column chromatography comprises a silica gel column. In some embodiments, the compound of formula (A) is eluted from a column with ethyl acetate in petroleum ether. In some embodiments, the compound of formula (D) is eluted from a column with 15% by volume ethyl acetate in petroleum ether.

[0083] In some embodiments, a compound of formula (B) or a salt thereof is prepared by converting a compound of formula (C) (C) or a salt thereof into a compound of formula (B) or a salt thereof. 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 obtained by reacting a compound of formula (C) or a salt thereof with di-tert-butyl dicarbonate. In some embodiments, converting a compound of formula (C) into a compound of formula (B) further comprises reacting the compound of formula (C) with di-tert-butyl dicarbonate in the presence of a base. In some embodiments, bases include, but are not limited to, N,N-diisopropylethylamine, trimethylamine, diethylamine, triethylamine, tributylamine, collidine, lutidine, pyridine, picoline, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, and the like. In some embodiments, the base is triethylamine.In some embodiments, the compound of formula (B) is purified by trituration in hexanes.

[0084] In some embodiments, a compound of formula (C) or a salt thereof is prepared by converting a compound of formula (D) (D) into a compound of formula (C) or a salt thereof. In some embodiments, the method comprises converting a compound of formula (D) into a compound of formula (C). In some embodiments, converting a compound of formula (D) into a compound of formula (C) or a salt thereof comprises reacting the compound of formula (D) with a reducing agent. In some embodiments, reducing agents include, but are 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 using acid-base extraction.

[0085] In some embodiments, a compound of formula (D) or a salt thereof is prepared by converting a compound of formula (E) (E) or a salt thereof into a compound of formula (D). In some embodiments, the method comprises converting a compound of formula (E) into a compound of formula (D). In some embodiments, converting a compound of formula (E) or a salt thereof into a compound of formula (D) comprises reacting the compound of formula (E) or a salt thereof with an azide reagent. In some embodiments, azide reagents include, but are not limited to, sodium azide, diphenylphosphoryl azide, trimethylsilyl azide, hydrazoic acid, and the like. In some embodiments, the reaction of a compound of formula (E) or a salt thereof with an azide reagent further comprises 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 comprises a silica gel column packed with 1% triethylamine in petroleum ether.In some embodiments, the compound of formula (D) is eluted from a petroleum ether column.

[0086] In some embodiments, a compound of formula (E) or a salt thereof is prepared by converting a compound of formula (F) (F) into a compound of formula (E) or a salt thereof. In some embodiments, converting a compound of formula (F) into a compound of formula (E) or a salt thereof comprises subjecting the compound of formula (F) to reducing conditions to form a compound of formula (E). In some embodiments, the reducing conditions comprise a reducing agent. In some embodiments, reducing agents include, but are not limited to, hydrogen in the presence of a catalyst such as a palladium catalyst, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, borane, and the like. In some embodiments, the reducing conditions comprise a reducing agent and a chiral reagent.In some embodiments, chiral reagents include, but are not limited to, chiral oxazaborolidines such as (3R)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazoborole (Corey-Bakshi-Shibata catalyst), (S)-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazoborole, (S)-1-butyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazoborole, and the like. In some embodiments, the reducing conditions include borane. In some embodiments, the reducing conditions include (3R)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazoborole and borane. In some embodiments, the reducing conditions include (3R)-1-methyl-3,3-bis(3,5-dimethylphenyl)-hexahydropyrrolo[1,2-c][1,3,2]oxazoborole and borane. In some embodiments, the compound of formula (E) is purified by column chromatography. In some embodiments, the column chromatography includes a silica gel column packed with 1% triethylamine in petroleum ether.In some embodiments, the compound of formula (D) is eluted from a column of ethyl acetate in petroleum ether. In some embodiments, the compound of formula (D) is eluted from a column of 30% by volume ethyl acetate in petroleum ether. In some embodiments, the compound of formula (D) is further purified by trituration in hexane.

[0087] Scheme 4 illustrates an alternative scheme for the synthesis of the HCl salt of the compound of formula (4).

