Synthesis of Nirogacestat

Abstract

The present disclosure is directed to a process for synthesizing (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide ("nirogacestat").

Description

[Technical field]

[0001] The present disclosure relates to a process for synthesizing (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide ("nirogacestat" or "compound 1"). [Background technology]

[0002] (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide ("nirogacestat" or "compound 1") shows promising activity in the treatment of tumors or cancers such as desmoid tumors, multiple myeloma, cancers with mutations in Notch pathway genes, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia (U.S. Patent No. 10,590,087). The known pathways for synthesizing nirogacestat provide few points for control of impurities other than at the time of final isolation (Bioorganic & Medicinal Chemistry Letters 21:2637-2640 (2011)). If impurity control is not optimal at the late intermediates, impurities are likely to be present in the product at reportable levels. This route also exhibits low yields when the norvaline moiety and the tetralone fragment are coupled (Bioorganic & Medicinal Chemistry Letters 21:2637-2640 (2011)). Thus, there is a need to develop new routes that introduce additional control points to purge impurities and minimize any loss of stereochemical integrity. Summary of the Invention

[0003] Provided herein is a process that involves reacting the novaline moiety with 1,1'-carbonyldiimidazole (CDI) to form an activated anhydride. For example, compound 9 can be reacted with [ka]

[0004] compound 10, [ka] Described herein is a process comprising reacting 1,1'-carbonyldiimidazole with 1,1'-carbonyldiimidazole under conditions suitable for forming 1,1'-carbonyldiimidazole or a pharma- ceutically acceptable salt thereof. In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, occurs in the presence of one or more additives. In some embodiments, the one or more additives include pyridine hydrobromide. In some embodiments, the one or more additives include triethylamine. In some embodiments, compound 10, or a pharma- ceutically acceptable salt thereof, is used in a subsequent process without isolation or purification.

[0005] Compound 10, compound 1 [ka] or a pharma- ceutically acceptable salt thereof under suitable conditions.

[0006] [ka] Also described herein is a process comprising reacting compound 10 with compound 11. In some embodiments, the process of reacting compound 10 with compound 11 occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), acetonitrile, or a combination thereof. In some embodiments, compound 11 is prepared without isolation or purification and reacted with compound 10. In some embodiments, compound 1 is not purified or isolated.

[0007] In some embodiments, Compound 1 is a free base. In some embodiments, Compound 1 is a pharma- ceutically acceptable salt. In some embodiments, Compound 1 is a dihydrobromide salt. In some embodiments, the dihydrobromide salt of Compound 1 is a crystalline solid.

[0008] In some embodiments, the process further comprises reacting the free base of Compound 1 with an aqueous inorganic acid under conditions suitable to form a pharma- ceutically acceptable salt of Compound 1. In some embodiments, the pH is adjusted to about 1 to about 1.5. In some embodiments, the inorganic acid is hydrobromic acid.

[0009] In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is isolated. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a hydrobromide salt. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a dihydrobromide salt.

[0010] Compound 12, [ka]

[0011] A compound of formula IV, [ka]

[0012] A compound of formula V, [ka] or a pharma- ceutically acceptable salt thereof, wherein LG is a leaving group and PG is a protecting group. In some embodiments, LG is -OR 2 and R 2 is -S(=O)2R 3 and R 3 is C1-C3 alkyl, C1-C3 haloalkyl, or optionally substituted phenyl. In some embodiments, R 2 is -S(=O)2CF3. In some embodiments, PG is C1-C6 alkyl. In some embodiments, PG is t-butyl. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof.

[0013] In some embodiments, the process of forming the compound of formula IV, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a base. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the solvent is removed in vacuum.

[0014] In some embodiments, the compound of formula V is dissolved in a polar aprotic solvent and an aqueous inorganic acid solution. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the pharma- ceutically acceptable salt of formula V is isolated. In some embodiments, the pharma- ceutically acceptable salt of formula V is isolated by filtration. In some embodiments, the inorganic acid is hydrochloric acid. In some embodiments, the pharma- ceutically acceptable salt of formula V is a hydrochloride salt.

[0015] The compound of formula V, or a pharma- ceutically acceptable salt thereof, may be reacted with compound 9, [ka] Also described herein is a process further comprising reacting the compound of formula V, or a pharmaceutically acceptable salt thereof, with an aqueous inorganic acid in a polar protic solvent under suitable conditions to form the compound of formula V, or a pharmaceutically acceptable salt thereof.In some embodiments, in the process of reacting the compound of formula V, or a pharmaceutically acceptable salt thereof, with an aqueous inorganic acid, the polar protic solvent is an alcohol.In some embodiments, the alcohol is isopropanol.

[0016] In some embodiments, in the process of reacting the compound of formula V, or a pharma- ceutically acceptable equivalent thereof, with aqueous inorganic acid, the pH is adjusted to about 2.6 to about 3.0.

[0017] In some embodiments, in the process of reacting the compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid, compound 9, or a pharma- ceutically acceptable salt thereof, is isolated. In some embodiments, compound 9, or a pharma- ceutically acceptable salt thereof, is isolated by filtration.

[0018] In some embodiments, in the process of reacting the compound of formula V, or a pharma- ceutically acceptable form thereof, with aqueous inorganic acid, the inorganic acid is hydrochloric acid.

[0019] The present disclosure further relates to a method for preparing compound 1 or a pharma- ceutically acceptable salt thereof by reacting compound 10 or a pharma- ceutically acceptable salt thereof with compound 11 or a pharma- ceutically acceptable salt thereof. In some embodiments, the process for preparing compound 1 or a pharma- ceutically acceptable salt thereof occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), acetonitrile, or a combination thereof.

[0020] Provided herein is a process comprising reacting the free base of Compound 1, prepared by any of the processes described above, with an aqueous inorganic acid under conditions suitable for forming a pharma- ceutically acceptable salt of Compound 1. In some embodiments, the pH of the process of the free base of Compound 1 and the aqueous inorganic acid is about 1 to about 1.5. In some embodiments, the inorganic acid is hydrobromic acid. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is isolated. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a hydrobromide salt. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a dihydrobromide salt.

[0021] The present disclosure further relates to a process comprising reacting compound 9 with 1,1'-carbonyldiimidazole in a solvent under conditions suitable for forming compound 10, the process further comprising reacting compound 10 with compound 11 under conditions suitable for forming compound 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the process of forming compound 1, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the process of forming compound 1, or a pharma- ceutically acceptable salt thereof, occurs in the presence of one or more additives. In some embodiments, the one or more additives include pyridine hydrobromide. In some embodiments, the one or more additives include triethylamine.

[0022] In some embodiments, the process further comprises reacting the free base of Compound 1 with an aqueous inorganic acid under conditions suitable to form a pharma- ceutically acceptable salt of Compound 1. In some embodiments, the pH is adjusted to about 1 to about 1.5. In some embodiments, the aqueous inorganic acid is hydrobromic acid.

