Process for preparing aficamten

Abstract

Provided herein are processes for the preparation 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, intermediates thereof, and salts of the foregoing. In one aspect, provided herein are processes for preparing a compound of formula (1), or a salt thereof, comprising: (i) converting a compound of formula (7), or a salt thereof, to a compound of formula (6), or a salt thereof; (ii) converting a compound of formula (6), or a salt thereof, to 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.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 203,888, filed August 3, 2021, the contents of which are hereby incorporated by reference in their entirety for all purposes.

[0002] Technical Field Provided herein are processes for the preparation 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, its intermediates, and salts of the foregoing. [Background technology]

[0003] The cardiac sarcomere is composed of a network of contractile and structural proteins that regulate myocardial function. Components of the cardiac sarcomere are targets for the treatment of various cardiac diseases and conditions, for example, by increasing contractility or promoting complete relaxation to regulate contractile and diastolic function, respectively. The force and velocity of myocardial contraction are major determinants of organ function and are regulated by the periodic interaction of actin and myosin. Regulation of actin-myosin binding is mediated by a network of myofilament regulatory proteins and intracellular Ca2+ binding. 2+ The troponin complex and tropomyosin are thin filament proteins that govern the availability of actin-binding sites, and the essential and regulatory light chains, as well as myosin-binding protein C, regulate the positioning and mechanical properties of myosin.

[0004] Abnormalities in myocardial sarcomeres have been identified as the cause inducing a wide variety of cardiac diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomere proteins cause disease by rendering the myocardium "hyper" or "hypo" contractile. Modulators of myocardial sarcomeres can be used to rebalance contractility and halt or reverse the course of the disease.

[0005] Current agents that target the myocardial sarcomere, such as inotropes (drugs that increase the contractility of the heart), have poor selectivity for cardiac tissue and cause recognized adverse effects that limit their use. These adverse effects include cellular damage caused by increased rates of energy expenditure, exacerbation of relaxation abnormalities, and the potential for proarrhythmic side effects that may result from elevated cytoplasmic 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. 10,836,755 discloses (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, a selective allosteric inhibitor of cardiac myosin with little or no effect on smooth muscle myosin. Advantages of this compound include a broader therapeutic window, less effect on cardiac relaxation, better pharmacokinetics, and greater safety, thus offering it the potential to treat cardiac diseases and conditions. There is a need for improved methods for preparing such compounds at low cost and in high overall yield and purity. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 10,836,755 Summary of the Invention [Means for solving the problem]

[0008] In one aspect, the present specification provides a compound of formula (1): [ka] or a salt thereof, comprising: (i) Equation (7) [ka] or a salt thereof, [ka] or a salt thereof; (ii) reacting a compound of formula (6) or a salt thereof with a compound of formula (5) [ka] 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, the reaction of a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of a Lewis acid. In some embodiments, the reaction of a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of a water scavenger. In some embodiments, the reaction of a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of titanium ethoxide. In some embodiments, the reaction of a compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of toluene at a temperature of about 75° C. to about 85° C.

[0009] In some embodiments, the conversion of a compound of formula (6) or a salt thereof to a compound of formula (5) or a salt thereof comprises reacting a compound of formula (6) with a reducing agent. In some embodiments, the reaction of a compound of formula (6) with a reducing agent is carried out in the presence of tetrahydrofuran at a temperature 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 workup or purification.

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

[0011] In some embodiments, the conversion of the compound of formula (5) or a salt thereof to the 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. [ka] In some embodiments, the conversion of 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 an 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, the conversion of 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. [ka] In some embodiments, the conversion of a compound of formula (3) or a salt thereof to a compound of formula (2) or a salt thereof comprises reacting hydroxylamine with a compound of formula (3) or a salt thereof. In some embodiments, the reaction of a compound of formula (3) or a salt thereof with hydroxylamine is carried out at a temperature of 25° C. or less. In some embodiments, the reaction of a compound of formula (3) or a salt thereof with hydroxylamine is carried out in the presence of N-methylpyrrolidone.

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

[0014] In another embodiment, the compound of formula (5): [ka] or a salt thereof to a compound of formula (4) or a salt thereof.

[0015] In some embodiments, the reducing agent has formula (6): [ka] 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 of obtaining a compound of formula (4) further comprises reacting (R)-tert-butanesulfinamide with a compound of formula (7): [ka] to form a compound of formula (6) or a salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] definition As used herein, and unless otherwise stated or implied by context, the terms used herein have the meanings defined below. Within their definitions and throughout this specification, unless another meaning is indicated or implied, for example by the inclusion of mutually exclusive elements or alternatives, the terms "a" and "an" mean one or more, and the term "or" means and / or, where permitted by context. Thus, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0019] At various points in this disclosure, e.g., in any disclosed embodiment or claim, reference is made to compounds, compositions, or methods that "comprise" one or more particular components, elements, or steps. The embodiments also specifically include compounds, compositions, compositions, or methods that are, consist of, or consist essentially of those particular components, elements, or steps. The term "comprised of" is used interchangeably with the term "comprising" and is described as an equivalent term. For example, disclosed compositions, devices, articles of manufacture, or methods that "comprise" a component or step are non-limiting and include or are read to include additional component(s) or step(s) in addition to those compositions or methods. However, those terms do not encompass undescribed elements that would impair the function of the disclosed composition, device, article of manufacture, or method for its intended purpose. Similarly, disclosed compositions, devices, articles of manufacture, or methods that "consist of" a component or step are exclusive and do not include or are not to be read as including compositions or methods having a substantial amount of additional component(s) or additional step(s). Additionally, the term "consisting essentially of" acknowledges the inclusion of unrecited elements that have no significant effect on the functionality of the disclosed composition, device, article of manufacture, or method for its intended purpose, as further defined herein. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0020] When used in the context of a numerical value or range of values ​​given to describe a particular property of a compound or composition, "about" as used herein indicates that the value or range of values ​​described for the particular property may vary to a degree that would be considered reasonable by a person skilled in the art. Reasonable deviations include those that are within the accuracy or precision of the instrument(s) used to measure, determine or derive the particular property. Specifically, the term "about" when used in this context indicates that the numerical value or range of values ​​described for the particular property may vary by 10% of the described value or range of values.

[0021] As used herein, unless otherwise stated or implied by the context, a "protecting group" refers to a moiety that prevents or substantially reduces the ability of the atom or functional group to which it is attached from participating in an undesired reaction. Exemplary protecting groups for atoms or functional groups are described in Greene (2014), "Protective groups in organic synthesis, 5 th ed.”, Wiley Interscience. Protecting groups for heteroatoms such as oxygen, sulfur, and nitrogen may be used to minimize or prevent their undesired reactions with electrophilic compounds. Protecting groups may also be used to reduce or eliminate the nucleophilic and / or basic nature of unprotected heteroatoms. A non-limiting example of a protected oxygen is -OR. PR where R PRis a protecting group for hydroxyl, which in some embodiments is protected as an ester (e.g., acetate, propionate, or benzoate). Other protecting groups for hydroxyl avoid interference of hydroxyl with the nucleophilicity of organometallic or other highly basic reagents, and for that purpose in some embodiments, hydroxyl is protected as an ether, 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 -NHR PR or -N(R PR ) 2 for primary or secondary amines, where R PR at least one of R is a nitrogen atom protecting group, or R PR together define a nitrogen atom protecting group.

