Synthesis of 2-(carbamoyloxy)-N, N, N-trimethylethyl-1-ammonium salt

Abstract

The present disclosure relates to a synthetic process for the preparation and purification of 2-(carbamoyloxy)-N, N, N-trimethylethyl-1-ammonium salts and pharmaceutical compositions thereof.

Description

Background Technology

[0001] Carbachol (also known as 2-(carbamoyloxy)-N,N,N-trimethylethyl-1-ammonium chloride) is a cholinergic drug that binds to and activates acetylcholine receptors.

[0002] Carbachol can be prepared via a two-step method starting with 2-chloroethanol and urea. The intermediate 2-chloroethyl-carbamate is then reacted with trimethylamine to form a quaternary ammonium product. Although carbachol can be produced by this method, it cannot be efficiently scaled up. Furthermore, current synthetic methods rely on the use of unfavorable solvents and / or reactants, the use of which has negative environmental impacts. Therefore, a more efficient and / or more environmentally friendly method for the preparation of carbachol is needed, avoiding expensive and undesirable challenges. Since carbachol has been found to be useful as a pharmaceutical ingredient, it is particularly important to purify carbachol to remove any residual reagents. This invention relates to a novel synthetic method for the industrial-scale preparation and purification of high-purity carbachol. Summary of the Invention

[0003] This disclosure provides a reaction pathway suitable for the large-scale preparation of 2-(carbamoyloxy)-N,N,N-trimethylethyl-1-ammonium or a pharmaceutically acceptable salt thereof (e.g., carbacholine chloride) starting from choline salts.

[0004] According to scheme 1, this paper provides preparation of compound I.

[0005] ,

[0006] A method using a pharmaceutically acceptable salt thereof, wherein the method comprises reacting a compound of formula II with a compound of formula III in a solvent, wherein R 1 and R 2 Each is an independent leaving group; to produce a compound of formula IV or a salt thereof.

[0007] Option 1

[0008]

[0009] Where R 1 and R 2 As described with respect to the compounds of the present invention and their embodiments and formulas.

[0010] In some aspects of these methods, according to scheme 2, a compound of formula IV or a salt thereof is reacted with ammonia to obtain a compound of formula I or a pharmaceutically acceptable salt thereof.

[0011] Option 2

[0012]

[0013] Where R 1 As described with respect to the compounds of the present invention and their embodiments and formulas.

[0014] In some aspects of this method, the solvent is an organic solvent. In some aspects, the organic solvent is THF, DMF, EtOAc, CH3CN, DMSO, CH2Cl2, EtOH, etc. In some aspects, the organic solvent is dichloromethane, acetonitrile, or dimethyl sulfoxide.

[0015] In some aspects of these methods, R 1 It is -O-(4-nitrophenyl) or imidazoline, and R 2 It is -Cl or imidazoline.

[0016] In some aspects of these methods, the reaction between the compound of formula I and the compound of formula II is carried out at a temperature of about 15°C to about 90°C.

[0017] In some aspects of these methods, ammonia is introduced into a solution of formula IV in gaseous form.

[0018] In some aspects of these methods, during the addition of gaseous ammonia, the solution of Form IV is stirred at a reaction temperature of about 0°C to about 25°C.

[0019] Some aspects of this disclosure include a method in which the compound of formula III is carbonyl diimidazole, the reaction temperature is from about 65°C to about 70°C, the solvent is acetonitrile, and gaseous ammonia is reacted with a solution of formula IV at a temperature from about 20°C to about 25°C.

[0020] In some aspects of these methods, the compound of formula I is recrystallized in water, one or more alcohol solvents, or a combination thereof.

[0021] In some aspects of these methods, at least 15 kg of a compound of formula I is synthesized by the disclosed method. In some aspects, at least 15 kg of a compound of formula I in the form of a pharmaceutically acceptable chloride salt is synthesized by the disclosed method. In some aspects of these methods, at least 100 kg of a compound of formula I is synthesized by the disclosed method. In some aspects of these methods, at least 150 kg of a compound of formula I is synthesized by the disclosed method. In any of these aspects, a compound of formula I in the form of a pharmaceutically acceptable chloride salt is synthesized by the disclosed method.

[0022] I also considered compounds of formula IV with the following structure:

[0023] ,

[0024] Or its tautomers, salts or solvates, wherein R1 It is a leaving group.

[0025] In some respects, R 1 It is an imidazoline.

[0026] In some respects, the compounds of formula IV are chloride salts.

[0027] In some respects, compound IV is 1 H -Imidazol-1-carboxylic acid 2-(trimethyl-λ) 4 -Azaneyl ethyl ester chloride.

[0028] Pharmaceutical compositions comprising a compound of formula I prepared by the disclosed method or a pharmaceutically acceptable salt thereof are also conceivable.

[0029] An additional embodiment of the invention is a compound according to formula IV:

[0030] .

[0031] In an additional aspect of this embodiment, the compound according to Formula IV shown above can be in the form of an alternative salt (i.e., by replacing Cl with different counterions). - ion).

[0032] In some respects, the composition also comprises at least one additional compound selected from the group consisting of:

[0033] i) Formula IV;

[0034] ii) Equation V;

[0035] ,

[0036] iii) Equation VI;

[0037] ,

[0038] iv) Leaving groups; and

[0039] Its salt.

[0040] In some aspects, the composition further comprises about 0.001 w / w% to about 10.0 w / w% of one or more of formula IV, formula V, formula VI or leaving groups or salts thereof. Detailed Implementation

[0041] definition

[0042] Unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the event of conflict, the application including the definitions shall prevail. Unless the context otherwise requires, singular terms shall include plural terms, and plural terms shall include singular terms. All publications, patents, and other references cited herein are incorporated by full reference for all purposes, as if each individual publication or patent application specifically and individually indicated to be incorporated by reference.

[0043] While methods and materials similar to or equivalent to those described herein may be used to practice or test this disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of this disclosure will become apparent from the embodiments and claims.

[0044] To further define this disclosure, the following terms and definitions are provided.

[0045] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include multiple references. The term “a” (or “an”) and the terms “one or more” and “at least one” are used interchangeably herein. In some respects, the term “a” or “an” means “single.” In other respects, the term “a” or “an” includes “two or more” or “a plurality.”

[0046] As used herein, the term “about” means approximately, roughly, around, or within a range. When the term “about” is used in conjunction with a numerical range, the term modifies the range by extending the boundaries above and below the stated numerical value. Typically, the term “about” is used herein to modify the values ​​above and below the stated value by a change of 10% upwards or downwards (higher or lower).

[0047] The term “and / or” as used herein should be considered as a specific disclosure of each of two specified features or components in the presence or absence of the other. Therefore, the term “and / or” as used herein, such as in phrases like “A and / or B”, is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0048] As used herein, the term “wrt” is an abbreviation for “relative”, where the quantity described is relative to another substance as disclosed.

[0049] As used herein, the term “pharmaceutically acceptable” means, to the extent of reasonable medical judgment, those compounds, materials, compositions, formulations and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0050] The term "pharmaceutically acceptable salt" is recognized in the field and includes relatively non-toxic inorganic and organic acid addition salts of compounds, as well as relatively non-toxic inorganic and organic base addition salts of compounds. Suitable pharmaceutically acceptable salts include, but are not limited to, those described in Berge, Bigley and Monkhouse, J. Pharm. Sci. (1977) 66, pp. 1-19.