[0023] The present disclosure further relates to a process comprising reacting a pharma- ceutically acceptable salt of Compound 1 with an aqueous inorganic acid in an alcohol. In some embodiments, the alcohol is isopropanol. In some embodiments, the pH is adjusted to about 3 to about 3.5. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is isolated. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is isolated by filtration. In some embodiments, the aqueous inorganic acid is hydrobromic acid.

[0024] In some embodiments, compound 1 is synthesized by any one of the processes described above. In some embodiments, a pharma- ceutically acceptable salt of compound 1 of the processes described herein is isolated. In some embodiments, a pharma- ceutically acceptable salt of compound 1 is a hydrobromide salt. In some embodiments, a pharma- ceutically acceptable salt of compound 1 is a dihydrobromide salt.

[0025] The present disclosure further provides a method for the preparation of a pharmaceutical composition comprising administering to a patient in need thereof a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and: (1) 0.7% to 0.01% of a compound of formula II,

[0026] [ka] During the ceremony, R 1 is selected from the group consisting of hydrogen, fluoro, or chloro; R 2 is selected from the group consisting of hydrogen or chloro; R 3 is selected from the group consisting of fluoro or chloro; R 4 is selected from the group consisting of -OH and -N(H)CH2C(CH3)3, or a pharma- ceutically acceptable salt thereof, (2) 0.05% to 0.005% imidazole or a pharma- ceutically acceptable salt thereof, or (3) A composition comprising 0.7% to 0.01% of a compound of formula II, or a pharma- ceutically acceptable salt thereof, and 0.05% to 0.005% of imidazole, or one or more of its pharma- ceutically acceptable salts, The compound of formula II is not compound 1, and the percentage of compound 1, the compound of formula II, and / or imidazole is determined by high performance liquid chromatography. In some embodiments, the compound of formula II is a hydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0027] In some embodiments, the compound of formula II is a compound of formula II-A: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-A is a hydrobromide salt. In some embodiments, the compound of formula II-A is a dihydrobromide salt.

[0028] In some embodiments, the compound of formula II is a compound of formula II-B: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-B is a hydrobromide salt. In some embodiments, the compound of formula II-B is a dihydrobromide salt.

[0029] In some embodiments, the compound of formula II is a compound of formula II-C: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-C is a hydrobromide salt. In some embodiments, the compound of formula II-C is a dihydrobromide salt.

[0030] In some embodiments, the compound of formula II is a compound of formula II-D: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-D is a hydrobromide salt. In some embodiments, the compound of formula II-D is a dihydrobromide salt.

[0031] In some embodiments, R 4 is -N(H)CH2C(CH3)3. In some embodiments, R 4In some embodiments, R 1 is fluoro and R 2 is hydrogen and R 3 In some embodiments, R 1 is chloro and R 2 is hydrogen and R 3 In some embodiments, R 1 is hydrogen and R 2 is chloro and R 3 In some embodiments, R 1 is fluoro and R 2 is hydrogen and R 3 is fluoro.

[0032] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.6% to 0.01% of Compound 2, [ka]

[0033] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 2 is a hydrobromide salt. In some embodiments, compound 2 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0034] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.3% to 0.01% of Compound 3; [ka]

[0035] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 3 is a hydrobromide salt. In some embodiments, compound 3 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0036] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 4, [ka]

[0037] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 4 is a hydrobromide salt. In some embodiments, compound 4 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0038] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 5, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 5 is a hydrobromide salt. In some embodiments, compound 5 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0039] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 6, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 6 is a hydrobromide salt. In some embodiments, compound 6 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0040] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 7, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 7 is a hydrobromide salt. In some embodiments, compound 7 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0041] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 8, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 8 is a hydrobromide salt. In some embodiments, compound 8 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0042] The present disclosure further relates to a composition comprising 98.0%-99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.05%-0.005% of imidazole, or a pharma- ceutically acceptable salt thereof. In some embodiments, the imidazole is a hydrobromide salt. In some embodiments, Compound 1 is a hydrobromide salt. In some embodiments, Compound 1 is a dihydrobromide salt.

[0043] The present disclosure further relates to a process for preparing a composition having an oxidation-sensitive active agent that is substantially free of compound 13, [ka] The process includes dissolving compound 11 in a solvent and combining the solution of compound 11 with compound 9 to form a mixture that is treated with hydrobromic acid. In some embodiments, the activator susceptible to oxidation is a hydrobromide salt of compound 1. In some embodiments, the activator susceptible to oxidation is a dihydrobromide salt of compound 1.

[0044] In some embodiments, the solvent used to dissolve compound 11 is an alcohol of formula R-OH, where R is an alkyl, with the proviso that R is not ethyl. In some embodiments, the solvent is a primary alcohol other than ethanol. In some embodiments, the solvent is a secondary alcohol. In some embodiments, the solvent is a tertiary alcohol. In some embodiments, the solvent is 2-methylpropan-1-ol. In some embodiments, the solvent is propanol. In some embodiments, the solvent is isopropanol. In some embodiments, the mixture is warmed to 0-5° C. during the hydrobromic acid treatment.

[0045] In some embodiments, the mixture is maintained at a pH of less than 6. In some embodiments, the mixture is maintained at a pH of less than 3.

[0046] The present disclosure further relates to a process for preparing a composition of compound 1 essentially free of compound 13, the process comprising combining compound 10 with compound 11 to form a mixture that is treated with hydrobromic acid in a solvent. In some embodiments, the composition of compound 1 is a hydrobromide salt. In some embodiments, the composition of compound 1 is a dihydrobromide salt.

[0047] In some embodiments, compound 1 is synthesized by any one of the processes described above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] Definitions and Abbreviations As used above and throughout the description, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0049] Unless otherwise explained, the terms "a" and "an" and similar references used in the context of describing particular aspects of this application (particularly in the context of the claims) can be construed to cover both the singular and the plural. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand process of referring individually to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein.

[0050] The term "alkyl" means any monovalent, saturated straight-chain, branched, or cyclic hydrocarbon radical. Examples of "alkyl" groups include methyl, ethyl, isopropyl, and the like.

[0051] The term "haloalkyl," by itself or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms.

[0052] The term "substituted" refers to the independent replacement of one or more hydrogen atoms on the substituted moiety with a substituent independently selected from the group of substituents specified for the particular group. In general, a non-hydrogen substituent may be any substituent that can be bonded to an atom of a given moiety that is specified to be substituted.

[0053] As used herein, the term "leaving group" refers to a group that leaves a pair of electrons in a heterolytic bond cleavage. Common leaving groups are Cl - , Br - , and I -Halides and tosylates (TsO - ) and other sulfonic acid esters.

[0054] As used herein, the term "protecting group" refers to a group that blocks or protects an amine functionality while reactions are carried out on other functional groups or moieties of the molecule. Those skilled in the art are familiar with the selection, attachment, and cleavage of protecting groups and will understand that different protecting groups are known in the art and that the suitability of one or another protecting group depends on the particular synthetic scheme planned. Articles on the subject such as Wuts, "Greene's Protective Groups in Organic Synthesis", 5th Ed., J. Wiley & Sons, Inc., NY, 2014, are available for consultation. Suitable protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), and benzyl (Bn) groups.