[0022] A protecting group is suitable for protection when it can prevent or substantially avoid undesired side reactions and / or premature loss of the protecting group under the reaction conditions required to effect the desired chemical transformation(s) elsewhere in the molecule, and, if necessary, during purification of the newly formed molecule, and can be removed under conditions that do not adversely affect the structure or stereochemical integrity of the newly formed molecule. In some embodiments, suitable protecting groups are those previously described for protecting 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 t-butyloxycarbonyl (Boc).

[0023] Each compound disclosed herein may be in salt form. Compounds may contain at least one amino group, and therefore may form acid addition salts with this amino group. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid 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] Salts may involve the inclusion of another molecule, such as acetate, succinate or other counter ions. Counter ions may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, pharmaceutically acceptable salts may have multiple charged atoms in their structure. In instances where multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counter ions. Thus, a salt may have one or more charged atoms and / or one or more counter ions.

[0025] "Pharmaceutically acceptable salt" refers to a salt that has a toxicity profile within the range that allows for usefulness in pharmaceutical applications. In some embodiments, the pharma-ceutically acceptable salt is selected from those described in PH Stahl and CG 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 formulation must exhibit, as determined by accelerated chemical and solid-state stability (i.e., to determine degradation or solid-state changes when stored at 40°C and 75% relative humidity), for example, suitable water solubility at various pH values ​​that vary depending on the intended route(s) of administration, crystallinity with flow properties, and low hygroscopicity (i.e., water absorption rate relative to relative humidity) suitable for handling and required shelf life.

[0026] method In one aspect, the present specification provides a compound of formula (1): [ka] or a salt thereof, comprising: (i) Equation (7) [ka] or a salt thereof, [ka] or a salt thereof; (ii) reacting a compound of formula (6) or a salt thereof with a compound of formula (5) [ka] 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, the conversion of the compound of formula (5) or a salt thereof to the compound of formula (1) or a salt thereof comprises converting the compound of formula (5) or a salt thereof to a compound of formula (4) or a salt thereof. [ka]

[0028] In some embodiments, the conversion of the compound of formula (5) or a salt thereof to the 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. [ka]

[0029] In some embodiments, the conversion of 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. [ka]

[0030] In some embodiments, the conversion of the compound of formula (5) or a salt thereof to the 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 of the foregoing embodiments, provided herein are methods for preparing compounds of Formula (1) according to the following schemes:

[0032] General Preparation of Compounds of Formula (1) [ka] Preparation of compounds of formula (1) In one aspect, the present specification provides a compound of formula (1): [ka] or a salt thereof, comprising the formula (2): [ka] or a salt thereof to a compound of formula (1) or a salt thereof. In some embodiments, a method of preparing a compound of formula (1) is provided that includes converting a compound of formula (2) to a compound of formula (1).

[0033] In some embodiments, the method of converting a compound of formula (2) or a salt thereof to a compound of formula (1) or a salt thereof comprises reacting a compound of formula (2) or a salt thereof with propionic acid, an 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 acid 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 the 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, the organic solvent includes, but is not limited to, acetonitrile (ACN or MeCN), benzene, chloroform, dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, N-methylpyrrolidone (NMP), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), toluene, and the like. In some embodiments, the organic solvent is free 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 recitation of an organic solvent may be combined with each recitation of a propionic acid, activated propionic acid, or propionyl equivalent as if each and every combination were specifically and individually listed.

[0035] In some embodiments, the reaction of the 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 the 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, the reaction of the compound of formula (2) or a salt thereof with propionic acid, activated propionic acid, or a propionyl equivalent 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, the organic base includes, but is not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, 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 can be combined with each description of the organic solvent and each description of the propionic acid, activated propionic acid, or propionyl equivalent, as if each and every combination were specifically and individually listed.

[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 about 0°C to about 153°C, about 0°C to about 150°C, about 0°C to about 100°C, about 20°C to about 100°C, about 20°C to about 80°C, about 30°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C. In some embodiments, the reaction is carried out at a temperature of about 110°C to about 130°C. In some embodiments, the reaction is carried out at a temperature of about 90°C to about 110°C. In some embodiments, the reaction is carried out at a temperature of 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 about 40° C. to about 80° C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of 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 a propionic acid, activated propionic acid, or propionyl equivalent, each description of an organic solvent, and / or each description of a base as if each and every combination were specifically and individually listed.

[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 foregoing, at a temperature of about 100° C. or less, about 90° C. or less, about 80° C. or less, about 70° C. or less, about 60° C. or less, about 50° C. or less, about 40° C. or less, or about 30° C. or less, followed by the addition of a base selected from DBU, DBN, potassium carbonate, and DIEA at an increased temperature of 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 less, followed by the addition of a base such as DBU and an increased temperature of about 20° C. or more. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50° C. or less, followed by the addition of a base such as DBU and an increased temperature of about 20° C. In some embodiments, the reaction is carried out in the presence of acetonitrile at a temperature of about 50° C. or less, followed by the addition of a base such as DBU and raising the temperature to about 70° C. It is understood that each description of a solvent can be combined with each description of a propionic acid, activated propionic acid, or propionyl equivalent, and / or each description of a base, just as if each and every combination were specifically and individually listed.

[0038] In another aspect, the present specification provides a compound of formula (1): [ka] or a salt thereof, comprising: (i) reacting propionic acid with a first carboxylic acid activator to form an activated propionic acid; and (ii) reacting the activated propionic acid of step (i) with the compound of formula (2): [ka] 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 of step (i) with a compound of formula (2) to form a compound of formula (1).

[0039] In some embodiments, the carboxylic acid activating agent includes an acid chloride, such as thionyl chloride, oxalyl chloride, or methanesulfonyl chloride; an acid anhydride, such as acetic anhydride; a carbodiimide, 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 hexafluorophosphate azabenzotriazole tetramethyluronium (HATU), hexafluorophosphate azabenzotriazole tetramethyluronium (HTA ... Examples of benzotriazole tetramethyluronium hexafluorophosphate include benzotriazole tetramethyluronium 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 in step (i) (reacting propionic acid with a first carboxylic acid activating agent to form an activated propionic acid) is carbonyldiimidazole.

[0040] In some embodiments, step (i) (reacting propionic acid with a first carboxylic acid activating agent to form an activated propionic acid) and step (ii) (reacting the activated propionic acid of step (i) with a compound of formula (2)) are each carried out in an organic solvent. In some embodiments, step (i) and step (ii) are each carried out in the same organic solvent. In some embodiments, the organic solvent includes, but is not limited to, acetonitrile (ACN or MeCN), benzene, chloroform, dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, N-methylpyrrolidone (DMP), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), toluene, and the like. 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 free or substantially free of water. In some embodiments, the organic solvent comprises water. In some embodiments, the organic solvent of step (i) comprises acetonitrile. In some embodiments, the organic solvent in step (ii) comprises acetonitrile. In some embodiments, the organic solvent in both step (i) and step (ii) comprises acetonitrile. In some embodiments, the organic solvent in step (ii) comprises 1,4-dioxane. In some embodiments, the organic solvent in both step (i) and step (ii) comprises 1,4-dioxane.

[0041] In some embodiments, step (ii) (the reaction of the activated propionic acid of step (i) with the compound of formula (2)) further comprises a base. In some embodiments, step (ii) is carried out in the presence of a base. In some embodiments, 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, the organic base includes, but is not limited to, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, tributylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, collidine, lutidine, pyridine, picoline, dicyclohexylamine, morpholine, DBU, DBN, imidazole, benzimidazole, histidine, guanidine, etc. 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 as if each and every combination were specifically and individually listed.