[0051] Inorganic acids that can be used to prepare pharmaceutically acceptable salts include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid. Organic acids that can be used to prepare pharmaceutically acceptable salts include (but are not limited to) aliphatic monocarboxylic acids and dicarboxylic acids, such as tartaric acid, oxalic acid, carbonic acid, citric acid, succinic acid, alkyl acids substituted with phenyl heteroatoms, aliphatic and aromatic sulfuric acids, etc. Therefore, pharmaceutically acceptable salts prepared from inorganic or organic acids include, but are not limited to, hydrochlorides, hydrobromic acids, nitrates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydroiodates, hydrofluoric acids, acetates, propionates, formates, oxalates, tartrates, citrates, lactates, p-toluenesulfonates, methanesulfonates, and maleates. Suitable pharmaceutically acceptable salts can also be formed by reacting the active component with an organic base (such as methylamine, ethylamine, ethanolamine, lysine, ornithine, etc.). Pharmaceutically acceptable salts include salts formed by carboxyl or sulfonate ions found on some active components and inorganic cations (such as sodium, potassium, ammonium, or calcium) or organic cations (such as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazoline). All such salts can be prepared from the active components of the present invention by conventional methods, for example, by reacting the active components of the present invention with a suitable acid or base.

[0052] As used herein, the term "leaving group" or "LG" refers to a chemical group that is readily replaced by a nucleophile or cleaved or hydrolyzed under basic or acidic conditions. In some respects, leaving groups are selected from halogen atoms (e.g., Cl, Br, I) or unstable heterocycles such as imidazolines or succinimides.

[0053] As used herein, the term "organic solvent" refers to a carbon-based liquid capable of dissolving or dispersing one or more other substances. Non-limiting exemplary organic solvents include, but are not limited to, acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, and chloroform, and combinations thereof.

[0054] As used herein, the term "phosgene equivalent" refers to an organic compound capable of reacting with a substrate in a manner similar to phosgene to efficiently add a carbonyl group to the substrate molecule. Non-limiting exemplary phosgene equivalents include, but are not limited to, bisphosgene, triphosgene, disuccinimide carbonate, carbonyl diimidazole (CDI), 4-(nitrophenyl) chloroformate (4-NPCF), chlorosulfonyl isocyanate (CSI), and combinations thereof.

[0055] Generally, "agitation" or "agitate" refers to the mechanical force that compels a fluid to flow within a container in a circulating or other manner. As used herein, the term "jet" refers to the process of injecting gas into a liquid phase via a diffuser.

[0056] As used herein, the terms “wt%” or “w / w” refer to the ratio of two components relative to their volume. For example, an aqueous solution containing 5% by weight ethanol means a solution containing 5 g of ethanol per 100 mL (i.e., 100 g) of water.

[0057] The term "excipient" refers to any substance that is not itself a therapeutic agent but can be used in a composition to deliver an active therapeutic agent to a subject, or in combination with an active therapeutic agent (e.g., to produce a pharmaceutical composition) to improve its handling or storage properties, or to allow or facilitate the formation of a dosage unit of the composition. Excipients can be inert, inactive, and / or non-pharmaceutical active substances.

[0058] As used herein, the terms “effective amount” or “pharmaceutical effective amount” or “therapeutic effective amount” refer to the amount or quantity of a drug or pharmaceutically active substance that is sufficient to elicit a desired or required therapeutic response, or in other words, the amount sufficient to elicit a significant biological response when administered to a patient.

[0059] "Administration" or "to administer" refers to the step of giving (i.e., providing) a pharmaceutical composition to a subject. The pharmaceutical compositions disclosed herein can be "topically administered," meaning applied at or near the site where a therapeutic result or outcome is desired. For example, to treat an ocular symptom such as corneal pain, the pharmaceutical composition can be applied topically directly to the subject's eye, and this is an example of topical administration.

[0060] Detailed description

[0061] This disclosure provides preparation of compound I:

[0062] ,

[0063] Or a pharmaceutically acceptable salt thereof, wherein, according to scheme 3, these methods comprise reacting compound II with compound III in a solvent, wherein R 1 and R 2 Each is an independent leaving group; to produce a compound of formula IV or a salt thereof.

[0064] Option 3

[0065]

[0066] R 1 and R 2 As described with respect to the compounds of the present invention and their embodiments and formulas.

[0067] In some aspects of these methods, the salt and / or pharmaceutically acceptable salt is an acetate, bicarbonate, tartrate, citrate, bromide, chloride, dihydrogen citrate, hydroxide, or tartrate. In some aspects of these methods, the leaving group is a halogen atom (e.g., Cl, Br, I). In some aspects of these methods, the leaving group is a chloride. In some aspects of these methods, the leaving group is a heterocyclic compound, such as an imidazoline or succinimide. In some aspects, the compound of formula III is a phosgene equivalent. In some aspects, the compound of formula III is bisphosgene, triphosgene, disuccinimide carbonate, carbonyl diimidazole (CDI), 4-(nitrophenyl) chloroformate (4-NPCF), chlorosulfonyl isocyanate (CSI), or combinations thereof. In some aspects, the compound of formula III is carbonyl diimidazole.

[0068] In some aspects, about 0.1 equivalents to about 5 equivalents of compound III are used relative to compound II. In some aspects, about 0.5 equivalents to about 3 equivalents of compound III are used relative to compound II. In some aspects, about 1 equivalent to about 2 equivalents of compound III are used relative to compound II. In some aspects, 1.2 equivalents of compound III are used relative to compound II.

[0069] In some aspects, Formulas II and III are combined with the solvent. In some aspects, the solvent is an organic solvent. In some aspects, the organic solvent is acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, chloroform, or combinations thereof. In some aspects, the organic solvent is acetonitrile.

[0070] In some respects, the reactants of Formula II and Formula III are stirred.

[0071] In some aspects, about 3 to about 20 equivalents of an organic solvent are used relative to the compound of formula II. In some aspects, about 5 to about 15 equivalents of an organic solvent are used relative to the compound of formula II. In some aspects, about 7 to about 12 equivalents of an organic solvent are used relative to the compound of formula II. In some aspects, about 8 to about 10 equivalents of an organic solvent are used relative to the compound of formula II. In some aspects, about 6 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 7 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 8 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 9 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 10 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 11 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 12 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 13 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 14 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 15 equivalents of a solvent are used relative to the compound of formula II. In some aspects, about 6 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 7 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 8 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 9 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 10 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 11 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 12 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 13 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 14 equivalents of acetonitrile are used relative to the compound of formula II. In some aspects, about 15 equivalents of acetonitrile are used relative to the compound of formula II.

[0072] In another aspect of these methods, according to scheme 4, a compound of formula IV or a salt thereof is reacted with ammonia to obtain a compound of formula I or a pharmaceutically acceptable salt thereof.

[0073] Option 4

[0074]

[0075] Where R 1 and R 2 As described with respect to the compounds of the present invention and their embodiments and formulas.

[0076] One embodiment is a compound according to formula IV:

[0077] .

[0078] In one aspect of this embodiment, the compound of formula IV has a salt form different from the chloride described above.

[0079] In some aspects of these methods, the salt of Formula IV is an acetate, bicarbonate, tartrate, citrate, bromide, chloride, dihydrogen citrate, hydroxide, or tartrate.

[0080] In some respects, the solvent is an organic solvent. In some respects, the organic solvent is dichloromethane, acetonitrile, or dimethyl sulfoxide. In some respects, the organic solvent is acetonitrile.