[0055] As used herein, the term "base" refers to an organic proton acceptor. Non-limiting bases include non-nucleophilic tertiary amines, such as NEt3, N,N-diisopropylethylamine, and nitrogen-containing heteroaromatic groups such as pyridine, and derivatives of pyridine, such as 2,4,6-trimethylpyridine.

[0056] As used herein, the terms "isolate," "isolated," "isolated," and "isolating" mean that a substance remains alone or away from solution.

[0057] As used herein, the terms "purify," "purified," "purification," and "purifying" refer to the removal of contaminants from a substance of interest, e.g., Compound 1.

[0058] Nirogacestat Synthesis Described herein is a process that involves reacting the norvaline moiety with 1,1'-carbonyldiimidazole (CDI) to form an activated anhydride. The process then continues by coupling the activated anhydride with an imidazole amine to obtain nirogacestat, or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide). This coupling reaction minimizes any loss of stereochemical integrity of the norvaline moiety by buffering the CDI with pyridine hydrobromide. All steps avoid aqueous work-up and distillation while allowing for facile crystallization. The isolation of nirogacestat, or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide), is well designed and provides crystalline material of high yield and purity.

[0059] The present disclosure also relates to a process for preparing compound 1, or a pharma- ceutically acceptable salt thereof (e.g., dihydrobromide), which comprises reacting a novaline moiety directly with an imidazole amine in the presence of an alcohol other than ethanol to produce nirogacestat, which process limits impurities in the final product of nirogacestat.

[0060] Compound 9, [ka]

[0061] compound 10, [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the 1,1'-carbonyldiimidazole is present in the process in an amount of about 1 to about 2 equivalents of compound 9. In some embodiments, the 1,1'-carbonyldiimidazole is present in the process in an amount of about 1.1 equivalents of compound 9.

[0062] In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the polar aprotic solvent is acetonitrile.

[0063] In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, occurs in the presence of one or more additives. In some embodiments, the one or more additives include pyridine hydrobromide. In some embodiments, the pyridine hydrobromide is present in the process in an amount of about 2 to about 3 equivalents of compound 9. In some embodiments, the pyridine hydrobromide is present in the process in an amount of about 2.1 equivalents of compound 9. In some embodiments, the one or more additives include triethylamine. In some embodiments, the triethylamine is present in the process in an amount of about 0.1 to 1 equivalents of compound 9. In some embodiments, the triethylamine is present in the process in an amount of about 0.7 equivalents of compound 9.

[0064] In some embodiments, the process of preparing compound 10, or a pharma- ceutically acceptable salt thereof, occurs at a temperature of about 20° C. to about 30° C. In some embodiments, the process of preparing compound 10, or a pharma- ceutically acceptable salt thereof, takes about 4 hours.

[0065] In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, is sampled for HPLC analysis. In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, is stopped until the HPLC area % of compound 9 is less than 10.0 area %. In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, is stopped until the HPLC area % of compound 9 is less than 2.0 area %. In some embodiments, the difference between two consecutive HPLC analyses of compound 9 is less than 0.5 area %. In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, is cooled to a temperature of about -15°C to about -5°C. In some embodiments, the process of forming compound 10, or a pharma- ceutically acceptable salt thereof, is cooled to a temperature of about -7°C. In some embodiments, compound 10 is used in a subsequent process without isolation or purification.

[0066] The present disclosure relates to a pharma- ceutically acceptable salt of compound 11, [ka] with a base in the presence of a polar aprotic solvent. In some embodiments, the pharma- ceutically acceptable salt of compound 11 is a hydrobromide salt. In some embodiments, the pharma- ceutically acceptable salt of compound 11 is a dihydrobromide salt. In some embodiments, compound 11 is a free base. In some embodiments, the base is selected from the group consisting of trimethylamine, triethylamine, N,N-diisopropylethylamine, and pyridine. In some embodiments, the base is triethylamine. In some embodiments, triethylamine is present in the process in an amount of about 2 to about 5 equivalents of compound 11. In some embodiments, triethylamine is present in the process in an amount of about 3.1 equivalents of compound 11. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the polar aprotic solvent is acetonitrile. In some embodiments, the process of preparing compound 11, or a free base thereof, occurs at a temperature of about -15°C to about -5°C. In some embodiments, the process of preparing compound 11, or a free base thereof, occurs at a temperature of about -7°C. In some embodiments, compound 11 is used in a subsequent process without isolation or purification.

[0067] Compound 10 and Compound 11 were mixed with Compound 1, [ka] Also described herein is a process comprising reacting compound 11 under conditions suitable to form 10 or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 11 is a free base. In some embodiments, compound 11 is present in the process in an amount of about 1 to about 2 equivalents of compound 10. In some embodiments, compound 11 is present in the process in an amount of about 1.2 equivalents of compound 10. In some embodiments, the process of reacting compound 10 with compound 11 occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the polar aprotic solvent is acetonitrile. In some embodiments, the process of reacting compound 10 with compound 11 occurs at a temperature of about -15°C to about 0°C. In some embodiments, the process of reacting compound 10 with compound 11 occurs at a temperature of about -7°C. In some embodiments, the process of reacting compound 10 with compound 11 takes about 6 hours. In some embodiments, the process of reacting compound 10 with compound 11 is sampled for HPLC analysis. In some embodiments, the process of reacting compound 10 with compound 11 is stopped until the HPLC area % of compound 10 is less than 5.0 area %. In some embodiments, the process of reacting compound 10 with compound 11 is stopped until the HPLC area % of compound 10 is less than 1.0 area %. In some embodiments, the difference between two consecutive HPLC analyses of compound 10 is less than 0.5 area %. In some embodiments, the pharma- ceutically acceptable salt of compound 1 is a hydrobromide salt. In some embodiments, the pharma- ceutically acceptable salt of compound 1 is a dihydrobromide salt. In some embodiments, compound 1 is a free base. In some embodiments, compound 1 is not purified or isolated.

[0068] The process further comprises reacting the free base of compound 1 with an aqueous inorganic acid under conditions suitable to form a pharma- ceutically acceptable salt of compound 1. In some embodiments, the inorganic acid is hydrobromic acid. In some embodiments, the hydrobromic acid is present in the process in an amount of about 5 to about 10 equivalents of compound 10. In some embodiments, the hydrobromic acid is present in the process in an amount of about 7.5 equivalents of compound 10.

[0069] In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 occurs at a temperature of about 30°C to about 50°C. In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 occurs at a temperature of about 40°C. In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 occurs in the presence of one or more additives. In some embodiments, the one or more additives include triethylamine. In some embodiments, the pH of the process of forming a pharma- ceutically acceptable salt of compound 1 is adjusted to about 1.0 to about 1.5. In some embodiments, seeds of a pharma- ceutically acceptable salt of compound 1 are added. In some embodiments, the amount of seeds is about 0.1% by weight. In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 is cooled at a temperature of about -15°C to about 0°C. In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 is cooled at a temperature of about -5°C. In some embodiments, the pharma- ceutical acceptable salt of compound 1 is isolated. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is isolated as a crystalline solid. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a hydrobromide salt. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a dihydrobromide salt.