[0042] In some embodiments, step (i) (reacting the propionic acid with a first carboxylic acid activating agent to form an activated propionic acid) is carried out 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 carried out at a temperature of about 0°C to about 80°C. In some embodiments, step (i) is carried out at a temperature of about 0°C to about 50°C. In some embodiments, step (i) is carried out at a temperature of 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) (the reaction of the activated propionic acid of step (i) with the compound of formula (2)) is carried out 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 carried out at a temperature of about 50°C. In some embodiments, step (ii) is carried out at a temperature of 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 less, followed by the addition of a base and raising the temperature to about 70° C. or greater.It is understood that each description of temperature may be combined with each description of base and / or organic solvent in the same manner as if each and every 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 less, and step (ii) is carried out in acetonitrile at a temperature of about 50° C., followed by the addition of DBU and raising the temperature to about 70° C. It is understood that each description of temperature or temperature range may be combined with each description of carboxyl activating agent, each description of organic solvent, and / or each description of base in the same manner as if each and every combination were specifically and individually recited.

[0043] In some embodiments, step (ii) (the reaction of the activated propionic acid of step (i) with the compound of formula (2)) is followed by the addition of water to the reaction mixture. In some embodiments, the diluted reaction mixture is polish filtered and the filtrate is concentrated to a slurry. In some embodiments, the diluted reaction mixture is polish filtered 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 70° C. to about 80° C. and then diluted with water to form a mixture, while maintaining the temperature of the mixture at at least about 70° C. In some embodiments, the mixture is filtered to obtain the compound of formula (1) as a solid. In some embodiments, prior to filtering the mixture, the mixture is cooled to a temperature of about 15° C. to about 25° C. to obtain the compound of formula (1) as a solid. In some embodiments, the compound of formula (1) is isolated as a wet cake solid. In some embodiments, the wet cake solid of formula (1) is washed with water and dried under vacuum to form a dry solid. In some embodiments, the dried solid of formula (1) is de-lumped.

[0044] It should be understood that the descriptions of the conditions for step (i) (reacting propionic acid with a first carboxylic acid activating agent to form an activated propionic acid) and step (ii) (reacting the activated propionic acid of step (i) with a compound of formula (2)) may be combined in the same manner as if each and every combination were specifically and individually recited. For example, in some embodiments, step (i) comprises reacting propionic acid with carbonyldiimidazole-containing acetonitrile to prepare an activated propionic acid, and step (ii) comprises reacting the activated propionic acid with a compound of formula (2) followed by reaction with DBU. For example, in some embodiments, step (i) comprises reacting propionic acid with acetonitrile containing carbonyldiimidazole at a temperature of 25° C. or less to prepare an activated propionic acid, and step (ii) comprises reacting the activated propionic acid with acetonitrile containing a compound of formula (2) at a temperature of about 50±5° C., followed by reaction with acetonitrile containing DBU at a temperature of about 70±5° C. For example, in some embodiments, step (i) comprises reacting propionic acid with acetonitrile containing carbonyldiimidazole at a temperature of 25° C. or less to prepare an activated propionic acid, and step (ii) comprises reacting the activated propionic acid with acetonitrile containing a compound of formula (2) at a temperature of about 50±5° C., followed by reaction with acetonitrile containing DBU at a temperature of about 70±5° C., followed by addition of water. For example, in some embodiments, step (i) comprises reacting propionic acid with acetonitrile containing carbonyldiimidazole at a temperature of 25° C. or less to prepare an activated propionic acid, and step (ii) comprises reacting the activated propionic acid with acetonitrile containing a compound of formula (2) at a temperature of about 50±5° C., followed by reaction with acetonitrile containing DBU at a temperature of about 70±5° C., followed by addition of water, polish filtration, concentration 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., followed by dilution with water to form a mixture, cooling to a temperature of about 15° C. to about 25° C., and filtering the mixture to obtain the compound of formula (1) as a solid.

[0045] Preparation of compounds of formula (2) In some embodiments, the compound of formula (2) or salt thereof has formula (3): [ka] or a salt thereof to a compound of formula (2) or a salt thereof. In some embodiments, the method includes converting a compound of formula (2) to a compound of formula (3). In some embodiments, the method includes reacting hydroxylamine with a compound of formula (3) or a salt thereof. In some embodiments, the hydroxylamine is obtained 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, the organic solvent includes, but is 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 provided as examples herein. In some embodiments, the organic solvent includes water. In some embodiments, the organic solvent includes ethanol. In some embodiments, the organic solvent includes 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 less, about 40°C or less, about 30°C or less, about 25°C or less, about 20°C or less, about 10°C or less, or about 0°C or less. 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 as if each and every combination were specifically and individually listed. For example, in some embodiments, the method includes reacting a compound of formula (3) with aqueous hydroxylamine-containing NMP at a temperature of about 10°C or less, and then warming to a temperature of about 15°C to about 25°C. For example, in some embodiments, the method includes reacting a compound of formula (3) with aqueous hydroxylamine-containing NMP at room temperature or a temperature of about 25°C.

[0047] In some embodiments, after the reaction between hydroxylamine and the compound of formula (3) is complete, the compound of formula (2) is precipitated by the addition of a co-solvent. In some embodiments, the co-solvent is water. In some embodiments, after the reaction between hydroxylamine and the compound of formula (3) is complete, the compound of formula (2) is precipitated by the addition of 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 carried out 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 co-solvent is carried out at a temperature of about 50° C. to about 80° C. In some embodiments, the addition of the co-solvent is carried out at a temperature of about 50° C. to about 75° C. In some embodiments, the addition of the co-solvent is carried out at a temperature of about 65° C. In some embodiments, the precipitated compound of formula (2) is isolated as a wet cake by suction filtration. 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 as if each and every combination were specifically and individually listed. For example, in some embodiments, the method includes reacting the compound of formula (3) with aqueous hydroxylamine-containing NMP at a temperature of about 10° C. or less, followed by warming 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 includes reacting the compound of formula (3) with aqueous hydroxylamine-containing NMP at room temperature or at a temperature of about 25° C., followed by adding water at room temperature or at a temperature of about 25° C.

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

[0049] In some embodiments, the carboxylic acid activating agent includes an acid chloride, such as thionyl chloride, oxalyl chloride, or methanesulfonyl chloride; an acid anhydride, such as acetic anhydride; a carbodiimide, 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 in 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 oxalyl chloride. In some embodiments, the second carboxylic acid activating agent in step (iii) includes a carbodiimide reagent. In some embodiments, the carbodiimide reagent includes 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 can be combined with each description of the carboxyl activator as if each and every combination were specifically and individually listed. For example, in some embodiments, the reaction is carried out in the presence of EDC, HOBt, and DIEA. In other embodiments, the reaction is carried out in the presence of EDC, HOAt, and DIEA.