[0081] In some respects, the solvent used for the reaction of compound IV with ammonia is the same as the solvent used for the reactions of compounds of formulas II and III. In other respects, the solvent used for the reaction of compound IV with ammonia is a different solvent than the solvent used for the reactions of compounds of formulas II and III.

[0082] In some aspects, an organic solvent is used in amounts of about 3 to about 20 equivalents relative to compound IV. In some aspects, an organic solvent is used in amounts of about 5 to about 15 equivalents relative to compound IV. In some aspects, an organic solvent is used in amounts of about 7 to about 12 equivalents relative to compound IV. In some aspects, an organic solvent is used in amounts of about 8 to about 10 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 6 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 7 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 8 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 9 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 10 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 11 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 12 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 13 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 14 equivalents relative to compound IV. In some aspects, a solvent is used in amounts of about 15 equivalents relative to compound IV. In some aspects, a solvent of about 16 equivalents relative to compound IV is used. In some aspects, a solvent of about 17 equivalents relative to compound IV is used. In some aspects, a solvent of about 18 equivalents relative to compound IV is used. In some aspects, a solvent of about 19 equivalents relative to compound IV is used. In some aspects, a solvent of about 20 equivalents relative to compound IV is used.

[0083] In some aspects, the solvent is acetonitrile. In some aspects, about 6 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 7 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 8 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 9 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 10 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 11 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 12 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 13 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 14 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 15 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 16 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 17 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 18 equivalents of acetonitrile relative to compound IV are used. In some aspects, about 19 equivalents of acetonitrile relative to compound IV are used. In some respects, acetonitrile is used in amounts of approximately 20 equivalents relative to compound IV.

[0084] In some aspects of the methods disclosed in this paper, R 1 It is -O-(4-nitrophenyl) or imidazoline, and R 2 It is -Cl or imidazoline. In some respects, R 1 and R 2 They are the same leaving group. In some respects, R 1 and R 2 They are not the same. In some respects, the leaving group is a halogen atom (e.g., Cl, Br, I). In some respects of these methods, the leaving group is a chloride.

[0085] In some aspects, the reaction between Formula II and Formula III is carried out at a temperature of about 15°C to about 90°C. In some aspects, the reaction between Formula II and Formula III is carried out at a temperature of about 15°C to about 85°C. In some aspects, the reaction between Formula II and Formula III is carried out at a temperature of about 15°C to about 80°C. In some aspects, the reaction between Formula II and Formula III is carried out at a temperature of about 45°C to about 70°C. In some aspects, the reaction between Formula II and Formula III is carried out at a temperature of about 55°C to about 60°C. In some aspects, the reaction between Formula II and Formula III is carried out at a temperature of reflux of the organic solvent.

[0086] In some aspects, about 0.1 to about 5.0 equivalents of compound III are used relative to compound II. In some aspects, about 1.0 to about 2.0 equivalents of compound III are used relative to compound II. In some aspects, about 1.1 to about 1.5 equivalents of compound III are used relative to compound II. In some other aspects, about 1.1 equivalents of compound III are used relative to compound II. In some other aspects, about 1.2 equivalents of compound III are used relative to compound II. In some other aspects, about 1.3 equivalents of compound III are used relative to compound II. In some other aspects, about 1.4 equivalents of compound III are used relative to compound II. In some other aspects, about 1.5 equivalents of compound III are used relative to compound II.

[0087] In some aspects, a salt of compound III is used. In some aspects, about 0.1 to about 5.0 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some aspects, about 1.0 to about 2.0 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some aspects, about 1.1 to about 1.5 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some other aspects, about 1.1 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some other aspects, about 1.2 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some other aspects, about 1.3 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some other aspects, about 1.4 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form. In some other aspects, about 1.5 equivalents of a salt of compound III are used relative to a compound of compound II or its salt form.

[0088] In some aspects, the salt of compound III is a chloride. In some aspects, about 0.1 to about 5.0 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some aspects, about 1.0 to about 2.0 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some aspects, about 1.1 to about 1.5 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some other aspects, about 1.1 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some other aspects, about 1.2 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some other aspects, about 1.3 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some other aspects, about 1.4 equivalents of the chloride salt of compound III are used relative to the compound of formula II or its salt form. In some other respects, about 1.5 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form.

[0089] In some aspects, the formula IV compound is separated and / or purified prior to the addition of ammonia. In some aspects, the formula IV compound is separated and / or purified by distillation, filtration, and / or washing with an organic solvent. In some aspects, the formula IV compound is filtered using a portable robotic filter (PRF). In some aspects, the formula IV compound is filtered through a PRF under reduced pressure. In some aspects, the formula IV compound is filtered through a PRF under reduced pressure under nitrogen. In some aspects, the formula IV compound is separated and / or purified by filtering the reaction mixture and then washing the filter cake with an organic solvent. In some aspects, the formula IV compound is purified and / or separated by filtering the reaction mixture and then washing the filter cake with a mixture containing more than one organic solvent. In some aspects, the formula IV compound is separated by filtering the reaction mixture and then washing the filter cake with ACN. In some other aspects, the formula IV compound is separated from the solution and redissolved in an organic solvent prior to the addition of ammonia.

[0090] In some embodiments, ammonia is introduced into a solution of formula IV in gaseous form. In some embodiments, ammonia is introduced into a purified solution of formula IV in gaseous form. In some embodiments, gaseous ammonia is introduced into a solution of formula IV, wherein the formula IV compound has been isolated and redissolved in an organic solvent. In some embodiments, ammonia is introduced by direct injection of undiluted gaseous ammonia. In some embodiments, ammonia in gaseous form is introduced by subsurface injection. In some embodiments, ammonia is diluted with a carrier gas. In some other embodiments, the carrier gas is nitrogen. In some embodiments, ammonia is introduced into a solution of formula IV while the reaction is maintained at atmospheric pressure. In some embodiments, ammonia is introduced into a solution of formula IV while the reaction is maintained at a positive pressure relative to atmospheric pressure.

[0091] In some aspects, ammonia is introduced as a solution in a solvent into the solution of formula IV. In some aspects, ammonia is introduced as a solution in an organic solvent into the solution of formula IV. In some aspects, the solvent is acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, chloroform, or combinations thereof. In some aspects, ammonia is in the form of a methanol solution. In some other aspects, ammonia is in the form of a methanol solution of about 4 M. In some other aspects, ammonia is in the form of a methanol solution of about 5 M. In some other aspects, ammonia is in the form of a methanol solution of about 6 M. In some other aspects, ammonia is in the form of a methanol solution of about 7 M. In some other aspects, ammonia is in the form of a methanol solution of about 8 M.

[0092] In some respects, ammonia is introduced as a saturated solution in a solvent. In some respects, ammonia is introduced as a saturated solution in an organic solvent. In some respects, it is introduced as a saturated solution of acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (EtOAc), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, chloroform, or combinations thereof. In some other respects, ammonia is introduced as a saturated solution in acetonitrile.

[0093] In some cases, ammonia is introduced in solution and cooled to approximately 0°C to approximately 5°C. In other cases, a saturated ammonia solution is used by bubbling gaseous ammonia through a solvent. In situ Prepared, and then a solution of formula IV is added thereto.