[0070] Compound 12, [ka]

[0071] A compound of formula IV, [ka]

[0072] A compound of formula V, [ka] or a pharma- ceutically acceptable salt thereof, wherein LG is a leaving group and PG is a protecting group. In some embodiments, LG is -OR 2 and R 2 is -S(=O)2R 3 and R 3 is C1-C3 alkyl, C1-C3 haloalkyl, or optionally substituted phenyl. In some embodiments, R 2is -S(=O)2CF3. In some embodiments, PG is C1-C6 alkyl. In some embodiments, PG is t-butyl. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dichloromethane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the polar aprotic solvent is dichloromethane. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, occurs at a temperature of about 20°C to about 30°C. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, occurs at a temperature of about 30°C. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, takes about 10 hours. In some embodiments, the process of forming compound V, or a pharma- ceutically acceptable salt thereof, is sampled for HPLC analysis. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, is stopped until the HPLC area % of compound 12 is less than 2.0 area %. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, is stopped until the HPLC area % of compound 12 is less than 1.0 area %. In some embodiments, the difference between two successive HPLC analyses of compound 12 is less than 0.5 area %.

[0073] In some embodiments, the process of forming the compound of formula IV, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a base. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the solvent is removed in vacuum.

[0074] In some embodiments, the compound of formula V is dissolved in a polar aprotic solvent and an aqueous inorganic acid. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the polar aprotic solvent is 1,4-dioxane. In some embodiments, the inorganic acid is hydrochloric acid. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, occurs at a temperature of about 15°C to about 25°C. In some embodiments, the process of forming the compound of formula V, or a pharma- ceutically acceptable salt thereof, takes about 1 to 2 hours. In some embodiments, the pharma- ceutically acceptable salt of formula V is isolated. In some embodiments, the pharma- ceutically acceptable salt of formula V is isolated by filtration. In some embodiments, the pharma- ceutically acceptable salt of Formula V is a hydrochloride salt.

[0075] The compound of formula V, or a pharma- ceutically acceptable salt thereof, may be reacted with compound 9, [ka] Also described herein is a process further comprising reacting the compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid in a polar protic solvent under conditions suitable to form the compound of formula V, or a pharma- ceutically acceptable salt thereof. In some embodiments, in the process of reacting the compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid, the polar protic solvent is an alcohol. In some embodiments, the alcohol is isopropanol. In some embodiments, in the process of reacting the compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid, the inorganic acid is hydrochloric acid. In some embodiments, the hydrochloric acid is present in the process in an amount of about 2 to about 6 equivalents of formula V. In some embodiments, the hydrochloric acid is present in the process in an amount of about 4.1 equivalents of formula V.

[0076] In some embodiments, the process of forming compound 9 occurs at a temperature of about 50° C. to about 70° C. In some embodiments, the process of forming compound 9 occurs at a temperature of about 58° C. to about 62° C. In some embodiments, the process of forming compound 9 occurs at a temperature of about 63° C. to about 67° C. In some embodiments, in the process of reacting a compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid, the pH is adjusted to about 0.2 to about 0.6. In some embodiments, in the process of reacting a compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid, the pH is adjusted to about 1.2 to about 2.5. In some embodiments, in the process of reacting a compound of formula V, or a pharma- ceutically acceptable salt thereof, with an aqueous inorganic acid, the pH is adjusted to about 2.6 to about 3.0. In some embodiments, the process of forming compound 9 occurs in the presence of one or more additives. In some embodiments, the one or more additives include sodium hydroxide. In some embodiments, the process of forming compound 9 is cooled at a temperature of about 15° C. to about 20° C. In some embodiments, compound 9, or a pharma- ceutically acceptable salt thereof, is isolated. In some embodiments, compound 9, or a pharma- ceutically acceptable salt thereof, is isolated by filtration.

[0077] The present disclosure further relates to a process for preparing compound 1 or a pharma- ceutically acceptable salt thereof by reacting compound 10 or a pharma- ceutically acceptable salt thereof with compound 11 or a pharma- ceutically acceptable salt thereof. In some embodiments, the process for preparing compound 1 or a pharma- ceutically acceptable salt thereof occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), acetonitrile, or a combination thereof. In some embodiments, the polar aprotic solvent is acetonitrile.

[0078] Provided herein is a process comprising reacting the free base of Compound 1, prepared by any of the processes described above, with an aqueous inorganic acid under conditions suitable for forming a pharma- ceutically acceptable salt of Compound 1. In some embodiments, the pH of the process of the free base of Compound 1 and the aqueous inorganic acid is about 1 to about 1.5. In some embodiments, the inorganic acid is hydrobromic acid. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is isolated. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a hydrobromide salt. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 is a dihydrobromide salt.

[0079] The present disclosure further relates to a process comprising reacting compound 9 with 1,1'-carbonyldiimidazole in a solvent under conditions suitable for forming compound 10, the process further comprising reacting compound 10 with compound 11 under conditions suitable for forming compound 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the process of forming compound 1, or a pharma- ceutically acceptable salt thereof, occurs in the presence of a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof. In some embodiments, the process of forming compound 1, or a pharma- ceutically acceptable salt thereof, occurs in the presence of one or more additives. In some embodiments, the one or more additives include pyridine hydrobromide. In some embodiments, the one or more additives include triethylamine. In some embodiments, the process further comprises reacting the free base of Compound 1 with an aqueous inorganic acid under conditions suitable to form a pharma- ceutically acceptable salt of Compound 1. In some embodiments, the pH is adjusted to about 1 to about 1.5. In some embodiments, the aqueous inorganic acid is hydrobromic acid.

[0080] The present disclosure further relates to a process comprising reacting a pharma- ceutically acceptable salt of compound 1 with an aqueous inorganic acid in an alcohol. In some embodiments, the alcohol is isopropanol. In some embodiments, the aqueous inorganic acid is hydrobromic acid. In some embodiments, the hydrobromic acid is present in the process in an amount of about 1 to about 3 equivalents of the pharma- ceutically acceptable salt of compound 1. In some embodiments, the hydrobromic acid is present in the process in an amount of about 2 equivalents of the pharma- ceutically acceptable salt of compound 1.

[0081] In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 occurs in the presence of one or more additives. In some embodiments, the one or more additives include triethylamine. In some embodiments, the pH of the process of forming a pharma- ceutically acceptable salt of compound 1 is about 3 to about 3.5.

[0082] In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 occurs at a temperature of about 40°C to about 50°C. In some embodiments, seeds of a pharma- ceutically acceptable salt of compound 1 are added. In some embodiments, the amount of seeds is about 0.5% by weight. In some embodiments, the process of forming a pharma- ceutically acceptable salt of compound 1 is cooled to about 5°C to about 15°C. In some embodiments, the pharma- ceutically acceptable salt of compound 1 is isolated. In some embodiments, the pharma- ceutically acceptable salt of compound 1 is isolated as a crystalline solid. In some embodiments, the pharma- ceutically acceptable salt of compound 1 is isolated by filtration.