[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 carried out 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 carried out at a temperature of less than about 80° C. In some embodiments, step (iii) is carried out at a temperature of less than about 61° C. In some embodiments, step (iii) is carried out at a temperature of less than about 55° C. In some embodiments, step (iii) is carried out at a temperature of less than about 50° C. In some embodiments, step (iii) is carried out at a temperature of less than about 40° C. In some embodiments, step (iii) is carried out at a temperature of less than 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 a temperature or temperature range may be combined with each description of a carboxyl activator and / or each description of a base as if each and every 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 the solvents described herein. In some embodiments, the solvent comprises a mixture of DMF and 2-MeTHF. It is understood that the solvents may be combined with each description of the carboxyl activating agent, each description of the base, and / or each description of the temperature or temperature range as if each and every combination were specifically and individually listed. For example, in some embodiments, step (iii) is carried out in the presence of EDC, HOBt, DIEA, and DMF at a temperature of about 40° C. to about 20° C. In another embodiment, 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 another embodiment, 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 another embodiment, step (iii) is carried out in the presence of oxalyl chloride and DMF at a temperature of less than about 35° C. In another embodiment, 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 another embodiment, the reaction is carried out in the presence of oxalyl chloride, 2-MeTHF, and DMF at a temperature of less than about 35° C.

[0053] In some embodiments, the crude product 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) is used without workup. In some embodiments, the crude product of step (iii) is used without purification.

[0054] In some embodiments, step (iv) (the reaction of the activated 1-methyl-1H-pyrazole-4-carboxylic acid of step (iii) with the compound of formula (4)) is carried out in the presence of a base. In some embodiments, the base is an inorganic base. In some embodiments, 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, and the like. 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 of 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 the solvents 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 in 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 in step (iv), and / or each description of the temperature or temperature range in step (iv) as if each and every combination were specifically and individually listed. For example, in some embodiments, step (iii) comprises reacting 1-methyl-1H-pyrazole-4-carboxylic acid with 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 a mixture of 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 of 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 a mixture of DMF and 2-MeTHF at a temperature less than 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 of step (iii) with a compound of formula (4)) in the presence of aqueous NaOH at a temperature less than 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 DMF containing HOBt, EDC, and DIEA.

[0056] In some embodiments, the compound of formula (3) is isolated by filtration to obtain a wet cake solid. In some embodiments, the wet cake solid is rinsed 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 a scheme for synthesizing compounds of formula (1). Scheme 1: [ka]

[0058] Scheme 2 shows an alternative scheme for the synthesis of compounds of formula (2). Scheme 2: [ka]

[0059] Preparation of polymorphs of the compound of formula (1) In some of the foregoing embodiments, the method of preparing a compound of formula (1) further comprises preparing a polymorph of the compound of formula (1). Methods of preparing polymorphs of the compound of formula (1) are disclosed in WO2021 / 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 polymorph Form I. In some embodiments, the polymorph is characterized by having an XRPD pattern including peaks at 2-theta angles of 3.7±0.2 degrees, 11.2±0.2 degrees, 12.9±0.2 degrees, 14.4±0.2 degrees, and 22.4±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern including peaks at 2-theta angles of 3.7±0.2 degrees, 11.2±0.2 degrees, 12.9±0.2 degrees, 13.5±0.2 degrees, 14.4±0.2 degrees, 18.6±0.2 degrees, 22.4±0.2 degrees, 24.7±0.2 degrees, 25.0±0.2 degrees, and 26.1±0.2 degrees.

[0061] In some embodiments, the polymorph of the compound of formula (1) is polymorph Form II. In some embodiments, the polymorph is characterized by having an XRPD pattern including peaks at 2-theta angles of 3.7±0.2 degrees, 9.8±0.2 degrees, 11.1±0.2 degrees, 12.8±0.2 degrees, and 20.4±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern including peaks at 2-theta angles of 3.7±0.2 degrees, 9.8±0.2 degrees, 11.1±0.2 degrees, 12.8±0.2 degrees, 14.7±0.2 degrees, 16.1±0.2 degrees, 18.5±0.2 degrees, 20.4±0.2 degrees, 22.3±0.2 degrees, and 23.3±0.2 degrees.

[0062] In some embodiments, the polymorph of the compound of Formula (1) is polymorph Form III. In some embodiments, the polymorph is characterized as having an XRPD pattern including peaks at 2-theta angles of 9.6±0.2 degrees, 10.9±0.2 degrees, 15.8±0.2 degrees, and 18.1±0.2 degrees.

[0063] In some embodiments, the polymorph of the compound of formula (1) is polymorph Form IV. In some embodiments, the polymorph is characterized as having an XRPD pattern that includes peaks at 2-theta angles of 11.1±0.2 degrees, 12.8±0.2 degrees, 13.5±0.2 degrees, 22.8±0.2 degrees, and 24.4±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized as having an XRPD pattern that includes peaks at 2-theta angles of 3.7±0.2 degrees, 11.1±0.2 degrees, 12.8±0.2 degrees, 13.5±0.2 degrees, 21.9±0.2 degrees, 22.8±0.2 degrees, 23.1±0.2 degrees, 23.5±0.2 degrees, 24.4±0.2 degrees, and 24.8±0.2 degrees.

[0064] In some embodiments, the polymorph of the compound of formula (1) is polymorph Form V. In some embodiments, the polymorph is characterized by having an XRPD pattern including peaks at 2-theta angles of 11.5±0.2 degrees, 16.3±0.2 degrees, 20.0±0.2 degrees, 21.2±0.2 degrees, and 24.7±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern including peaks at 2-theta angles of 11.5±0.2 degrees, 16.3±0.2 degrees, 19.1±0.2 degrees, 20.0±0.2 degrees, 20.2±0.2 degrees, 21.2±0.2 degrees, 24.0±0.2 degrees, 24.7±0.2 degrees, 25.6±0.2 degrees, and 26.7±0.2 degrees. In some embodiments, the polymorph of the compound of Formula (1) is characterized by having an XRPD pattern including peaks at 2-theta angles of 5.7±0.2 degrees, 8.3±0.2 degrees, 11.5±0.2 degrees, 16.3±0.2 degrees, 17.2±0.2 degrees, 19.1±0.2 degrees, 20.0±0.2 degrees, 20.2±0.2 degrees, 20.7±0.2 degrees, 21.2±0.2 degrees, 23.3±0.2 degrees, 24.0±0.2 degrees, 24.7±0.2 degrees, 25.6±0.2 degrees, 26.7±0.2 degrees, 28.1±0.2 degrees, 29.2±0.2 degrees, 29.7±0.2 degrees, 29.9±0.2 degrees, and 31.1±0.2 degrees.

[0065] In some embodiments, the polymorph of the compound of formula (1) is polymorph Form VI. In some embodiments, the polymorph is characterized by having an XRPD pattern including peaks at 2-theta angles of 10.6±0.2 degrees, 12.1±0.2 degrees, 15.0±0.2 degrees, 16.1±0.2 degrees, and 17.8±0.2 degrees. In some embodiments, the polymorph of the compound of formula (1) is characterized by having an XRPD pattern including peaks at 2-theta angles of 5.4±0.2 degrees, 5.9±0.2 degrees, 8.1±0.2 degrees, 9.6±0.2 degrees, 10.6±0.2 degrees, 12.1±0.2 degrees, 14.0±0.2 degrees, 15.0±0.2 degrees, 16.1±0.2 degrees, and 17.8±0.2 degrees.