[0088] In another aspect, the present document provides a method for producing a compound of formula (4): (4), or a salt thereof, by isolating the compound of formula (4) ((R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile or a salt thereof) by chiral purification of 1-amino-2,3-dihydro-1H-indene-5-carbonitrile or a salt thereof. In some embodiments, 1-amino-2,3-dihydro-1H-indene-5-carbonitrile or a salt thereof is obtained by reductive amination of a compound of formula (F) using methods known in the art.

[0089] In some embodiments, the method for producing a compound of formula (1) or a salt thereof further comprises producing a compound of formula (4) or a salt thereof by any of the methods described herein.

[0090] Chromatography, recrystallization, and other conventional separation procedures may also be used with intermediate or final products if it is desired to obtain a specific isomer of a compound or otherwise purify the reaction product.

[0091] Certain methods presented herein are described with reference to the illustrative synthetic schemes shown below and the following specific examples. Certain reactions and transformations described herein can be carried out using methods known in the art. For example, U.S. Patent No. 10,836,755 describes methods and reagents that can be used to synthesize certain compounds disclosed herein. Those skilled in the art will appreciate that to prepare the various compounds described herein, starting materials can be appropriately selected so that the desired substituents can ultimately be carried through the reaction scheme with or without protection, as appropriate, to yield the desired product.Alternatively, it may be necessary or desirable to use a suitable group in place of the desired substituent, which can be carried through the reaction scheme and replaced with the desired substituent if necessary. Furthermore, one skilled in the art will appreciate that protecting groups can be used to protect certain functional groups (amino groups, carboxyl groups, or side chain groups) from reaction conditions and that such groups are removed under standard conditions when necessary.

[0092] If it is desired to obtain a specific enantiomer of a compound, this can be accomplished from the corresponding mixture of enantiomers using any suitable conventional procedure for the separation or resolution of enantiomers. For example, diastereomeric derivatives can be prepared by reacting a mixture of enantiomers, for example, a racemate, and a suitable chiral compound. The diastereomers can then be separated by any convenient means, for example, by crystallization, and the desired enantiomer can be recovered. In another separation method, the racemate can be separated using chiral high-performance liquid chromatography. Alternatively, if desired, a specific enantiomer can be obtained using a suitable chiral intermediate in one of the described processes. EXAMPLES

[0093] The abbreviations used in this document are explained in the following table. Reduction Meaning ACN Acetonitrile Water Water CDI Carbonyldiimidazole 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 limit IPC Technological control NMP N-methylpyrrolidone THF Tetrahydrofuran 2-MeTHF 2-methyltetrahydrofuran Example 1. Synthesis of 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile

[0094] 5-Chloro-1-indanone (70.0 kg, 420.17 mol, 1.00 equiv) was dissolved in a mixture of dimethylformamide (DMF, 280 kg, 296.6 L) and 2-methyltetrahydrofuran (2-MeTHF, 280 kg, 327.9 L) and thoroughly degassed. XPhos (2.2 kg, 4.61 mol, 0.011 equiv) and Pd2(dba)3 (2.1 kg, 2.29 mol, 0.0055 equiv) 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 eq); the heterogeneous mixture was degassed and this suspension was added to the hot reaction mixture above. Stirring at 85-95°C was continued until the in-process control (IPC) limit of ≤ 5% area of ​​5-chloro-1-indanone was met. The mixture was then cooled to 20-30°C and dichloromethane (DCM, 500 kg, 375.9 L) was added to the reaction mixture.

[0095] In a separate vessel, potassium carbonate (116.9 kg, 845.9 mol, 2.0 equiv) and water (630 kg, 630 L) were stirred at 20-30 °C to obtain a homogeneous solution, which was then added to the above crude reaction mixture. The quenched reaction mixture was filtered through a pad of celite (20.3 kg) and washed with DCM (690 kg, 518.8 L). The layers of the two-phase filtrate were separated, and the upper aqueous layer was extracted with an additional portion of DCM (210 kg, 157.9 L). The combined lower organic phases were washed with water (350 kg, 350 L) and filtered through a pad of silica gel (21 kg) and washed with DCM (140 kg, 105.3 L). The reaction mixture was concentrated and the solvent was exchanged with ethanol (EtOH, 2×70 kg, 2×88.7 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, filtered while hot, and cooled to 60°C. The filtrate was concentrated under vacuum at <60°C to yield a solid.Ethanol (180 kg, 228.1 L) was added to the crude product and the mixture was heated to 50-60°C to influence dissolution. Water (28 kg, 28 L) was added and the reaction mixture was then cooled to 0-10°C. The recrystallized product was isolated by filtration and dried at <60°C to afford 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile 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.