[0083] In some embodiments, compound 1 is synthesized by any one of the processes described above. In some embodiments, a pharma- ceutically acceptable salt of compound 1 of the processes described herein is isolated. In some embodiments, a pharma- ceutically acceptable salt of compound 1 is a hydrobromide salt. In some embodiments, a pharma- ceutically acceptable salt of compound 1 is a dihydrobromide salt.

[0084] The present disclosure further provides a method for the preparation of a pharmaceutical composition comprising administering to a patient in need thereof a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and: (1) 0.7% to 0.01% of a compound of formula II, [ka]

[0085] During the ceremony, R 1 is selected from the group consisting of hydrogen, fluoro, or chloro; R 2 is selected from the group consisting of hydrogen or chloro; R 3 is selected from the group consisting of fluoro or chloro; R 4 is selected from the group consisting of -OH and -N(H)CH2C(CH3)3, or a pharma- ceutically acceptable salt thereof, (2) 0.05% to 0.005% imidazole or a pharma- ceutically acceptable salt thereof, or (3) A composition comprising 0.7% to 0.01% of a compound of formula II, or a pharma- ceutically acceptable salt thereof, and 0.05% to 0.005% of imidazole, or one or more of its pharma- ceutically acceptable salts, The compound of formula II is not compound 1, and the percentage of compound 1, the compound of formula II, and / or imidazole is determined by high performance liquid chromatography. In some embodiments, the compound of formula II is a hydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0086] In some embodiments, the compound of formula II is a compound of formula II-A: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-A is a hydrobromide salt. In some embodiments, the compound of formula II-A is a dihydrobromide salt.

[0087] In some embodiments, the compound of formula II is a compound of formula II-B: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-B is a hydrobromide salt. In some embodiments, the compound of formula II-B is a dihydrobromide salt.

[0088] In some embodiments, the compound of formula II is a compound of formula II-C: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-C is a hydrobromide salt. In some embodiments, the compound of formula II-C is a dihydrobromide salt.

[0089] In some embodiments, the compound of formula II is a compound of formula II-D: [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula II-D is a hydrobromide salt. In some embodiments, the compound of formula II-D is a dihydrobromide salt.

[0090] In some embodiments, R 4 is -N(H)CH2C(CH3)3. In some embodiments, R 4 In some embodiments, R 1 is fluoro and R 2 is hydrogen and R 3 In some embodiments, R 1 is chloro and R 2is hydrogen and R 3 In some embodiments, R 1 is hydrogen and R 2 is chloro and R 3 In some embodiments, R 1 is fluoro and R 2 is hydrogen and R 3 is fluoro.

[0091] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.6% to 0.01% of Compound 2, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 2 is a hydrobromide salt. In some embodiments, compound 2 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0092] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.3% to 0.01% of Compound 3; [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 3 is a hydrobromide salt. In some embodiments, compound 3 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0093] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 4, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 4 is a hydrobromide salt. In some embodiments, compound 4 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0094] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 5, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 5 is a hydrobromide salt. In some embodiments, compound 5 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0095] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 6, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 6 is a hydrobromide salt. In some embodiments, compound 6 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0096] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 7, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 7 is a hydrobromide salt. In some embodiments, compound 7 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0097] The present disclosure further provides a pharmaceutical composition comprising 98.0% to 99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.5% to 0.01% of Compound 8, [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, compound 8 is a hydrobromide salt. In some embodiments, compound 8 is a dihydrobromide salt. In some embodiments, compound 1 is a hydrobromide salt. In some embodiments, compound 1 is a dihydrobromide salt.

[0098] The present disclosure further relates to a composition comprising 98.0%-99.9% of Compound 1, or a pharma- ceutically acceptable salt thereof, and 0.05%-0.005% of imidazole, or a pharma- ceutically acceptable salt thereof. In some embodiments, the imidazole is a hydrobromide salt. In some embodiments, Compound 1 is a hydrobromide salt. In some embodiments, Compound 1 is a dihydrobromide salt.

[0099] The present disclosure further relates to a process for preparing a composition having an oxidation-sensitive active agent that is substantially free of compound 13, [ka] The process includes dissolving compound 11 in a solvent and combining the solution of compound 11 with compound 9 to form a mixture that is treated with hydrobromic acid. In some embodiments, the activator susceptible to oxidation is a hydrobromide salt of compound 1. In some embodiments, the activator susceptible to oxidation is a dihydrobromide salt of compound 1.

[0100] In some embodiments, the solvent used to dissolve compound 11 is an alcohol of formula R-OH, where R is an alkyl, with the proviso that R is not ethyl. In some embodiments, the solvent is a primary alcohol other than ethanol. In some embodiments, the solvent is a secondary alcohol. In some embodiments, the solvent is a tertiary alcohol. In some embodiments, the solvent is 2-methylpropan-1-ol. In some embodiments, the solvent is propanol. In some embodiments, the solvent is isopropanol. In some embodiments, the mixture is warmed to 0-5° C. during the hydrobromic acid treatment.

[0101] In some embodiments, the mixture is maintained at a pH of less than 6. In some embodiments, the mixture is maintained at a pH of less than 3.

[0102] The present disclosure further relates to a process for preparing a composition of compound 1 essentially free of compound 13, the process comprising combining compound 10 with compound 11 to form a mixture that is treated with hydrobromic acid in a solvent. In some embodiments, the active agent susceptible to oxidation is a hydrobromide salt of compound 1. In some embodiments, the active agent susceptible to oxidation is a dihydrobromide salt of compound 1.

[0103] In some embodiments, compound 1 is synthesized by any one of the processes described above. EXAMPLES

[0104] The following synthetic examples are illustrative, but not limiting, of the methods described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in the art and obvious to those skilled in the art are within the spirit and scope of the invention.

[0105] Synthesis Example 1 Formula V bearing the protecting group tert-butyl (1.0 equiv.) is added to isopropanol and water and reacted with aqueous hydrochloric acid (about 4.1 equiv.) at about 58-62° C. to give compound 9. The pH of the solution is adjusted with sodium hydroxide (about 0.2-0.6), heated to about 65° C., and the pH is adjusted again to about 1.2-2.5. The solution is cooled (about 15-20° C.) and adjusted to a final pH of about 2.6-3.0 to crystallize the product. Compound 9 is filtered, washed with water and isopropanol, and dried (<75° C.).

[0106] Synthesis Example 2 Compound 9 is added to acetonitrile and pyridine hydrobromide (about 2.1 equivalents). 1,1'-carbonyldiimidazole (about 1.1 equivalents) is added and the mixture is heated (about 20-30°C) to give compound 10. Triethylamine (about 0.7 equivalents) and acetonitrile are added and the mixture is cooled (about -7°C) and carried on to the next step.