[0066] Preparation of compounds of formula (4) In another aspect, the present specification provides a compound of formula (4): [ka] or a salt thereof, comprising the formula (5): [ka] or a salt thereof to a compound of formula (4), or a salt thereof. In some embodiments, the method comprises converting a compound of formula (5) to a compound of formula (4), or a salt thereof. In some embodiments, the method of preparing 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, the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. In some embodiments, the aqueous acid is an organic acid. In some embodiments, the organic acid includes acetic acid, propionic acid, ascorbic acid, citric acid, trifluoroacetic acid, toluenesulfonic acid, and the like. In some embodiments, the aqueous acid is any compatible mixture of acids, such as those 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 sulfinamide is carried out in an organic solvent. In some embodiments, the organic solvent includes, but is 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 provided as embodiments herein. In some embodiments, the organic solvent comprises water. It should be understood that each description of an acid or base can be combined with each description of an organic solvent as if each and every combination were specifically and individually listed. For example, in some embodiments, the hydrolysis of sulfinamide is carried out in the presence of aqueous HCl. For example, in some embodiments, the hydrolysis of sulfinamide is carried out in the presence of IPAc. For example, in some embodiments, the hydrolysis of sulfinamide is carried out in the presence of aqueous HCl and IPAc.

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

[0071] Preparation of compounds of formula (5) In some embodiments, the compound of formula (5) or salt thereof can be prepared by reacting a reducing agent with a compound of formula (6): [ka] or a salt thereof to form a compound of formula (5) or a salt thereof. In some embodiments, the method includes reacting a reducing agent with a compound of formula (6) to form a compound of formula (5). In some embodiments, the reducing agent includes, but is not limited to, hydrogen 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 the reducing agent is carried out in the presence of a solvent. In some embodiments, the organic solvent includes, but is not limited to, dimethylformamide, 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 about -15°C to about -5°C. It should be understood that any combination of the foregoing conditions is contemplated, for example, the reaction of the compound of formula (6) with the reducing agent can be carried out in the presence of toluene, tetrahydrofuran, or toluene and tetrahydrofuran. For example, the reaction of the compound of formula (6) with the reducing agent can be carried out in the presence of toluene, tetrahydrofuran, or toluene and tetrahydrofuran at a temperature of 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.

[0074] Preparation of compounds of formula (6) In some embodiments, the compound of formula (6) is prepared by converting (R)-tert-butanesulfinamide to formula (7): [ka] to form a compound of formula (6) or a salt thereof. In some embodiments, the reaction is carried out in the presence of a Lewis acid and a water scavenger. In some embodiments, reagents that act as both Lewis acids and water scavengers include, but are not limited to, CuSO4, GaCl3, Ti(OEt)4, and the like. In some embodiments, the reaction is carried out in the presence of Ti(OEt)4. In some embodiments, the reaction is carried out in toluene. In some embodiments, the reaction is carried out at a temperature of 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 foregoing conditions is contemplated, for example, the reaction of (R)-tert-butanesulfinamide with a compound of formula (7) can be carried out in toluene in the presence of Ti(OEt)4. For example, the reaction of (R)-tert-butanesulfinamide with a compound of formula (7) can be carried out in the presence of Ti(OEt)4 in toluene at a temperature of about 75°C to about 85°C.

[0075] Preparation of compounds of formula (7) In some embodiments, the compound of formula (7) is represented by the formula (8): [ka] to a compound of formula (7). In some embodiments, the conversion of a compound of formula (8) to a compound of formula (7) comprises reacting a compound of formula (8) with a cyanation reagent via a palladium catalyzed cyanation reaction. In some embodiments, the cyanation reagent includes, but is 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 carried out at a temperature of 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, the recrystallization is carried out at a temperature of about 0° C. to about 78° C. In some embodiments, the recrystallization is carried out at a temperature of about 0° C. to about 70° C. In some embodiments, the recrystallization is carried out at a temperature of about 0° C. to about 60° C. In some embodiments, the recrystallization begins 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 foregoing conditions is contemplated, for example, in some embodiments, the reaction includes 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 includes 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 about 85° C. to about 95° C., followed by hot filtration in ethanol, followed by recrystallization in a mixture of ethanol and water.

[0078] Scheme 3 shows a scheme for synthesizing the HCl salt of the compound of formula (4). Scheme 3: [ka]

[0079] The above-described method for preparing the 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), represents an improvement over previous synthetic methods in the art. For example, the method described herein requires fewer synthetic steps, avoids the isolation and / or purification of certain intermediates, requires fewer isolated intermediates, and provides a higher overall yield than the methods provided in U.S. Publication Nos. US2006 / 0173183A1 and WO2006 / 083454, which describe the preparation of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride from 5-bromo-indan-1-ylamine. For example, the methods described herein, in addition to eliminating the need for tin or azide reagents, require fewer synthetic steps, provide higher overall yields, and eliminate the need for protecting groups, as compared to the methods provided in U.S. Pat. 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.

[0080] Alternative preparation of compounds of formula (4) In another aspect, the present specification provides a compound of formula (4): [ka] A method for preparing a compound of formula (A), or a salt thereof, is provided, [ka] or a salt thereof to a compound of formula (4) or a salt thereof. In some embodiments, the method includes converting a compound of formula (A) to a compound of formula (4) or a salt thereof. In some embodiments, the conversion of a compound of formula (A) to a compound of formula (4) includes reacting a 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 hydrous 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 a salt thereof is isolated by suction filtration. In some embodiments, the compound of formula (4) or a salt thereof is purified by washing the solid with an organic solvent. In some embodiments, the compound of formula (4) or a salt thereof is purified by washing the solid with petroleum ether.

[0081] In some embodiments, the compound of formula (A) or salt thereof is represented by formula (B): [ka] or a salt thereof to a compound of formula (A). In some embodiments, the method includes converting a compound of formula (B) to a compound of formula (A). In some embodiments, the conversion of a compound of formula (B) or a salt thereof to a compound of formula (A) or a salt thereof includes reacting a compound of formula (B) or a salt thereof via a palladium catalyzed cyanation reaction. In some embodiments, the reaction includes reacting a compound of formula (B) or a salt thereof with potassium ferricyanide in the presence of a palladium catalyst. In some embodiments, the reaction includes reacting a 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 hexane. In some embodiments, the compound of formula (A) is purified by trituration in hexane containing 10% ethyl acetate by volume. 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 the column with petroleum ether containing ethyl acetate. In some embodiments, the compound of formula (D) is eluted from the column with petroleum ether containing 15% ethyl acetate by volume.

[0083] In some embodiments, the compound of formula (B) or salt thereof is represented by formula (C): [ka] or a salt thereof to a compound of formula (B) or a salt thereof. In some embodiments, the method includes converting a compound of formula (C) or a salt thereof to a compound of formula (B). In some embodiments, the compound of formula (B) is prepared by reacting a compound of formula (C) or a salt thereof with di-tert-butyl dicarbonate. In some embodiments, the conversion of a compound of formula (C) to a compound of formula (B) further includes reacting a compound of formula (C) with di-tert-butyl dicarbonate in the presence of a base. In some embodiments, the base includes, but is not limited to, N,N-diisopropylethylamine, trimethylamine, diethylamine, triethylamine, tributylamine, 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 hexane.