[0096] (R)-tert-Butanesulfinamide (66.7 kg, 550.3 mol, 2.22 equiv) and titanium ethoxide (Ti(OEt)4, 113.3 kg, 496.7 mol, 2.00 equiv) were stirred in toluene (135.3 kg, 156.1 L), and the mixture was heated to 75-85°C for 3 hours. A solution of 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (39.0 kg, 248.1 mol, 1.00 equiv) in toluene (286 kg) was then added to the reaction mixture while maintaining the temperature at 75-85°C. The mixture was stirred at this temperature for 3-4 hours. The preparation of the intermediate (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide was considered complete when IPC-1 was achieved with a tolerance limit of ≤ 0.5% residual 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile.

[0097] The reaction mixture was cooled to 20-30°C and THF (172.8 kg, 194.4 L) was added followed by portionwise addition of sodium borohydride (NaBH4, 4.7 kg, 124.2 mol, 0.5 equiv), maintaining the reaction temperature between -15 and -10°C. The reaction mixture was stirred at -10 and -5°C for 14-20 h until IPC-2 was achieved with the target limit of residual (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide ≤ 2%.

[0098] The reaction mixture was heated to 20-30°C and added to 2.5 M potassium glycolate solution (483.8 kg). The reactor was washed with toluene (182.1 kg, 210.0 L), and the washings were added to the quench solution. The thick slurry was stirred for 20-40 min, and then the layers were allowed to separate for 1-3 h. The lower aqueous layer was separated, and the solids were saved with the organic layer. The organic layer was washed twice with 2.5 M potassium glycolate (2 x 132.6 kg) and twice with 10% sodium chloride (2 x 124.8 kg). The organic layer was then filtered through a pad of celite (4.6 kg) and washed with toluene (2 x 39 kg, 2 x 45 L).

[0099] The combined toluene layers were concentrated to dryness and the solvent was 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, after which n-heptane (234 kg, 242.1 L) was slowly added, maintaining the temperature at 60°C-70°C for 1-2 hours. The reaction mixture was cooled to 0-5°C over a period of 4-5 hours and stirred for another 2-3 hours at this temperature. The solids were isolated by centrifugation, and the precipitate was washed with 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 h to yield 42.2 kg (64.8%) of (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide. Example 3. Synthesis of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride

[0100] Isopropyl acetate (IPAc, 942 kg, 1082.8 L) was added to (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (42.2 kg, 160.8 mol, 1.00 equiv), and the solution was treated with 6 M HCl (39 kg, 197.7 mol, 1.23 equiv) for 16-20 hours to reach IPC-3; residual (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide ≤ 0.5%. Crude (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride was isolated by centrifugation. The wet cake was washed with IPAc (130 kg, 149.4 L) and dried at 30-40°C for 16-24 h, and the LOD was measured (report, result: 0.28% w / w). The product (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride was analyzed for purity (call: ≥98.0% area, result: 99.7% area), chiral purity (call: ≥99.0%, result: 99.7% area), and Karl-Fischer titration (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-indene-1.

[0101] To a solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (50 g, 237 mmol, 1.0 equiv.) in THF (400 mL) under nitrogen atmosphere was added (3R)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazoborole (37 mL of 1 M in toluene, 0.15 equiv.). The mixture was cooled to -10°C, and borane dimethyl sulfide (10 M in THF) (32.2 g, 1.4 equiv.) was added dropwise with stirring over 1 h. After stirring for 3 h at -10°C, the reaction mixture was quenched by slow addition of water (200 mL). The resulting solution was extracted with ethyl acetate (200 mL) three times. The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silica gel column packed with 1% TEA in petroleum ether (30% ethyl acetate / petroleum ether) to give a solid that was triturated with hexane (300 mL) to yield 38.0 g (75%) of (1S)-5-bromo-2,3-dihydro-1H-inden-1-ol as a light yellow solid.LRMS (ES): calculated for C9H9BrO, 212.0 Da, measured 195 m / z [M+H-18]. + Example 5. Synthesis of (R)-1-azido-5-bromo-2,3-dihydro-1H-indene