[0094] In some aspects, during the addition of gaseous ammonia, the solution of Form IV is stirred at a reaction temperature of about 0°C to about 25°C. In some aspects, during the addition of gaseous ammonia, the solution of Form IV is stirred at a reaction temperature of about 20°C to about 25°C. In some aspects, the pH of the solution of Form IV is monitored during the addition of ammonia. In some aspects, the pH of the solution of Form IV is adjusted before the addition of ammonia. In some aspects, the pH of the solution of Form IV is maintained during the addition of ammonia by adding an acid or base. In some aspects, ammonia is continuously supplied throughout the reaction by gently bubbling the gas through the reactor. In some aspects, ammonia is gently bubbled throughout the reactor with moderate stirring. In some aspects, ammonia is introduced in a single dose and the reaction vessel is closed. In some aspects, ammonia is manually supplied by the operator based on mass, temperature, or pressure values ​​observed by the operator. In some aspects, ammonia is supplied via an electronically controlled valve based on mass, temperature, or pressure values ​​observed by sensors. In some aspects, ammonia is supplied manually or automatically based on the proportion of products observed by online NMR monitoring. In some respects, ammonia is given based on the proportion of products observed after sampling and analysis of a portion of the reaction mixture.

[0095] In some respects, the compound of formula III is a carbonyl diimidazole, the reaction temperature is from about 65°C to about 70°C, the solvent is acetonitrile, and gaseous ammonia is reacted with a solution of formula IV at a temperature from about 20°C to about 25°C.

[0096] In some aspects, the compound of formula I is recrystallized in water, one or more alcohol solvents, or combinations thereof. In some aspects, the compound of formula I is recrystallized in a combination of water and ethanol. In some aspects, the solution containing the compound of formula I is heated during recrystallization. In some aspects, the solution containing the compound of formula I is heated to reflux during recrystallization. In some aspects, the solution containing the compound of formula I is heated from about 60°C to about 90°C during recrystallization. In some aspects, the solution containing the compound of formula I is heated from about 60°C to about 80°C during recrystallization. In some aspects, the solution containing the compound of formula I is heated and cooled more than once during recrystallization. In some aspects, the solution containing the compound of formula I is concentrated by distillation. In some aspects, the solution containing the compound of formula I is concentrated by distillation under nitrogen. In some aspects, the compound of formula I is filtered, washed, and / or dried under heating and / or reduced pressure prior to recrystallization. In some aspects, the solution is reduced to about 8 to about 10 parts relative to the compound of formula I. In some aspects, the solution is reduced to about 8.5 to about 9.5 parts relative to the compound of formula I. In some respects, the solvent is reduced to about 9 parts relative to the compound of formula I by distillation under nitrogen at one atmosphere at about 77°C to about 79°C.

[0097] In some aspects, the compound of formula I is recrystallized in a solution of ethanol and water, wherein the water content is less than 10% w / v or v / v relative to ethanol. In some aspects, the compound of formula I is recrystallized in a solution of ethanol and water, wherein the water content is about 0.1% to about 20% w / v or v / v relative to ethanol. In some aspects, the water content is about 1% to about 15% w / v or v / v relative to ethanol. In some aspects, the water content is about 1% to about 10% w / v or v / v relative to ethanol. In some aspects, the water content is about 0.1% to about 5% w / v or v / v relative to ethanol. In some aspects, the water content is about 0.1% to about 3% w / v or v / v relative to ethanol. In some aspects, the water content is about 1% to about 3% w / v or v / v relative to ethanol. In some aspects, the water content is about 2% to about 4% w / v or v / v relative to ethanol. In some aspects, the recrystallization solvent is about 97.5% w / v or v / v ethanol, with the remainder being water.

[0098] In some aspects, the total amount of recrystallization solvent is about 5 to about 15 parts relative to compound I. In some aspects, about 3 to about 20 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 5 to about 15 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 7 to about 12 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 8 to about 10 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 6 equivalents of solvent are used relative to compound IV. In some aspects, about 7 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 8 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 9 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 10 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 11 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, about 12 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 13 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 14 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 15 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 16 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 17 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 18 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 19 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 20 equivalents of recrystallization solvent are used relative to compound IV. In some aspects, approximately 6 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 7 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 8 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 9 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 10 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 11 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 12 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 13 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 14 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 15 equivalents of 94% v / v ethanol are used relative to compound IV. In some aspects, approximately 16 equivalents of 94% v / v ethanol are used relative to compound IV.In some aspects, approximately 17 equivalents of 94% v / v ethanol are used relative to Formula IV. In some aspects, approximately 18 equivalents of 94% v / v ethanol are used relative to Formula IV. In some aspects, approximately 19 equivalents of 94% v / v ethanol are used relative to Formula IV. In some aspects, approximately 20 equivalents of 94% v / v ethanol are used relative to Formula IV. In some aspects, Formula I is heated to reflux until a clear solution is formed. In some aspects, Formula I is heated to reflux until a clear solution is formed after 2 hours. In some aspects, Formula I is recrystallized more than once. In some aspects, Formula I is recrystallized once or more after purity analysis. In some aspects, the cooling rate during recrystallization is temperature-controlled or limited. In some aspects, the product suspension is stirred and cooled before collecting the product by filtration. In some aspects, recrystallization is promoted by inserting seed crystals into the solution during the cooling step. In some aspects, the recrystallized solution is purified using a 1 µm TFE FC (Teflon filter cartridge). In some aspects, the solution is cooled to about 20°C to about 25°C over a period of about 5 hours. In some aspects, the product suspension is stirred and cooled to about 0°C to about 5°C before collecting the product by filtration. In some aspects, the product suspension is stirred and cooled to about 0°C to about 5°C over a period of about 1 to about 3 hours before collecting the product by filtration. In some aspects, the product suspension is stirred and cooled to about 0°C to about 5°C over a period of about 1 to about 2 hours before collecting the product by filtration.

[0099] In some aspects, the filter cake is washed with a solvent. In some aspects, the solvent is an organic solvent. In some aspects, the filter cake is washed with anhydrous ethanol. In some aspects, the filter cake is washed twice with anhydrous ethanol in an amount equivalent to 2 equivalents of the compound of formula I. In some aspects, the filter cake is dried in a vacuum oven. In some aspects, the filter cake is dried in a vacuum oven at about 50°C.

[0100] In one aspect of these methods, the compound of formula III is a carbonyl diimidazole, the reaction temperature is from about 65°C to about 70°C, the solvent is acetonitrile, gaseous ammonia is reacted with a solution of formula IV at a temperature of from about 20°C to about 25°C, and the compound of formula I is recrystallized in a combination of ethanol and water, as shown in Scheme 5.

[0101] Option 5

[0102]

[0103] The non-restricted reaction sequence for producing chloride salts of compound I from choline chloride, CDI, and ammonia.

[0104] In some aspects, a compound of formula I or a pharmaceutically acceptable salt thereof is recrystallized and then filtered, washed, and / or dried under reduced pressure to obtain a purified compound of formula I or a pharmaceutically acceptable salt thereof. In some aspects, the conversion and / or purity of the compound of formula I or a pharmaceutically acceptable salt thereof before or after recrystallization is determined by ion chromatography (IC), high-performance liquid chromatography (HPLC), ultra-high-performance liquid chromatography-CAD with an electrosol detector (UPLC-CAD), and / or liquid chromatography-mass spectrometry (LC-MS).

[0105] In some aspects, at least 15 kg of the compound of formula I or a pharmaceutically acceptable salt thereof is synthesized. In some aspects, at least 15 kg of the compound of formula I is in chloride salt form. In some aspects, at least 100 kg of the compound of formula I or a pharmaceutically acceptable salt thereof is synthesized. In some aspects, at least 150 kg of the compound of formula I or a pharmaceutically acceptable salt thereof is synthesized. In any of the foregoing aspects, the compound of formula I is in chloride salt form.