[0084] In some embodiments, the compound of formula (C) or salt thereof is represented by formula (D): [ka] The compound of formula (C) or a salt thereof is prepared by converting a compound of formula (D) to a compound of formula (C). In some embodiments, the method includes converting a compound of formula (D) to a compound of formula (C) or a salt thereof. In some embodiments, the conversion of a compound of formula (D) to a compound of formula (C) or a salt thereof includes reacting a compound of formula (D) with a reducing agent. In some embodiments, the reducing agent includes, but is not limited to, triphenylphosphine, zinc, sodium borohydride, tin chloride, lithium aluminum hydride, sodium borohydride, hydrogen in the presence of a catalyst such as a palladium catalyst, and the like. In some embodiments, the reducing agent is tin chloride. In some embodiments, the compound of formula (C) is used without purification. In some embodiments, the compound of formula (C) is purified by acid-base extraction.

[0085] In some embodiments, the compound of formula (D) or salt thereof is represented by formula (E): [ka] or a salt thereof to a compound of formula (D). In some embodiments, the method includes converting a compound of formula (E) to a compound of formula (D). In some embodiments, the conversion of a compound of formula (E) or a salt thereof to a compound of formula (D) includes reacting a compound of formula (E) or a salt thereof with an azide reagent. In some embodiments, the azide reagent includes, but is not limited to, sodium azide, diphenylphosphoryl azide, trimethylsilyl azide, hydroazic acid, and the like. In some embodiments, the reaction of a compound of formula (E) or a salt thereof with an azide reagent further includes a base. In some embodiments, the base is DBU. In some embodiments, the compound of formula (D) is purified by column chromatography. In some embodiments, the column chromatography includes a silica gel column packed with 1% triethylamine-containing petroleum ether. In some embodiments, the compound of formula (D) is eluted from the column with petroleum ether.

[0086] In some embodiments, the compound of formula (E) or salt thereof is represented by formula (F): [ka] to a compound of formula (E) or a salt thereof. In some embodiments, the conversion of a compound of formula (F) to a compound of formula (E) or a salt thereof comprises subjecting a 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, the reducing agent includes, but is 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, the chiral reagent includes, but is not limited to, chiral oxazaborolidines such as (3R)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole (Corey-Bakshi-Shibata catalyst), (S)-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole, (S)-1-butyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole, 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]oxazaborole 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]oxazaborole 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 petroleum ether containing 1% triethylamine. In some embodiments, the compound of formula (D) is eluted from the column with petroleum ether containing ethyl acetate. In some embodiments, the compound of formula (D) is eluted from the column with petroleum ether containing 30% by volume of ethyl acetate. In some embodiments, the compound of formula (D) is further purified by trituration in hexane.

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

[0088] In another aspect, the present specification provides a compound of formula (4): [ka] or a salt thereof, is provided 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, the 1-amino-2,3-dihydro-1H-indene-5-carbonitrile or a salt thereof is prepared by reductive amination of the compound of formula (F) by methods known in the art.

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

[0090] Where it is desired to obtain a particular isomer of a compound or otherwise purify the product of a reaction, chromatography, recrystallization, and other conventional separation procedures may also be used on intermediates or final products.

[0091] Certain steps provided herein are described with reference to the exemplary synthetic schemes shown below and the specific examples described below. 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. To obtain various compounds herein, those skilled in the art will recognize that starting materials can be appropriately selected so that the ultimately desired substituents, with or without protection as appropriate, are carried through the reaction scheme to obtain the desired products. Alternatively, it may be necessary or desirable to employ a suitable group in place of the ultimately desired substituent that can be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions as appropriate.

[0092] If it is desired to obtain a particular enantiomer of a compound, this can be achieved from the corresponding enantiomeric mixture by using any suitable conventional procedure for separating or resolving enantiomers.Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, for example a racemate, with a suitable chiral compound.The diastereomers can then be separated by any convenient means, for example by crystallization, and the desired enantiomer is recovered.In another resolution step, the racemate can be separated using chiral high performance liquid chromatography.Alternatively, if desired, a particular enantiomer can be obtained by using a suitable chiral intermediate in one of the steps described. EXAMPLES

[0093] The abbreviations used herein are set out in the table below. [Table 1]

[0094] Example 1. Synthesis of 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile [ka] 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, zinc cyanide (Zn(CN)2, 27.3 kg, 232.5 mol, 0.55 equiv.) was added to 2-MeTHF (140 kg, 163.9 L), the heterogeneous mixture was degassed, and this slurry was added to the above hot reaction mixture. Stirring at 85-95 °C was continued until the in-process control (IPC) tolerance limit of 5-chloro-1-indanone was met, which was 5% or less by area. 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 homogenous solution, which was then added to the crude reaction mixture above. 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 biphasic filtrate were separated and the top aqueous layer was extracted with an additional portion of DCM (210 kg, 157.9 L). The combined lower organic phase was washed with water (350 kg, 350 L), filtered through a pad of silica gel (21 kg) and washed with DCM (140 kg, 105.3 L). The reaction mixture was concentrated and a solvent exchange to ethanol (EtOH, 2 x 70 kg, 2 x 88.7 L) was performed and the solution was concentrated to dryness. Ethanol (700 kg, 887.2 L) was added to the residue and the mixture was heated to 70-80°C, hot filtered and cooled to 60°C. The filtrate was concentrated under vacuum below 60°C to give a solid. Ethanol (180 kg, 228.1 L) was added to the crude product and the mixture was warmed to 50-60°C to dissolve. 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 below 60°C to give 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile as a yellow solid in 70.2% yield.

[0096] Example 2. Synthesis of (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide [ka] (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 warmed to 75-85° C. over 3 h. 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 h. 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 met, with the tolerance limit of residual 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile being 0.5% or less.

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

[0098] The reaction mixture was warmed to 20-30°C and added to a solution of 2.5 M potassium glycolate (483.8 kg). The reactor was rinsed with toluene (182.1 kg, 210.0 L) and the washes were added to the quench solution. The thick slurry was stirred for 20-40 minutes and then the layers were allowed to separate for 1-3 hours. The lower aqueous layer was separated and the solids were retained 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 celite pad (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 a solvent exchange to ethyl acetate (EtOAc, 2×117 kg, 2×129.7 L) was performed 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 h before n-heptane (234 kg, 242.1 L) was added slowly and the temperature was maintained at 60-70° C. for 1-2 h. The reaction mixture was cooled to 0-5° C. over 4-5 h and stirred at this temperature for an additional 2-3 h. The solid was isolated by centrifugation and the cake was washed with a chilled (0-5° C.) solution of EtOAc (26 kg, 28.8 L) and n-heptane (51.8 kg, 75.7 L). The crude product was dried at 20-30° C. for 8-10 hours to give 42.2 kg (64.8%) of (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide.

[0100] Example 3: Synthesis of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride [ka] (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.) was added isopropyl acetate (IPAc, 942 kg, 1082.8 L) and the solution was treated with 6 M HCl (39 kg, 197.7 mol, 1.23 equiv.) for 16-20 h until residual (R)-N-((R)-5-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide was below 0.5% IPC-3. The 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), dried at 30-40 °C for 16-24 h, and the LOD was measured (reported, result: 0.28 w / w%). The (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride product was analyzed for purity (spec: ≥ 98.0 area%, result: 99.7 area%), chiral purity (spec: ≥ 99.0%, result: 99.7 area%), and Karl Fischer titration (reported, result: 0.45 w / w%). The title compound was isolated in 91.1% yield.