[0102] To a solution of (S)-5-bromo-2,3-dihydro-1H-inden-1-ol (42 g, 197 mmol, 1.0 equiv.) in toluene (500 mL) was added diphenylphosphoryl azide (74.3 g, 270.0 mmol, 1.4 equiv.) under a nitrogen atmosphere. DBU (45 g, 295 mmol, 1.5 equiv.) was added dropwise to the mixture with stirring at 0°C over 1 h. After stirring for 3 h at 0 to 15°C, the mixture was diluted with ethyl acetate (400 mL) and washed with water (400 mL) three times. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified using a silica gel column packed with 1% TEA in petroleum ether (eluted with petroleum ether) to afford 44.4 g (95%) of (R)-1-azido-5-bromo-2,3-dihydro-1H-indene as a dark brown oil. The dark brown oil was used in the next step without further purification. LRMS (ES): calculated for C9H8BrN3, 237.0 Da, measured 195, 197 m / z [M+H-42] + Example 6. Synthesis of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine

[0103] To a solution of (R)-1-azido-5-bromo-2,3-dihydro-1H-indene (44.3 g, 186 mmol, 1.0 equiv.) in methanol (600 mL) was slowly added SnCl2 2H2O (76 g, 337 mmol, 1.81 equiv.). After stirring overnight at rt, the mixture was diluted with ethyl acetate (500 mL) and NaOH (2 N, 700 mL), stirred at rt 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 with HCl (1 N, 500 mL) twice, and the aqueous layers were combined. The aqueous layer was adjusted to pH 11 with saturated sodium hydroxide solution and 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-inden-1-amine as a yellow oil. LRMS (ES): calculated for C9H 10 BrN, 211.0 Yes, measured 195, 197 m / z [M+H-16] + Example 7. Synthesis of tert-butyl (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate

[0104] To a solution of (R)-5-bromo-2,3-dihydro-1H-indene-1-amine (31.8 g, 150 mmol, 1.0 equiv.) in CH2Cl2 (500 mL) were added TEA (22.7 g, 224.8 mmol, 1.5 equiv.) and a solution of (Boc)2O (39.2 g, 180 mmol, 1.2 equiv.) in CH2Cl2 (150 mL) dropwise at -5 °C over a period of 45 min. The mixture was then warmed to rt, stirred for 2 h, diluted with CH2Cl2 (200 mL), washed with water (500 mL) and brine (200 mL) twice, dried over anhydrous sodium sulfate, and concentrated. The solid was triturated with hexanes (300 mL) to give 38.7 g (83%) of tert-butyl (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate as a white solid. LRMS (ES): calculated for C 14 H 18 BrNO2, 311.1 Yes, measured 256, 258 m / z [M+H-56] + Example 8. Synthesis of tert-butyl (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate

[0105] To a solution of tert-butyl (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate (25.5 g, 81.7 mmol, 1.00 equiv.) in dioxane under a nitrogen atmosphere (270 mL) were added K4Fe(CN)6 3H2O (17.3 g, 41 mmol, 0.5 equiv.), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (2nd generation XPhos precatalyst, 965 mg, 1.2 mmol, 0.02 equiv.), X-phos (584 mg, 1.2 mmol, 0.01 eq) and a solution of KOAc (16.0 g, 163 mmol, 2.0 eq) in water (270 mL) were added. After stirring at 105 °C for 5 h, the resulting solution was diluted with ethyl acetate (500 mL). The solids were removed by filtration. The filtrate was separated and the aqueous layer was extracted with ethyl acetate (300 mL) twice. The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated, and purified using silica gel chromatography (15% ethyl acetate / petroleum ether) to yield 20.0 g (94%) of tert-butyl (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate.LRMS (ES): calculated for C. 15 H 18 N2O2, 258.1 Yes, measured 259 m / z [M+H] + Example 9. Synthesis of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride

[0106] To a solution of tert-butyl (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate (20.0 g, 77 mmol, 1.0 equiv.) in CH2Cl2 was added 4 M HCl in dioxane (192.5 mL, 770 mmol, 10 equiv.). The mixture was stirred overnight and diluted with ethyl acetate (500 mL). The precipitated solids were collected by filtration, washed with petroleum ether (200 mL) twice, and dried to give (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride (13.0 g, 86%) as a white solid. LRMS (ES): calculated for C 10 H 10 O2, 158.1 Yes, measured 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-carboxamide

[0107] 1-Methyl-1H-pyrazole-4-carboxylic acid (12.2 kg, 96.73 mol, 1.00 equiv), 2-MeTHF (76.9 kg, 89.4 L), and DMF (62.9 g, 66.6 mL, 0.861 mol, 0.0089 equiv) were charged into the reactor. Oxalyl chloride (11.7 kg, 91.89 mol, 0.95 equiv) 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 liquid was sent to the reactor. The resulting mixture was stirred at 30±5°C. After stirring at 30±5°C for at least 8 h (actual reaction time: 19.3 h), a sample of IPC was recovered and analyzed by HPLC. The reaction was considered complete when IPC was reached (characteristic: 1-methyl-1H-pyrazole-4-carboxylic acid ≤ 15% area; result 9.6% 1-methyl-1H-pyrazole-4-carboxylic acid). The reaction mixture was used directly for the synthesis of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide without workup.

[0108] Solid NaOH (14.6 kg, 366.0 mol, 3.78 equiv) was dissolved in 78.3 kg water.

[0109] (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride (17.9 kg, 91.89 mol, 0.95 equiv) and 2-MeTHF (63.9 kg, 74.3 L) were charged into a separate reactor. The resulting 4 N NaOH solution (92.9 kg) was added to the mixture while maintaining the temperature <30°C. The drum containing the NaOH solution was washed with water (12.2 kg), and the washing liquid was transferred to the reaction vessel. The mixture was stirred at 20°C for 30 min and a clear two-phase solution was obtained. The resulting solution of 1-methyl-1H-pyrazole-4-carboxylic acid and acid chloride in 2-MeTHF was slowly transferred to the free amine solution over at least 20 minutes, maintaining an internal temperature of <30°C. The reactor used for the acid chloride was rinsed with 2-MeTHF (12.2 kg, 14.2 L), and the rinse was added to the reaction mixture. After the addition of the acid chloride, a large amount of solid formed.The resulting mixture was stirred at 20±5°C for at least 5 hours (actual reaction time: 17.8 h) and the reaction was considered complete when IPC (characteristic: (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile ≤ 5%; result 0.7%) was reached.

[0110] The solid product, (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, was collected by filtration, and the wet cake was washed with 2-MeTHF (24.4 kg, 28.4 L), water (3 × 211.5 kg, 1 × 36.6 kg). The pH of the filtrate after the last water wash was tested (characteristic: pH 8.5 ± 1.5; result pH 8.7).

[0111] The material was dried in a centrifugal dryer under vacuum <45°C with slow nitrogen outflow for at least 20 h until LOD was reached (characteristic: ≤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-carboxamide, which was analyzed for purity (Characteristic: ≥97.0% area, Result: 99.4% area). Example 11. Synthesis of (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0112] A solution of NMP (108.2 kg, 105.3 L, 5.0 vol) of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (21.0 kg, 78.86 mol, 1.00 equiv) was cooled to 5 ± 5°C, and 50% aqueous hydroxylamine (15.6 kg, 236.58 mol, 3.00 equiv) was slowly added over a period of at least 10 min while maintaining the internal temperature ≤ 10°C. The mixture was 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). IPC was used to complete the reaction (characteristic: ≤ 2% CK-3834025 result: 0.05% CK-3834025, 0.65% byproduct amide).