[0106] This disclosure includes compounds of formula IV having the following structures:

[0107] ,

[0108] Or its tautomers, salts or solvates, wherein R 1 For leaving groups. In some aspects of these methods, the salt of formula IV is an acetate, bicarbonate, tartrate, citrate, bromide, chloride, dihydrogen citrate, hydroxide, or tartrate. In some aspects, R 1 It is either an imidazoline or a succinimide. In some respects, R 1 These are halogen atoms (e.g., Cl, Br, I).

[0109] In some respects, the compounds of formula IV are chloride salts.

[0110] In some respects, the compound of formula IV is 1H-imidazol-1-carboxylic acid 2-(trimethyl-λ4-azalkyl)ethyl ester chloride or an alternative salt thereof.

[0111] Pharmaceutical Composition

[0112] This disclosure includes pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof prepared by the methods described herein.

[0113] In some respects, the pharmaceutical composition also comprises at least one additional compound selected from the group consisting of:

[0114] i) Formula IV;

[0115] ii) Equation V;

[0116] ,

[0117] iii) Equation VI;

[0118] ,

[0119] iv) Leaving groups; and

[0120] Its pharmaceutically acceptable salt.

[0121] In some aspects, the composition may further comprise about 0.001 w / w% to about 10.0 w / w% of one or more of formulas IV, V, VI, or leaving groups, or pharmaceutically acceptable salts thereof. In some aspects, the composition may further comprise about 0.005 w / w% to about 5.0 w / w% of one or more of formulas IV, V, VI, or leaving groups, or pharmaceutically acceptable salts thereof. In some aspects, the composition may further comprise about 0.01 w / w% to about 3.0 w / w% of one or more of formulas IV, V, VI, or leaving groups, or pharmaceutically acceptable salts thereof. In some aspects, the composition may further comprise about 0.1 w / w% to about 2.0 w / w% of one or more of formulas IV, V, VI, or leaving groups, or pharmaceutically acceptable salts thereof. In some aspects, the composition further comprises about 0.001 w / w% to about 1.0 w / w% of one or more of formula IV, formula V, formula VI or leaving groups or their pharmaceutically acceptable salts.

[0122] In some aspects, the pharmaceutical composition comprises about 2% to about 4% by weight of a compound of formula I or a pharmaceutically acceptable salt thereof, about 0.05% to about 1% by weight of one or more viscosities, and about 0.05% to about 1% by weight of one or more buffers.

[0123] In some aspects, the pharmaceutical composition comprises about 0.25% to about 0.5% by weight, about 0.25% to about 0.75% by weight, about 0.25% to about 1% by weight, about 0.25% to about 1.25% by weight, about 0.25% to about 1.5% by weight, about 0.25% to about 1.75% by weight, about 0.25% to about 2% by weight, about 0.25% to about 2.25% by weight, about 0.25% to about 2.5% by weight, about 0.25% to about 2.75% by weight, about 0.25% to about 3% by weight, about 0.25% to about 3.25% by weight, about 0.25% to about 3.5% by weight, and about 0.25% to about 3.7% by weight. 5% by weight, about 0.25% by weight to about 4% by weight, about 0.25% by weight to about 4.25% by weight, about 0.25% by weight to about 4.5% by weight, about 0.25% by weight to about 4.75% by weight, about 0.25% by weight to about 5% by weight, about 0.5% by weight to about 0.75% by weight, about 0.5% by weight to about 1% by weight, about 0.5% by weight to about 1.25% by weight, about 0.5% by weight to about 1.5% by weight, about 0.5% by weight to about 1.75% by weight, about 0.5% by weight to about 2% by weight, about 0.5% by weight to about 2.25% by weight, about 0.5% by weight to about 2.5% by weight, about 0.5% by weight to about 2.75% by weight, about 0.5% by weight to about 3% by weight. About 0.5 wt% to about 3.25 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 3.75 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.25 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 4.75 wt%, about 0.5 wt% to about 5 wt%, about 0.75 wt% to about 1 wt%, about 0.75 wt% to about 1.25 wt%, about 0.75 wt% to about 1.5 wt%, about 0.75 wt% to about 1.75 wt%, about 0.75 wt% to about 2 wt%, about 0.75 wt% to about 2.25 wt%, about 0.75 wt% to about 2.5 wt%, about 0.75 wt% to about 2.75 wt%, about 0.75 wt% to about 3 wt%, about 0.75 wt% to about 3.25 wt%, about 0.75 wt% to about 3.5 wt%, about 0.75 wt% to about 3.75 wt%, about 0.75 wt% to about 4 wt%, about 0.75 wt% to about 4.25 wt%, about 0.75 wt% to about 4.5 wt%, about 0.75 wt% to about 4.75 wt%, about 0.75 wt% to about 5 wt%, about 1 wt% to about 1.25 wt%, about 1 wt% to about 1.5 wt%, about 1 wt% to about 1.75 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 2.25 wt%, about 1 wt% to about 2.5% by weight, about 1% by weight to about 2.75% by weight, about 1% by weight to about 3% by weight, about 1% by weight to about 3.25% by weight, about 1% by weight to about 3.5% by weight, about 1% by weight to about 3.75% by weight, about 1% by weight to about 4% by weight, about 1% by weight to about 4.25% by weight, about 1% by weight to about 4.5% by weight, about 1% by weight to about 4.75% by weight, about 1% by weight to about 5% by weight, about 1.25% by weight to about 1.5% by weight, about 1.25% by weight to about 1.75% by weight, about 1.25% by weight to about 2% by weight, about 1.25% by weight to about 2.25% by weight, about 1.25% by weight to about 2.5% by weight, about 1.25% by weight to about 2.75% by weight. % by weight, about 1.25% by weight to about 3% by weight, about 1.25% by weight to about 3.25% by weight, about 1.25% by weight to about 3.5% by weight, about 1.25% by weight to about 3.75% by weight, about 1.25% by weight to about 4% by weight, about 1.25% by weight to about 4.25% by weight, about 1.25% by weight to about 4.5% by weight, about 1.25% by weight to about 4.75% by weight, about 1.25% by weight to about 5% by weight, about 1.5% by weight to about 1.75% by weight, about 1.5% by weight to about 2% by weight, about 1.5% by weight to about 2.25% by weight, about 1.5% by weight to about 2.5% by weight, about 1.5% by weight to about 2.75% by weight, about 1.5% by weight to about 3% by weight. About 1.5 wt% to about 3.25 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 3.75 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.25 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 4.75 wt%, about 1.5 wt% to about 5 wt%, about 1.75 wt% to about 2 wt%, about 1.75 wt% to about 2.25 wt%, about 1.75 wt% to about 2.5 wt%, about 1.75 wt% to about 2.75 wt%, about 1.75 wt% to about 3 wt%, about 1.75 wt% to about 3.25 wt%, about 1.75 wt% to about 3.5 wt%, about 1 0.75 wt% to about 3.75 wt%, about 1.75 wt% to about 4 wt%, about 1.75 wt% to about 4.25 wt%, about 1.75 wt% to about 4.5 wt%, about 1.75 wt% to about 4.75 wt%, about 1.75 wt% to about 5 wt%, about 2 wt% to about 2.25 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 2.75 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.25 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% to about 3.75 wt%, about 2 wt% to about 4 wt%, about 2 wt% to about 4.25 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 4.75 wt%, about 2 wt% to about 5 wt%, about 2.25 wt% to about 2.5 wt%, about 2.25 wt% to about 2.75 wt%, about 2.25 wt% to about 3 wt%, about 2.25 wt% to about 3.25 wt%, about 2.25 wt% to about 3.5 wt%, about 2.25 wt% to about 3.75 wt%, about 2.25 wt% to about 4 wt%, about 2.25 wt% to about 4.25 wt%, about 2.25 wt% to about 4.5 wt%, about 2.25 wt% to about 4.75 wt%, about 2.25 wt% to about 5 wt%, about 2.5 wt% to about 2.75 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.25 wt%. Weight%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 3.75 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.25 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 4.75 wt%, about 2.5 wt% to about 5 wt%, about 2.75 wt% to about 3 wt%, about 2.75 wt% to about 3.25 wt%, about 2.75 wt% to about 3.5 wt%, about 2.75 wt% to about 3.75 wt%, about 2.75 wt% to about 4 wt%, about 2.75 wt% to about 4.25 wt%, about 2.75 wt% to about 4.5 wt%, about 2.75 wt% to about 4.75 wt%. About 2.75 wt% to about 5 wt%, about 3 wt% to about 3.25 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 3.75 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.25 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 4.75 wt%, about 3 wt% to about 5 wt%, about 3.25 wt% to about 3.5 wt%, about 3.25 wt% to about 3.75 wt%, about 3.25 wt% to about 4 wt%, about 3.25 wt% to about 4.25 wt%, about 3.25 wt% to about 4.5 wt%, about 3.25 wt% to about 4.75 wt%, about 3.25 wt% to about 5 wt%, about 3.5 wt%. By weight % to about 3.75 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.25 wt%, about 3.5 wt% to about 4.5 wt%, about 3.5 wt% to about 4.75 wt%, about 3.5 wt% to about 5 wt%, about 3.75 wt% to about 4 wt%, about 3.75 wt% to about 4.25 wt%, about 3.75 wt% to about 4.5 wt%, about 3.75 wt% to about 4.75 wt%, about 3.75 wt% to about 5 wt%, about 4 wt% to about 4.25 wt%, about 4 wt% to about 4.5 wt%, about 4 wt% to about 4.75 wt%, about 4 wt% to about 5 wt%, about 4.25 wt% to about 4.5 wt%, about 4.The pharmaceutical composition comprises, in amounts of 25% by weight to about 4.75% by weight, about 4.25% by weight to about 5% by weight, about 4.5% by weight to about 4.75% by weight, about 4.5% by weight to about 5% by weight, or about 4.75% by weight to about 5% by weight, a compound of formula I or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises about 2% by weight to about 4% by weight of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0124] In some aspects, the pharmaceutical composition includes one or more viscosity agents. Non-limiting examples of viscosity agents include hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other acceptable viscosity modifiers include, but are not limited to, acacia / gum arabic, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, carbopol, xanthan gum, cellulose, microcrystalline cellulose (MCC), carob, chitin, carboxymethyl chitosan, chondrus, dextrose, furcelellaran, gelatin, ghatti gum, guar gum, lithium saponite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, sterculia gum, xanthan gum, and astragalus gum. tragacanth), ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygelatin peptides, povidone, propylene carbonate, ethylene methyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), silica, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin and sucralose) and combinations thereof.