[0107] Synthesis Example 3 The dihydrobromide salt of compound 11 (about 1 equivalent) is added to acetonitrile and converted to the free base compound 11 by the addition of triethylamine (about 3.1 equivalents) at about −7° C. This solution is carried on to the next step.

[0108] Synthesis Example 4 A solution of compound 11 (about 1.20 equivalents) is combined with a solution of compound 10 (about 1 equivalent) at about -7°C to give the dihydrobromide salt of compound 1. The reaction mixture is treated with aqueous hydrobromic acid (about 7.5 equivalents) and heated to about 40°C. Triethylamine is added to give a final mixture pH of about 1 to about 1.5. A seed of the dihydrobromide salt of compound 1 (about 0.1 wt%) is added and the mixture is cooled (about 5°C) to crystallize the product. The crude solid of the dihydrobromide salt of compound 1 is filtered, washed with water and acetonitrile, and dried (about 40-50°C).

[0109] Synthesis Example 5 The crude compound of the dihydrobromide salt of compound 1 (about 1 equivalent) is dissolved in isopropanol and water together with aqueous hydrobromic acid (about 2 equivalents). The solution is heated (about 40 to about 50 °C), neutralized with triethylamine (about 1 equivalent), and a seed of the dihydrobromide salt of compound 1 (about 0.5 wt%) is added. Triethylamine diluted in isopropanol is added in small portions until the target pH (about 3 to 3.5) is reached. The solution is cooled (about 5 to 15 °C) and the product is crystallized. The solid of nirogacestat hydrobromide salt (e.g., nirogacestat dihydrobromide salt) is filtered, washed with pre-cooled (about 8 to 12 °C) isopropanol, and dried (≦65 °C).

[0110] Synthesis Example 6 A dry, clean reactor was evacuated and then filled with nitrogen. Methyl tert-butyl ether (MTBE) and purified water were charged to the reactor at about 15 to about 25° C. The mixture was degassed by bubbling nitrogen subsurface. At 15 to 25° C., the hydrogen phosphate salt of compound 12 (about 1 equivalent) was added to the mixture via a solid addition funnel and stirred for about 0.5 to about 1 hour. At about 15 to about 25° C., sodium hydroxide solution (about 2 equivalents) was added to the mixture. The mixture was sampled for pH until the pH was ≧11. The mixture was filtered. The filter cake was rinsed with MTBE. The filtrate was allowed to settle for about 0.5 to about 2 hours and then separated into organic and aqueous phases. The aqueous phase was washed twice with MTBE, each time stirred for about 0.5 to about 1 hour, allowed to settle for about 0.5 to about 2 hours, and then separated into organic and aqueous phases. The organic layer was collected and washed with purified water at about 15 to about 25° C. The organic phase was then concentrated under reduced pressure at a temperature of ≦40° C. until about 30 to about 45 L remained. The mixture was sampled for Karl Fischer (KF) analysis (KF≦0.1%). The free base of compound 12 was synthesized.

[0111] Dichloromethane (DCM) was added to the reactor at about 15 to about 25° C. The mixture was stirred for about 20 to about 30 minutes.

[0112] DCM was added to the second reactor at about 15 to about 25° C. and the mixture was sampled for KF analysis (KF≦0.1%). N,N-diisopropylethylamine (about 3.4 equivalents) and tert-butyl (R)-2-hydroxypentanoate (about 1.7 equivalents) were added to the second reactor at about 15 to about 25° C. and the mixture was then stirred for about 10 to about 20 minutes. The mixture was cooled to about −20 to about −30° C.

[0113] DCM was added to the third reactor at about 15 to about 25 °C, and the mixture was sampled for KF analysis (KF ≦ 0.1%). Trifluoromethanesulfonic anhydride (about 2 equivalents) was added to the third reactor at about 15 to about 25 °C by pump, and then the mixture was stirred for about 10 to about 20 minutes. Then, a DCM solution prepared with trifluoromethanesulfonic anhydride (trifluoromethanesulfonic anhydride:DCM = 1: 6.4 equivalents) was added to the second reactor at -20 to -30 °C with stirring. The mixture was reacted at about -20 to about -30 °C. After about 0.5 to about 1 hour, the mixture was sampled for HPLC analysis every about 1 to about 2 hours until the area % of tert-butyl (R)-2-hydroxypentanoate was ≦ 3.0 area %. The compound of formula IV was synthesized with the leaving group as trifluoromethanesulfonate and the protecting group as tert-butyl.

[0114] A solution of the free base of compound 12 was added to the solution of the compound of formula IV at a rate of about 100 to about 150 Kg / h at about -20 to about -30°C. The mixture was heated to about 20 to about 30°C. After about 10 hours, the mixture was sampled for HPLC analysis about every 4 to 6 hours until the area % of the free base of compound 12 was ≦2.0 area % or the difference between two consecutive samples was ≦0.5%. A potassium bicarbonate solution (about 5.0 equivalents) was added to the mixture at about 20 to about 30°C and the mixture was stirred for about 0.5 to about 1 hour. The mixture was transferred to a stainless steel reactor. The mixture was stirred for about 0.5 to about 1 hour at about 20 to about 30°C, allowed to settle for about 0.5 to about 1 hour, and then separated into an organic phase and an aqueous phase. The organic phase was concentrated under reduced pressure at a temperature of ≦40°C until about 60 to about 90 L remained. 1,4-dioxane (about 10.0 equiv.) was added to the organic phase at a temperature of ≦40° C. The mixture was concentrated under reduced pressure at a temperature of ≦40° C. until about 60 to about 90 L remained. The mixture was sampled for DCM residue analysis until the DCM residue was ≦1%. Additional 1,4-dioxane (about 10.0 equiv.) was added to the mixture at about 15 to about 25° C. and stirred for about 0.5 to about 1 hour. The mixture was then filtered. The filter cake was rinsed with 1,4-dioxane. The filtrate was transferred to a reactor at about 15 to about 25° C. and the mixture was then stirred for about 10 to about 20 minutes. Purified water (about 6.0 equiv.) was added to the mixture at about 15 to about 25° C. The mixture was adjusted until the KF was about 1 to about 2% and then stirred for about 10 to about 20 minutes. A 4M HCl / dioxane solution (about 2 equivalents of HCl) was added to the mixture at about 15 to about 25° C. The mixture was stirred at about 15 to about 25° C. for crystallization. After about 1 to about 2 hours, the mixture was sampled for HPLC analysis until the mother liquor of the compound of formula V having a tert-butyl protecting group was ≦0.8 wt % or the difference between two consecutive samples was ≦0.3%. The slurry in the mixture was filtered. The filter cake was rinsed three times with 1,4-dioxane, and then the filter cake was rinsed twice with n-heptane. The solid was dried at a temperature of about 40 to 50° C. After 10 hours, the solid was sampled every 3 to 6 hours until the 1,4-dioxane residue was ≦0.5% and the n-heptane residue was ≦0.5%. After drying, the solid was cooled to 15 to 25° C.The hydrochloride salt of compound of formula V was synthesized with the protecting group as tert-butyl.