[0101] Example 4: Synthesis of (S)-5-bromo-2,3-dihydro-1H-inden-1-ol [ka] To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol, 1.0 equiv.) in THF (400 mL) was added (3R)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole (37 mL of 1 M in toluene, 0.15 equiv.) under nitrogen atmosphere. The mixture was cooled to -10°C and borane dimethylsulfide (10 M in THF) (32.2 g, 1.4 equiv.) was added dropwise over 1 h with stirring. After stirring at -10°C for 3 h, the reaction was quenched by slow addition of water (200 mL). The resulting solution was extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified using a silica gel column packed with 1% TEA in petroleum ether (30% ethyl acetate / petroleum ether) to give a solid which was triturated with hexanes (300 mL) to give 38.0 g (75%) of (1S)-5-bromo-2,3-dihydro-1H-inden-1-ol as a pale yellow solid. LRMS (ES): Calcd for C9H9BrO, 212.0 Da, Measured 195 m / z [M+H-18] + .

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

[0103] Example 6: Synthesis of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine [ka] 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 room temperature, the mixture was diluted with ethyl acetate (500 mL) and NaOH (2N, 700 mL), stirred at room temperature for 1 h, and filtered. The filtrate was separated and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were extracted twice with HCl (1N, 500 mL) and the aqueous layers were combined. The pH of the aqueous layer was adjusted to 11 with saturated sodium hydroxide 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): C9H 10Calculated for BrN, 211.0 Da, Found 195, 197 m / z [M+H-16] + .

[0104] Example 7: Synthesis of tert-butyl (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl) carbamate [ka] To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (31.8 g, 150 mmol, 1.0 equiv) in CHCl (500 mL) was added TEA (22.7 g, 224.8 mmol, 1.5 equiv) and a solution of (Boc)O (39.2 g, 180 mmol, 1.2 equiv) in CHCl (150 mL) was added dropwise over 45 min at −5° C. The mixture was then allowed to warm to room temperature and stirred for 2 h, diluted with CHCl (200 mL), washed twice with water (500 mL) and brine (200 mL), 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): C 14 H 18 Calculated for BrNO2, 311.1 Da, Found 256, 258 m / z [M+H-56] + .

[0105] Example 8: Synthesis of tert-butyl (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl) carbamate [ka] 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 (270 mL) under nitrogen atmosphere, KFe(CN)3H0 (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) (second generation XPhos precatalyst, 965 mg, 1.2 mmol, 0.02 equiv), X-phos (584 mg, 1.2 mmol, 0.01 equiv), and KOAc (16.0 g, 163 mmol, 2.0 equiv) in water (270 mL) were added. After stirring at 105° C. for 5 hours, 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 twice with ethyl acetate (300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated, and purified using silica gel chromatography (15% ethyl acetate / petroleum ether) to give 20.0 g (94%) of tert-butyl (R)-(5-cyano-2,3-dihydro-1H-inden-1-yl)carbamate. LRMS (ES): C 15 H 18 Calculated for N2O2, 258.1 Da, Measured 259 m / z [M+H] + .

[0106] Example 9: Synthesis of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride [ka] 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 CHCl was added 4M HCl in dioxane (192.5 mL, 770 mmol, 10 equiv.). The mixture was stirred overnight and diluted with ethyl acetate (500 mL). The precipitated solid was collected by filtration, washed twice with petroleum ether (200 mL), 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): C 10 H 10 Calculated for O2, 158.1 Da, Measured 159 m / z [M + H] + .

[0107] Example 10: Synthesis of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide [ka] The reactor was charged with 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). Oxalyl chloride (11.7 kg, 91.89 mol, 0.95 equiv) was added slowly over at least 45 min while maintaining the temperature below 35° C. The transfer line was rinsed with 2-MeTHF (6.1 kg) and the rinse 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), an IPC sample was drawn and analyzed by HPLC. The reaction was deemed complete when the IPC was met (spec: 1-methyl-1H-pyrazole-4-carboxylic acid ≦15 area %; result 9.6% of 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 of water.

[0109] A separate reactor was charged with (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). A prepared 4N NaOH solution (92.9 kg) was added to the mixture while maintaining the temperature below 30° C. The drum containing the NaOH solution was rinsed with water (12.2 kg) and the rinse was transferred to the reaction vessel. The mixture was stirred at 20° C. for 30 minutes to obtain a clear biphasic solution. The prepared 1-methyl-1H-pyrazole-4-carboxylic acid and acid chloride in 2-MeTHF solution was slowly transferred to the free amine solution over at least 20 minutes while maintaining the internal temperature below 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. A large amount of solid formed after the addition of the acid chloride. The resulting mixture was stirred at 20±5° C. for at least 5 h (actual reaction time: 17.8 h) and the reaction was deemed complete when the IPC was met (spec: (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile≦5%; result 0.7%).

[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 (spec: pH 8.5±1.5; result pH 8.7).

[0111] The material was dried in a tray dryer under vacuum with a slow nitrogen bleed at less than 45° C. for at least 20 hours until the LOD was met (spec:≦3 w / w%; result: 0.8 w / w%). The product was dried for 64.7 hours to give 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 (spec:≧97.0 area%, result: 99.4 area%).

[0112] Example 11: Synthesis of (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide [ka] A solution 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) in NMP (108.2 kg, 105.3 L, 5.0 vol) was cooled to 5±5° C. and 50% aqueous hydroxylamine (15.6 kg, 236.58 mol, 3.00 equiv) was added slowly over at least 10 minutes, maintaining the internal temperature below 10° C. The mixture was allowed to warm slowly to 20±5° C. over at least 2 hours and stirred at 20±5° C. for at least 16 hours (actual reaction time: 19.7 hours). An IPC was taken for reaction completion (spec: ≦2% CK-3834025 result: 0.05% CK-3834025, 0.65% by-product amide).

[0113] After the reaction was complete, the mixture was heated to 65±5° C. (clear solution). IPAc (182.8 kg, 209.6 L, 10.0 vol) was charged slowly over at least 1 hour while maintaining the internal temperature above 50° C. A large amount of solids formed after the addition of IPAc. The resulting mixture was stirred at 60±5° C. for 1 hour. The mixture was slowly cooled to 20±5° C. over 4 hours and stirred at 20±5° C. for at least 8 hours (actual duration: 15.3 hours stirring). The solids were 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 first dried on the filter by vacuum suction for at least 1 hour. A sample of the (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide wet cake was aspirated and analyzed by HPLC. Results: 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. No starting material (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was detected. The material was dried in a vacuum tray dryer at ≤50° C. for at least 24 hours (actual drying time: 24.3 hours) until the LOD specification was met (spec: LOD≦1 w / w%; result: 0.10 w / w%).

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

[0115] 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 [ka] The reactor (vessel 1) was charged with CDI (11.9 kg, 73.67 mol, 1.05 equiv.) and CH3CN (131.4 kg, 167.2 L) and the resulting mixture was treated with propionic acid (5.7 kg, 77.18 mol, 1.10 equiv.) while maintaining the temperature below 25° C. The transfer line was rinsed with CH3CN (10.2 kg, 13.0 L) and the rinse was transferred to the bulk reaction mixture. The resulting clear solution was stirred at 20±5° C. for at least 1 hour. The reaction was considered complete when the IPC was filled (spec: 1 Free propionic acid ≤ 20 mol % by 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 activated imidazole solution from vessel 1 was transferred to vessel 2. Vessel 1 was rinsed with CH3CN (20.2 kg, 25.7 L) and the rinse was added and transferred to vessel 2. The mixture was heated to 50±5°C. The reaction was stirred at this temperature for at least 12 hours (actual reaction time: 16.6 hours). The mixture was an easily stirred slurry. An IPC sample was taken (specification: (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide <= 2%, result: 0.28%).