[0113] After completion of the reaction, the mixture was heated to 65 ± 5 °C (clear solution). IPAc (182.8 kg, 209.6 L, 10.0 vol) was slowly added over a period of at least 1 h while maintaining the internal temperature ≥ 50 °C. A large amount of solids formed after the addition of IPAc. The resulting mixture was stirred at 60 ± 5 °C for 1 h. The mixture was slowly cooled to 20 ± 5 °C over a period of 4 h and stirred at 20 ± 5 °C for at least 8 h (actual period: stirred for 15.3 h). The solid was collected by filtration. The wet cake was washed with IPAc [2 × 98.8 kg (2 × 113.3 L, 2 × 5.4 vol)]. The material was initially dried on a filter under vacuum for at least 1 hour. A sample of the wet cake of (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was extracted and analyzed by HPLC.Result: 99.49% product (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, 0.27% by-product amide. Starting material (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was not detected. The material was dried in a vacuum centrifugal dryer at ≤ 50°C for at least 24 h (actual drying time: 24.3 h) until the LOD characteristic was reached (characteristic: LOD ≤ 1% w / w; result: 0.10% w / w).

[0114] (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed for purity (characteristic: ≥95% area; result: 99.5% area of ​​(R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, 0.26% area of ​​by-product amide). A total of 21.8 kg of (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (yield 92.4%) was obtained. Example 12. Synthesis of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0115] CDI (11.9 kg, 73.67 mol, 1.05 equiv) and CH3CN (131.4 kg, 167.2 L) were charged into the reactor (vessel 1), and the resulting mixture was treated with propionic acid (5.7 kg, 77.18 mol, 1.10 equiv) while maintaining the temperature <25°C. The transfer line was flushed with CH3CN (10.2 kg, 13.0 L), and the majority of the reaction mixture was transferred to the flush. The resulting clear solution was stirred at 20±5°C for at least 1 h. The reaction was considered complete when IPC (characteristic: free propionic acid ≤ 20 mol% 1 H NMR; result: 4.8% free propionic acid).

[0116] A separate reactor (vessel 2) was charged with (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (21.0 kg, 70.16 mol, 1.00 equiv) and CH3CN (40.4 kg, 51.4 L). The freshly prepared active imidazole solution from vessel 1 was transferred to vessel 2. Vessel 1 was washed with CH3CN (20.2 kg, 25.7 L), and the washings were transferred to vessel 2. The mixture was heated to 50±5°C. The reaction mixture was stirred at this temperature for at least 12 hours (actual reaction time: 16.6 hours). The mixture was an easily stirred suspension. IPC sample was collected (characteristic: (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide ≤ 2%, result: 0.28%).

[0117] DBU (21.4 kg, 140.32 mol, 2.00 equiv) was then charged into the reaction mixture. The transfer line was washed with CH3CN (6.5 kg, 8.3 L), and the washing liquid was transferred to the main solution. The temperature was adjusted to 70 ± 5 °C, and the mixture was stirred at 70 ± 5 °C for at least 2 h until IPC was achieved (characteristic: imidazole intermediate ≤ 2% area; result: 0.16% imidazole intermediate).

[0118] The reaction mixture was quenched by adding water (64.6 kg) while maintaining the temperature ≥ 50°C. The temperature was brought to 55 ± 5°C and subjected to control filtration. The solution was concentrated at a temperature ≤ 50°C, but not below 10°C, to a mixture volume of ~ 200 L. The thick suspension was heated to 75 ± 5°C and the clear solution was diluted with water (417.3 kg) while maintaining the temperature ≥ 70°C. The temperature was brought 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).

[0119] The solid was collected by filtration, and the wet cake was washed with water (3 × 161.5 kg). The solid was dried in a vacuum oven at ≤ 50°C with slow nitrogen outflow for at least 24 h (actual drying time: 48 h) and analyzed for LOD (characteristic: LOD ≤ 1% w / w; result: LOD 0.05% w / w).

[0120] Dried (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed for purity (characteristic: ≥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-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (yield 92.8%) was obtained. The product (22.0 kg) was then triturated to yield 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-carboxamide