[0115] Synthesis Example 7 To obtain compound 1, compound 9 may be added to acetonitrile and pyridine hydrobromide (about 2.1 equivalents). 1,1'-carbonyldiimidazole (about 1.07 equivalents) may then be added and the mixture may be heated (about 20-30°C) to obtain compound 10. Triethylamine (about 0.66 equivalents) and acetonitrile may then be added and the mixture may be cooled (about -7°C). The mixture may then be combined with a solution of compound 11 (1.20 equivalents) at about -7°C to obtain compound 1. The reaction mixture may then be treated with aqueous hydrobromic acid (about 7.5 equivalents) and heated to about 40°C. Triethylamine may then be added to obtain a pH of the final mixture of about 1-1.5. Seeds of compound 1 (about 0.1% by weight) may then be added and the mixture may be cooled (about 5°C) to crystallize the product. The crude solid compound 1 may then be filtered, washed with water and acetonitrile, and dried (about 40-50°C). Crude compound 1 (1.0 equiv.) may then be dissolved in isopropanol and water along with aqueous hydrobromic acid (2.0 equiv.). This solution can be heated (approximately 40-50° C.) and neutralized with triethylamine (1.0 equiv.), and compound 1 seeds (approximately 0.5 wt.%) can again be added. Triethylamine diluted in isopropanol is then added in portions until the target pH (approximately 3-3.5) is reached. The solution is cooled (approximately 5-15° C.) and the product is allowed to crystallize. Compound 1 is then filtered, washed with pre-cooled (approximately 8-12° C.) isopropanol, and dried (≦65° C.).

Claims

1. Compound 9, 【Chemical 1】 In a solvent, compound 10, 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, with 1,1'-carbonyldiimidazole under conditions suitable to form Optionally, the process occurs in the presence of a polar aprotic solvent; Optionally, the polar aprotic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof.

2. 10. The process of claim 1, wherein the process occurs in the presence of one or more additives, optionally wherein the one or more additives comprise pyridine hydrobromide or triethylamine.

3. The process converts compound 10 into compound 1 【Chemistry 3】 or a pharmaceutically acceptable salt thereof. 【Chemistry 4】 3. The process of claim 1 or 2, further comprising reacting

4. 4. The process of claim 3, wherein the process occurs in the presence of a polar aprotic solvent. Optionally, the polar aprotic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), acetonitrile, or a combination thereof.

5. The process described in claim 3 or 4, wherein compound 1 is a free base.

6. The process described in claim 3 or 4, wherein compound 1 is a pharmaceutically acceptable salt, optionally wherein compound 1 is a dihydrobromide salt, and preferably wherein the dihydrobromide salt of compound 1 is a crystalline solid.

7. The free base of Compound 1 is 【Chemistry 5】 6. The process of claim 5, further comprising reacting with an aqueous inorganic acid under conditions suitable to form a pharmaceutically acceptable salt of Compound 1. Optionally, the pH is adjusted to about 1 to about 1.5; Optionally, the process wherein the inorganic acid is hydrobromic acid.

8. A compound of formula V: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, comprising reacting compound 12 with compound 13 under conditions suitable to form a compound of formula V or a pharmaceutically acceptable salt thereof: 【Chemistry 7】 A compound of formula IV, 【Chemistry 8】 During the ceremony, LG is a leaving group; PG is a protecting group, optionally C 1 -C 6 alkyl, preferably t-butyl; with said compound of formula IV.

9. LG is -OR ２ and R ２ But -S(=O) ２ R ３ , optionally -S(=O)2CF3; R ３ But C １ -C ３ Alkyl, C １ -C ３ 9. The process of claim 8, wherein the alkyl group is haloalkyl, or optionally substituted phenyl.

10. 10. The process according to claim 8 or 9, wherein the process occurs in the presence of a polar aprotic solvent, Optionally, the polar aprotic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof.

11. 11. The process according to any one of claims 8 to 10, wherein the process occurs in the presence of a base, Optionally, the base is N,N-diisopropylethylamine.

12. 12. The process of claim 10 or 11, wherein the solvent is removed in vacuo. Optionally, the compound of formula V is dissolved in a polar aprotic solvent and an aqueous inorganic acid; Optionally, the polar aprotic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof; Optionally, the process wherein said inorganic acid is hydrochloric acid.

13. 13. The process of any one of claims 10 to 12, wherein the pharmaceutically acceptable salt of Formula V is the hydrochloride salt.

14. wherein the process comprises producing compound 9, 【Chemistry 9】 14. The process of any one of claims 10 to 13, further comprising reacting the compound of formula V, or a pharmaceutically acceptable salt thereof, with an aqueous solution of an inorganic acid in a polar protic solvent under conditions suitable to form:

15. 15. The process of claim 14, wherein the polar protic solvent is an alcohol. Optionally, the alcohol is isopropanol; Optionally, the process wherein said inorganic acid is hydrochloric acid.

16. 16. The process of claim 14 or 15, wherein the pH is adjusted to about 2.6 to about 3.

0.

17. Compound 1, 【Chemistry 10】 or a pharmaceutically acceptable salt thereof, comprising reacting compound 10, or a pharmaceutically acceptable salt thereof, with compound 11, or a pharmaceutically acceptable salt thereof, under conditions suitable to form compound 1 or a pharmaceutically acceptable salt thereof.

18. 18. The process of claim 17, wherein the process occurs in the presence of a polar aprotic solvent. Optionally, the polar aprotic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), acetonitrile, or a combination thereof.

19. 19. The process of claim 17 or 18, wherein Compound 1 is a free base.

20. A process wherein Compound 1 is a pharmaceutically acceptable salt, optionally wherein Compound 1 is said hydrobromide salt, preferably wherein said hydrobromide salt of Compound 1 is isolated as a crystalline solid.

21. The process comprises reacting the free base of Compound 1 with 【Chemistry 11】 20. The process of claim 19, further comprising reacting with an aqueous inorganic acid, optionally hydrobromic acid, under conditions suitable to form a pharmaceutically acceptable salt of Compound 1: Optionally, said pharmaceutically acceptable salt of Compound 1 is a hydrobromide salt; Optionally, the hydrobromide salt is a dihydrobromide salt; Optionally, the process wherein the pH is from about 1 to about 1.

5.

22. Compound 9, 【Chemistry 12】 with 1,1'-carbonyldiimidazole in a solvent under conditions suitable to form compound 10; 【Chemistry 13】 The process further comprises converting compound 10 into compound 1, 【Chemistry 14】 or a pharmaceutically acceptable salt thereof. 【Chemistry 15】 The process further comprising reacting with

23. 23. The process of claim 22, wherein the process occurs in the presence of a polar aprotic solvent. Optionally, the polar aprotic solvent is dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetone, dichloromethane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, acetonitrile, or a combination thereof.

24. 24. The process of claim 22 or 23, wherein the process occurs in the presence of one or more additives, Optionally, the one or more additives comprise pyridine hydrobromide or triethylamine.