[0117] The reaction was then charged with DBU (21.4 kg, 140.32 mol, 2.00 equiv). The transfer line was rinsed with CH3CN (6.5 kg, 8.3 L) and the rinse was transferred to the bulk solution. The temperature was adjusted to 70±5°C and the mixture was stirred at 70±5°C for at least 2 hours until the IPC was met (spec: imidazole intermediate ≦2 area%; result: 0.16% imidazole intermediate).

[0118] The reaction mixture was quenched by the addition of water (64.6 kg) while maintaining the temperature above 50° C. The temperature was adjusted to 55±5° C. and polish filtered. The solution was concentrated at a temperature below 50° C. and above 10° C. until the batch volume was about 200 L. The thick slurry was heated to 75±5° C. and the clear solution was diluted with water (417.3 kg) while maintaining the temperature at 70° C. The temperature was adjusted to 75±5° C. and the mixture was stirred at 75±5° C. for 2 hours. The mixture was then slowly cooled to 20±5° C. over at least 4 hours. The mixture was stirred at 20±5° C. for at least 2 hours (actual reaction time: 11.5 hours).

[0119] The solids were collected by filtration and the wet cake was washed with water (3×161.5 kg). The solids were placed in a vacuum oven and dried at ≦50° C. with a slow nitrogen bleed for at least 24 hours (actual drying time: 48 hours) and analyzed for LOD (spec: LOD≦1 w / w%; result: LOD 0.05 w / w%).

[0120] The 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 (spec: ≧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 (92.8% yield) was obtained. The product (22.0 kg) was then de-lumped to give 21.4 kg (97.3%).

[0121] Example 13: Synthesis of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide [ka] 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): C 15 H 14 Calculated for NO, 266.1 Da, Measured 267.1 m / z [M + H] + .

[0122] Example 14: (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide [ka] 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): C 15 H 17 Calculated for N5O2, 299.1 Da, Measured 300.1 m / z [M + H] + .

[0123] Example 15: (R)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide [ka] Hydroxylamine (50 w / w% in water, 17.7 g, 3.0 equiv.) was added 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). The mixture was stirred at room temperature for 18 h, water (240 mL) was added, and the reaction mixture was obtained as a thin slurry, which was filtered and washed with DI water (120 mL x 3) over 2 h 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): C 15 H 17 Calculated for N5O2, 299.1 Da, Measured 300.1 m / z [M + H] + .

Claims

1. Formula (1): 【Chemical 1】 or a salt thereof, comprising the steps of: (i) Formula (7) 【Chemistry 2】 The compound of formula (6) 【Chemistry 3】 converting the compound (ii) reacting the compound of formula (6) with a compound of formula (5) 【Chemistry 4】 and (iii) converting the compound of formula (5) into the compound of formula (1) or a salt thereof.

2. 2. The method of claim 1, wherein converting the compound of formula (7) to the compound of formula (6) comprises reacting the compound of formula (7) with (R)-tert-butanesulfinamide.

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

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

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

6. 3. The method of claim 2, wherein the reaction of the compound of formula (7) with (R)-tert-butanesulfinamide is carried out in the presence of toluene at a temperature of about 75°C to about 85°C.

7. 10. The method of claim 1, wherein converting the compound of formula (6) to the compound of formula (5) comprises reacting the compound of formula (6) with a reducing agent.

8. 8. The method of claim 7, wherein the reaction of 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.

9. 9. The method of claim 7 or 8, wherein the reducing agent is sodium borohydride.

10. 10. The method of claim 1, wherein the compound of formula (6) is used without workup or purification.

11. The conversion of the compound of formula (5) to the compound of formula (1) or a salt thereof comprises converting the compound of formula (5) to the compound of formula (4) 【Chemistry 5】 or a salt thereof.

12. 12. The method of claim 11, wherein the conversion of the compound of formula (5) to the compound of formula (4) or a salt thereof comprises hydrolyzing the sulfinamide of the compound of formula (5).

13. 13. The method of claim 12, wherein the hydrolysis of the sulfinamide of the compound of formula (5) is carried out in the presence of an aqueous acid.

14. The method of any one of claims 11 to 13, wherein the compound of formula (4) is prepared as the hydrochloride salt.

15. The method of any one of claims 11 to 13, wherein the compound of formula (4) is prepared as a 4-methylbenzenesulfonate salt.

16. 12. The method of claim 11, further comprising obtaining the compound of formula (4) by reacting the salt of the compound of formula (4) with a base.

17. The conversion of the compound of formula (5) to the compound of formula (1) or a salt thereof is carried out by converting the compound of formula (4) or a salt thereof into a compound of formula (3) 【Chemistry 6】 or a salt thereof.

18. The conversion of the compound of formula (4) or a salt thereof to the compound of formula (3) or a salt thereof is (i) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a carboxylic acid activator to form activated 1-methyl-1H-pyrazole-4-carboxylic acid; and (ii) reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid with the compound of formula (4) or a salt thereof to form the compound of formula (3) or a salt thereof.

19. 19. The method of claim 18, wherein the carboxylic acid activating agent is oxalyl chloride.

20. 20. The method of claim 18, wherein the carboxylic acid activating agent comprises a carbodiimide reagent.

21. 21. The method of claim 18 or 20, wherein the carboxylic acid activating agent comprises a carbodiimide reagent and a hydroxybenzotriazole.

22. The conversion of the compound of formula (5) to the compound of formula (1) or a salt thereof comprises converting the compound of formula (3) or a salt thereof into a compound of formula (2) 【Chemistry 7】 or a salt thereof.

23. 23. The method of claim 22, wherein the conversion of the compound of formula (3) or a salt thereof to the compound of formula (2) or a salt thereof comprises reacting hydroxylamine with the compound of formula (3) or a salt thereof.

24. 24. The method of claim 23, wherein the reaction of the compound of formula (3) or a salt thereof with hydroxylamine is carried out at a temperature of 25°C or less.

25. The method according to claim 23 or 24, wherein the reaction of the compound of formula (3) or a salt thereof with hydroxylamine is carried out in the presence of N-methylpyrrolidone.

26. 23. The method of claim 22, wherein the conversion of the compound of formula (5) to the compound of formula (1) or a salt thereof further comprises converting the compound of formula (2) or a salt thereof to the compound of formula (1) or a salt thereof.

27. The conversion of the compound of formula (2) or a salt thereof to the compound of formula (1) or a salt thereof is (i) reacting propionic acid with a second carboxylic acid activator to form an activated propionic acid; and 27. The method of claim 26, comprising: (ii) reacting the activated propionic acid with the compound of formula (2) or a salt thereof.

28. 28. The method of claim 27, wherein the second carboxylic acid activating agent is carbonyldiimidazole.

29. Formula (4) 【Chemistry 8】 or a salt thereof, comprising a compound of formula (5): 【Chemistry 9】 to the compound of formula (4) or a salt thereof.

30. The reducing agent is reacted with a compound of formula (6): 【Chemistry 10】 to form said compound of formula (5).

31. 31. The method of claim 30, wherein the reducing agent is a borohydride reducing agent.

32. (R)-tert-butanesulfinamide is reacted with a compound of formula (7): 【Chemistry 11】 to form said compound of formula (6).

Images