[0125] In some respects, the pharmaceutical composition contains hydroxypropyl methylcellulose or carboxymethyl cellulose.

[0126] In some aspects, the pharmaceutical composition comprises one or more viscosity agents in amounts of about 0.05 wt% to about 0.1 wt%, about 0.05 wt% to about 0.25 wt%, about 0.05 wt% to about 0.5 wt%, about 0.05 wt% to about 0.75 wt%, about 0.05 wt% to about 1 wt%, about 0.1 wt% to about 0.25 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 0.75 wt%, about 0.1 wt% to about 1 wt%, about 0.25 wt% to about 0.5 wt%, about 0.25 wt% to about 0.75 wt%, about 0.25 wt% to about 1 wt%, about 0.5 wt% to about 0.75 wt%, about 0.5 wt% to about 1 wt%, or about 0.75 wt% to about 1 wt%. In some aspects, the pharmaceutical composition comprises one or more viscosity agents in amounts of about 0.05 wt% to about 1 wt%.

[0127] In some aspects, the pharmaceutical composition comprises one or more viscosity agents in the following amounts: about 0.05% by weight, about 0.1% by weight, about 0.15% by weight, about 0.2% by weight, about 0.25% by weight, about 0.5% by weight, about 0.75% by weight, or about 1% by weight. In some aspects, the pharmaceutical composition comprises about 0.2% by weight of one or more viscosity agents. In some aspects, the viscosity of the pharmaceutical composition is about 1 cP to about 5 cP, about 1 cP to about 10 cP, about 1 cP to about 15 cP, about 1 cP to about 20 cP, about 1 cP to about 30 cP, about 1 cP to about 40 cP, about 1 cP to about 50 cP, about 1 cP to about 60 cP, about 1 cP to about 80 cP, about 1 cP to about 100 cP, about 1 cP to about 125 cP, about 1 cP to about 150 cP, about 1 cP to about 175 cP, about 1 cP to about 200 cP, about 1 cP to about 400 cP, about 5 cP to about 10 cP, about 5 cP to about 15 cP, about 5 cP to about 20 cP, about 5 cP to about 30 cP, about 5 cP to about 40 cP, about 5 cP to about 50 cP, about 5 cP to about 60 cP, about 5 cP to about 80 cP, about 5 cP to about 5 cP. cP to approximately 100 cP, approximately 5 cP to approximately 125 cP, approximately 5 cP to approximately 150 cP, approximately 5 cP to approximately 175 cP, approximately 5 cP to approximately 200 cP, approximately 5 cP to approximately 400 cP, approximately 10 cP to approximately 15 cP, approximately 10 cP to approximately 20 cP, approximately 10 cP to approximately 30 cP, approximately 10 cP to approximately 40 cP, approximately 10 cP to approximately 50 cP, approximately 10 cP to approximately 60 cP, approximately 10 cP to approximately 80 cP, approximately 10 cP to approximately 100 cP, approximately 10 cP to approximately 125 cP, approximately 10 cP to approximately 150 cP, approximately 10 cP to approximately 175 cP, approximately 10 cP to approximately 200 cP, approximately 10 cP to approximately 400 cP, approximately 15 cP to approximately 20 cP, approximately 15 cP to approximately 30 cP, approximately 15 cP to approximately 400 cP. cP, approximately 15 cP to approximately 50 cP, approximately 15 cP to approximately 60 cP, approximately 15 cP to approximately 80 cP, approximately 15 cP to approximately 100 cP, approximately 15 cP to approximately 125 cP, approximately 15 cP to approximately 150 cP, approximately 15 cP to approximately 175 cP, approximately 15 cP to approximately 200 cP, approximately 15 cP to approximately 400 cP, approximately 20 cP to approximately 30 cP, approximately 20 cP to approximately 40 cP, approximately 20 cP to approximately 50 cP, approximately 20 cP to approximately 60 cP, approximately 20 cP to approximately 80 cP, approximately 20 cP to approximately 100 cP, approximately 20 cP to approximately 125 cP, approximately 20 cP to approximately 150 cPcP, approximately 20 cP to approximately 175 cP, approximately 20 cP to approximately 200 cP, approximately 20 cP to approximately 400 cP, approximately 30 cP to approximately 40 cP, approximately 30 cP to approximately 50 cP, approximately 30 cP to approximately 60 cP, approximately 30 cP to approximately 80 cP, approximately 30 cP to approximately 100 cP, approximately 30 cP to approximately 125 cP, approximately 30 cP to approximately 150 cP, approximately 30 cP to approximately 175 cP, approximately 30 cP to approximately 200 cP, approximately 30 cP to approximately 400 cP, approximately 40 cP to approximately 50 cP, approximately 40 cP to approximately 60 cP, approximately 40 cP to approximately 80 cP, approximately 40 cP to approximately 100 cP, approximately 40 cP to approximately 125 cP, approximately 40 cP to approximately 150 cP, approximately 40 cP to approximately 175 cP, approximately 40 cP to approximately 200 cP cP, approximately 40 cP to approximately 400 cP, approximately 50 cP to approximately 60 cP, approximately 50 cP to approximately 80 cP, approximately 50 cP to approximately 100 cP, approximately 50 cP to approximately 125 cP, approximately 50 cP to approximately 150 cP, approximately 50 cP to approximately 175 cP, approximately 50 cP to approximately 200 cP, approximately 50 cP to approximately 400 cP, approximately 60 cP to approximately 80 cP, approximately 60 cP to approximately 100 cP, approximately 60 cP to approximately 125 cP, approximately 60 cP to approximately 150 cP, approximately 60 cP to approximately 175 cP, approximately 80 cP to approximately 200 cP, approximately 60 cP to approximately 400 cP, approximately 80 cP to approximately 100 cP, approximately 80 cP to approximately 125 cP, approximately 80 cP to approximately 150 cP, approximately 80 cP to approximately 175 cP, approximately 80 cP to about 200 cP, about 80 cP to about 400 cP, about 100 cP to about 125 cP, about 100 cP to about 150 cP, about 100 cP to about 175 cP, about 100 cP to about 200 cP, about 100 cP to about 400 cP, about 125 cP to about 150 cP, about 125 cP to about 175 cP, about 125 cP to about 200 cP, about 125 cP to about 400 cP, about 150 cP to about 175 cP, about 150 cP to about 200 cP, about 150 cP to about 400 cP, about 175 cP to about 200 cP, about 175 cP to about 400 cP, or about 200 cP to about 400 cP. In some aspects, the viscosity of the pharmaceutical composition is about 10 cP to about 30 cP.