25. The process of any one of claims 22 to 24, wherein Compound 1 is a free base.

26. 25. The process of any one of claims 22 to 24, wherein compound 1 is a pharmaceutically acceptable salt, Optionally, the process wherein Compound 1 is a dihydrobromide salt, and preferably, said dihydrobromide salt of Compound 1 is isolated as a crystalline solid.

27. The process comprises reacting the free base of Compound 1 with 【Chemistry 16】 26. The process of claim 25, further comprising reacting with an aqueous inorganic acid, optionally hydrobromic acid, under conditions suitable to form a pharmaceutically acceptable salt of Compound 1: Optionally, said pharmaceutically acceptable salt of Compound 1 is a hydrobromide salt; Optionally, the hydrobromide salt is a dihydrobromide salt; Optionally, the pH is adjusted to about 1 to about 1.

5.

28. A pharmaceutically acceptable salt of Compound 1, 【Chemistry 17】 1. A process comprising reacting with an aqueous inorganic acid in an alcohol, Optionally, the alcohol is isopropanol; Optionally, the aqueous inorganic acid is hydrobromic acid; Optionally, the pH is adjusted to about 3 to about 3.

5.

29. 29. The process of claim 28, wherein the pharmaceutically acceptable salt of compound 1 is a hydrobromide salt, preferably wherein the pharmaceutically acceptable salt of compound 1 is a dihydrobromide salt.

30. Compound 1, 98.0% to 99.9% 【Chemistry 18】 or a pharmaceutically acceptable salt thereof, as well as (1) 0.7% to 0.01% of a compound of formula II, 【Chemistry 19】 During the ceremony, R １ is selected from the group consisting of hydrogen, fluoro and chloro; R ２ is selected from the group consisting of hydrogen and chloro; R ３ is selected from the group consisting of fluoro and chloro; R ４ is —OH and —N(H)CH ２ C(CH ３ ) ３ selected from the group consisting of a compound, or a pharmaceutically acceptable salt thereof, (2) 0.05% to 0.005% imidazole, or a pharmaceutically acceptable salt thereof; or (3) 0.7% to 0.01% of a compound of formula II, or a pharmaceutically acceptable salt thereof, and 0.05% to 0.005% of imidazole, or a pharmaceutically acceptable salt thereof; and the compound of Formula II is not Compound 1, and the proportion of Compound 1, the compound of Formula II, and / or imidazole is determined by high performance liquid chromatography; Optionally, the composition wherein said compound of Formula II is a hydrobromide salt.

31. The compound of formula II is a compound of formula II-A, 【Chemistry 20】 or a pharmaceutically acceptable salt thereof. Optionally, the composition wherein said compound of formula II-A is a hydrobromide salt.

32. The compound of formula II is a compound of formula II-B: 【Chemical 21】 or a pharmaceutically acceptable salt thereof. Optionally, the composition wherein said compound of formula II-B is a hydrobromide salt.

33. The compound of formula II is a compound of formula II-C: 【Chemical 22】 or a pharmaceutically acceptable salt thereof. Optionally, the composition wherein said compound of formula II-C is a hydrobromide salt.

34. The compound of formula II is a compound of formula II-D: 【Chemical 23】 or a pharmaceutically acceptable salt thereof. Optionally, the composition wherein said compound of formula II-D is a hydrobromide salt.

35. R ４ is -N(H)CH ２ C(CH ３ ) ３ The composition according to any one of claims 30 to 34, wherein the aryl group is -CH or -OH.

36. (i) R １ is fluoro and R ２ is hydrogen, and R ３ But it's Chloro. (ii) R 1 is chloro, R 2 is hydrogen, and R 3 is fluoro; (iii) R 1 is hydrogen, R 2 is chloro, and R 3 is fluoro; or (iv) R 1 is fluoro, R 2 is hydrogen, and R 3 is fluoro; The composition according to any one of claims 30 to 35. (a)(1) 98.0% to 99.9% of Compound 1 【Chemistry 24】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt, Compound 1; and (2) 0.6% to 0.01% of Compound 2; 【Chemistry 25】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt, Compound 2; (b)(1) 98.0% to 99.9% of Compound 1; 【Chemical 26】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.3% to 0.01% of Compound 3; 【Chemical 27】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt, Compound 3; (c)(1) 98.0% to 99.9% of Compound 1 【Chemical Formula 28】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.5% to 0.01% of Compound 4; 【Chemical formula 29】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt, Compound 4; (d)(1) 98.0% to 99.9% of Compound 1 【Chemistry 30】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.5% to 0.01% of Compound 5; 【Chemical 31】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt, (e)(1) 98.0% to 99.9% of Compound 1; 【Chemical 32】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.5% to 0.01% of Compound 6; 【Chemical 33】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt, (f)(1) 98.0% to 99.9% of Compound 1; 【Chemical 34】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.5% to 0.01% of Compound 7; 【Chemical 35】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt, Compound 7; (g)(1) 98.0% to 99.9% of Compound 1; 【Chemical 36】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.5% to 0.01% of Compound 8; 【Chemical 37】 or a pharmaceutically acceptable salt thereof, optionally a dihydrobromide salt; (h) (1) 98.0% to 99.9% of Compound 1 【Chemical Formula 38】 or a pharmaceutically acceptable salt thereof, optionally a hydrobromide salt; and (2) 0.05% to 0.005% imidazole or a pharmaceutically acceptable salt thereof, optionally the imidazole hydrobromide salt; 31. The composition of claim 30, comprising:

38. 38. The composition of any one of claims 30 to 37, wherein Compound 1 is a dihydrobromide salt.

39. 1. A process for preparing a composition having an oxidation-sensitive active agent substantially free of compound 13, comprising: 【Chemical Formula 39】 dissolving compound 11 in a solvent; 【Chemistry 40】 and combining with compound 9 to form a mixture that is treated with hydrobromic acid; 【Chemistry 41】 The process wherein the activator is the dihydrobromide salt of Compound 1. 【Chemistry 42】

40. 1. A process for preparing a composition essentially free of compound 13, comprising: 【Chemistry 43】 Compound 10, 【Chemical 44】 In combination with compound 11, 【Chemistry 45】 Compound 1 【Chemistry 46】 forming a mixture which is treated with hydrobromic acid in a solvent to form an activator of the dihydrobromide salt of

41. The solvent is (i) Alcohols of formula R—OH, where R is alkyl, with the proviso that R is not ethyl; (ii) is a primary alcohol other than ethanol; (iii) is a secondary alcohol, or (iv) is a tertiary alcohol; Optionally, the solvent is 2-methylpropan-1-ol, propanol, or isopropanol; 40. The process of claim 39.

42. 40. The process of claim 39, wherein the mixture is warmed to 0-5°C during the hydrobromic acid treatment. Optionally, the mixture is maintained at a pH of less than 6, or at a pH of less than 3.

43. (i) a process according to any one of claims 1 to 7, (ii) a process according to any one of claims 17 to 21; (iii) the process of any one of claims 22 to 27, (iv) the process of claim 28 or 29, (v) a process according to claim 39, 41 or 42; or (vi) the process of claim 40 Compound 1 prepared by

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