[0121] To a mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (2.3 g, 18.2 mmol, 1.2 equiv), HOBt (2.1 g, 15.1 mmol, 1.0 equiv), and EDC (5.8 g, 30.3 mmol, 2.0 equiv) in DMF (10 mL) was added DIEA (7.5 mL, 45.4 mmol, 3.0 equiv). The mixture was stirred for 10 min, followed by the addition of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride (2.9 g, 15.1 mmol, 1.0 equiv). 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-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide as an off-white solid. 1 H NMR (400 MHz, methylene chloride-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): calculated for C 15 H 14 NO, 266.1 Yes, measured 267.1 m / z [M+H] +Example 14. (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0122] To a suspension of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (3.0 g, 11.3 mmol, 1.0 equiv.) in EtOH (20 mL) was added hydroxylamine (50% w / w in water, 4.0 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'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide as an off-white solid. LRMS (ES): calculated for C 15 H 17 N5O2, 299.1 Yes, measured 300.1 m / z [M+H] + Example 15. (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0123] To a solution of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (24.0 g, 89.5 mmol, 1.0 equiv.) in NMP (120 mL) was added hydroxylamine (50% w / w in water, 17.7 g, 3.0 equiv.). The mixture was stirred at rt for 18 h, and water (240 mL) was added. The reaction mixture provided a liquid suspension that was filtered and washed with DI water (120 mL x 3) for 2 hours to give 25.1 g (93.1%) of (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide as an off-white solid. LRMS (ES): calculated for C 15 H 17 N5O2, 299.1 Yes, measured 300.1 m / z [M+H] + .

Claims

1. Method for obtaining a compound of formula (5): including: (i) transformation of the compound of formula (7) in a compound of formula (6) by reacting the compound of formula (7) with (R)-tert-butanesulfinamide; and (ii) converting the compound of formula (6) into a compound of formula (5) by reacting the compound of formula (6) with a reducing agent.

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

4. The method according to any one of claims 1 to 3, 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 according to any one of claims 1 to 4, wherein the reaction of the compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of toluene at a temperature of from about 75°C to about 85°C.

6. The method according to any one of claims 1 to 5, wherein the reaction of the compound of formula (6) with a reducing agent is carried out in the presence of tetrahydrofuran at a temperature from about -15°C to about -5°C.

7. The method according to any one of claims 1 to 6, wherein the reducing agent is sodium borohydride.

8. The method according to any one of claims 1 to 7, wherein the compound of formula (6) is used without treatment or purification.

9. The method according to any one of paragraphs 1-8, further comprising converting the compound of formula (5) into a compound of formula (4) or its salt by hydrolysis of the sulfinamide of the compound of formula (5).

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

11. The method according to claim 9 or 10, wherein the compound of formula (4) is obtained in the form of a hydrochloride salt.

12. The method according to any one of claims 9-10, wherein the compound of formula (4) is obtained as a 4-methylbenzenesulfonate salt.

13. The method according to any one of claims 9 to 12, further comprising obtaining a compound of formula (4) by reacting a salt of the compound of formula (4) with a base.

14. The method according to any one of paragraphs 9-13 further comprising converting the compound of formula (4) or a salt thereof into a compound of formula (3) or its salt by means of: (i) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a carboxylic acid activating agent to form activated 1-methyl-1H-pyrazole-4-carboxylic acid, and (ii) reacting activated 1-methyl-1H-pyrazole-4-carboxylic acid with a compound of formula (4) or a salt thereof.

15. The method of claim 14, wherein the carboxylic acid activating agent is oxalyl chloride.

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

17. The method according to claim 14 or 16, wherein the carboxylic acid activating agent comprises a carbodiimide reagent and hydroxybenzotriazole.

18. The method according to any one of paragraphs 14-17, further comprising converting the compound of formula (3) or a salt thereof into a compound of formula (2) or its salt by reacting hydroxylamine with a compound of formula (3) or its salt.

19. The method according to 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 below.

20. The method according to claim 18 or 19, wherein the reaction of the compound of formula (3) or its salt with hydroxylamine is carried out in the presence of N-methylpyrrolidone.

21. The method according to any one of paragraphs 18-20, further comprising converting the compound of formula (2) or a salt thereof into a compound of formula (1) or its salt by means of (i) reacting propionic acid with a second carboxylic acid activating agent to form activated propionic acid, and (ii) reacting activated propionic acid with a compound of formula (2) or a salt thereof.

22. The method of claim 21, wherein the second carboxylic acid activating agent is carbonyldiimidazole.

23. Method for obtaining a compound of formula (4) or its salt, which involves converting the compound of formula (5): into a compound of formula (4) or a salt thereof by hydrolysis of the sulfinamide of the compound of formula (5).

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

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

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

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