[0128] In some aspects, the viscosity of the pharmaceutical composition is about 1 cP, about 5 cP, about 10 cP, about 15 cP, about 20 cP, about 30 cP, about 40 cP, about 50 cP, about 60 cP, about 80 cP, about 100 cP, about 125 cP, about 150 cP, about 175 cP, about 200 cP, or about 400 cP. In some aspects, the viscosity of the pharmaceutical composition is about 30 cP.

[0129] In some aspects, the pharmaceutical composition comprises one or more buffers. Non-limiting examples of buffers include acetate buffers, borate buffers, borate-citrate buffers, citrate buffers, lactate buffers, phosphate buffers, succinate buffers, borate-polyol complex buffers, carbonate buffers, organic buffers, amino acid buffers, and combinations thereof. In some aspects, the pharmaceutical composition comprises one or more buffers, wherein the one or more buffers are phosphate buffers.

[0130] In some aspects, phosphate buffers comprise phosphoric acid; alkali metal phosphates, such as disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate, disodium hydrogen phosphate heptahydrate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate; alkaline earth metal phosphates, such as calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimagnesium phosphate (magnesium hydrogen phosphate), and trimagnesium phosphate; ammonium phosphate, such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate; or combinations thereof. In some aspects, phosphate buffers comprise one or more acid anhydrides. In some aspects, phosphate buffers comprise one or more hydrates.

[0131] Organic buffers include, but are not limited to, Good's Buffers, such as 2-(N-morpholino)ethanesulfonic acid (MES), N-(2-acetamido)iminodiacetic acid, N-(carbamoylmethyl)iminodiacetic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), β-hydroxy-4-morpholinopropanesulfonic acid, 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), choline chloride, 3-(N-morpholino)propanesulfonic acid (MOPS), N,N-bis(2- Hydroxyethyl)-2-aminoethanesulfonic acid (BES), 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), 3-(N,N-bis[2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid (DIPSO), acetamylglycine, 3-{[1,3-dihydroxy-2-(hydroxymethyl)-2-propyl]amino}-2-hydroxy-1-propanesulfonic acid (TAPSO), piperazine-1,4,-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) hydrate (HEPPSO), 3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid (HEPPS), tris(hydroxymethyl)methylglycine (tricine), glycineamide, N,N-dihydroxyethylglycine (bicine) or N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid sodium salt (TAPS); glycine; diethanolamine (DEA); and combinations thereof. Amino acid buffers include, but are not limited to, taurine, aspartic acid and its salts (e.g., potassium salts, etc.), ε-aminohexanoic acid, and combinations thereof.

[0132] In some aspects, the pharmaceutical composition comprises one or more buffers in amounts of about 0.05 wt% to about 0.1 wt%, about 0.05 wt% to about 0.25 wt%, about 0.05 wt% to about 0.5 wt%, about 0.05 wt% to about 0.75 wt%, about 0.1 wt% to about 0.25 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 0.75 wt%, about 0.1 wt% to about 1 wt%, about 0.25 wt% to about 0.5 wt%, about 0.25 wt% to about 0.75 wt%, about 0.25 wt% to about 1 wt%, about 0.3 wt% to about 0.4 wt%, about 0.3 wt% to about 0.35 wt%, about 0.5 wt% to about 0.75 wt%, about 0.5 wt% to about 1 wt%, or about 0.75 wt% to about 1 wt%. In some aspects, the pharmaceutical composition comprises one or more buffers in amounts of about 0.05 wt% to about 1 wt%.

[0133] In some aspects, the pharmaceutical composition comprises one or more buffers in the following amounts: about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, or about 1 wt%. In some aspects, the pharmaceutical composition comprises about 0.3 wt% of one or more buffers. In some aspects, the pharmaceutical composition comprises about 0.35 wt% of one or more buffers.

[0134] In some aspects, the pH of the pharmaceutical composition is about 6 to about 6.5, about 6 to about 7, about 6 to about 7.2, about 6 to about 7.4, about 6 to about 7.6, about 6 to about 7.8, about 6 to about 8, about 6.5 to about 7, about 6.5 to about 7.2, about 6.5 to about 7.4, about 6.5 to about 7.6, about 6.5 to about 7.8, about 6.5 to about 8, about 7 to about 7.2, about 7 to about 7.4, about 7 to about 7.8, about 7 to about 8, about 7.2 to about 7.4, about 7.2 to about 7.6, about 7.2 to about 7.8, about 7.4 to about 7.6, about 7.4 to about 7.8, or about 7.6 to about 7.8. In some aspects, the pH of the pharmaceutical composition is about 7 to about 7.6.

[0135] In some respects, the pH of the pharmaceutical composition is about 6, about 6.5, about 7, about 7.2, about 7.6, or about 8. In some respects, the pH of the pharmaceutical composition is about 7.4.

[0136] In some respects, the pH of the pharmaceutical composition is adjusted by a strong acid or a strong base. Examples of strong acids and strong bases are well known in the art and include, but are not limited to, NaOH, KOH, HCl, and H₂SO₄. In some respects, the strong acid or strong base is HCl or NaOH.

[0137] In some respects, the pharmaceutical composition contains a preservative. Non-limiting examples of preservatives include benzalkonium chloride, stable oxychloride complex (Purite®), phenylmercuric acetate, chlorobutanol, benzyl alcohol, p-hydroxybenzoate, EDTA, and thimerosal.

[0138] In some respects, the pharmaceutical composition does not contain preservatives.

[0139] In some respects, the pharmaceutical composition does not contain ethylenediaminetetraacetic acid (EDTA).

[0140] In some aspects, the pharmaceutical composition comprises a penetration enhancer. Non-limiting examples of penetration enhancers include benzalkonium chloride, laurocapram (azone), bile acids and their alkali metal salts (including chenodeoxycholoc acid, cholic acid, taurocholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, or ursodeoxycholic acid, glycocholate), n-dodecyl-β-D-maltose glycoside, sucrose dodecanoate, octylmaltose glycoside, decylmaltose glycoside, tridecaylmaltose glycoside, tetradecaylmaltose glycoside, hexamethylene lauramide, hexamethylene octamide, glyceryl monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, methanesulfonylmethane, sodium fusidate, saponins, or any combination thereof. In some aspects, the pharmaceutical composition comprises benzalkonium chloride.

[0141] In some aspects, the pharmaceutical composition comprises a penetration enhancer in amounts of: about 0.0025 wt% to about 0.005 wt%, about 0.0025 wt% to about 0.0075 wt%, about 0.0025 wt% to about 0.01 wt%, about 0.0025 wt% to about 0.0125 wt%, about 0.0025 wt% to about 0.02 wt%, about 0.005 wt% to about 0.0075 wt%, about 0.005 wt% to about 0.01 wt%, about 0.005 wt% to about 0.0125 wt%, about 0.005 wt% to about 0.02 wt%, about 0.0075 wt% to about 0.01 wt%, about 0.0075 wt% to about 0.02 wt%, about 0.01 wt% to about 0.0125 wt%, about 0.01 wt% to about 0.02 wt%, or about 0.0125 wt% to about 0.02 wt%. In some respects, the pharmaceutical composition contains about 0.0075% by weight to about 0.0125% by weight of a penetration enhancer.

[0142] In some aspects, the pharmaceutical composition comprises a penetration enhancer in the following amounts: about 0.0025% by weight, about 0.005% by weight, about 0.0075% by weight, about 0.0110% by weight, about 0.0115% by weight, about 0.0125% by weight, or about 0.02% by weight. In some aspects, the pharmaceutical composition comprises about 0.01% by weight of a penetration enhancer.

[0143] In some aspects, the pharmaceutical composition comprises benzalkonium chloride in amounts of about 0.0025% by weight to about 0.005% by weight, about 0.0025% by weight to about 0.0075% by weight, about 0.0025% by weight to about 0.01% by weight, about 0.0025% by weight to about 0.0125% by weight, about 0.0025% by weight to about 0.02% by weight, about 0.005% by weight to about 0.0075% by weight, about 0.005% by weight to about 0.01% by weight, about 0.005% by weight to about 0.0125% by weight, about 0.005% by weight to about 0.02% by weight, about 0.0075% by weight to about 0.01% by weight, about 0.0075% by weight to about 0.02% by weight, about 0.01% by weight to about 0.0125% by weight, or about 0.0125% by weight to about 0.02% by weight. In some respects, the pharmaceutical composition comprises about 0.0075% by weight to about 0.0125% by weight of benzalkonium chloride.

[0144] In some aspects, the pharmaceutical composition comprises benzalkonium chloride in amounts of about 0.0025% by weight, about 0.005% by weight, about 0.0075% by weight, about 0.0110% by weight, about 0.0115% by weight, about 0.0125% by weight, or about 0.02% by weight. In some aspects, the pharmaceutical composition comprises about 0.01% by weight of benzalkonium chloride.

[0145] In some respects, the pharmaceutical composition does not contain a penetration enhancer.

[0146] In some respects, the pharmaceutical composition does not contain benzalkonium chloride.

[0147] In some aspects, the pharmaceutical composition comprises one or more stabilizers. Stabilizers include, but are not limited to, fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ether, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In some aspects, amide analogs of the stabilizer are also used. In some aspects, the selected stabilizer alters the hydrophobicity of the formulation, improves the mixability of the various components in the formulation, controls the moisture content in the formulation, or controls the mobility of the phase.

[0148] In some respects, the pharmaceutical composition contains one or more stabilizers in an amount sufficient to inhibit the degradation of the active agent. Examples of such stabilizers include, but are not limited to: glycerol, methionine, monothioglycerol, EDTA, ascorbic acid, polysorbate 80, polysorbate 20, arginine, heparin, dextran sulfate, cyclodextrin, pentosan polysulfate and other heparin-like substances, divalent cations (such as magnesium and zinc), or combinations thereof.

[0149] In some respects, the pharmaceutical composition does not contain ethylenediaminetetraacetic acid (EDTA).

[0150] In some respects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also comprises about 0.01% by weight to about 5% by weight of a compound of formula IV or a pharmaceutically acceptable salt thereof.In some aspects, the pharmaceutical composition comprises the following amounts of a compound of formula IV or a pharmaceutically acceptable salt thereof: about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 1.5 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 2.5 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 3.5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 4.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 1.5 wt%, about 0 0.1 wt% to about 2 wt%, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 3.5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 1 0.5 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 5 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 5 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% % to about 4 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 5 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 5 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 5 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.5 wt%, about 4 wt% to about 5 wt%, or about 4.5 wt% to about 5 wt%.

[0151] In some aspects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also comprises about 5% by weight of a compound of formula IV or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises the following amounts of a compound of formula IV or a pharmaceutically acceptable salt thereof: about 4.5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.01% by weight.

[0152] In some respects, the pharmaceutical composition does not contain compound IV.

[0153] In some respects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also comprises about 0.01% by weight to about 5% by weight of a compound of formula V or a pharmaceutically acceptable salt thereof.In some aspects, the pharmaceutical composition comprises the following amounts of a compound of formula V or a pharmaceutically acceptable salt thereof: about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 1.5 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 2.5 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 3.5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 4.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 1.5 wt%, about 0 0.1 wt% to about 2 wt%, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 3.5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 1 0.5 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 5 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 5 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% % to about 4 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 5 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 5 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 5 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.5 wt%, about 4 wt% to about 5 wt%, or about 4.5 wt% to about 5 wt%.

[0154] In some aspects, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also comprises about 5% by weight of the compound of formula V or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises the compound of formula V or a pharmaceutically acceptable salt thereof in the following amounts: about 4.5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.01% by weight.

[0155] In some respects, the pharmaceutical composition does not contain compound V.

[0156] In some respects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also comprises about 0.01% to about 5% by weight of a compound of formula VI or a pharmaceutically acceptable salt thereof.In some aspects, the pharmaceutical composition comprises the following amounts of a compound of formula VI or a pharmaceutically acceptable salt thereof: about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 1.5 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 2.5 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 3.5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 4.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 1.5 wt%, about 0 0.1 wt% to about 2 wt%, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 3.5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 1 0.5 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 5 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 5 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% % to about 4 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 5 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 5 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 5 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.5 wt%, about 4 wt% to about 5 wt%, or about 4.5 wt% to about 5 wt%.

[0157] In some aspects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also comprises about 5% by weight of a compound of formula VI or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises the following amounts of a compound of formula VI or a pharmaceutically acceptable salt thereof: about 4.5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.01% by weight.

[0158] In some respects, the pharmaceutical composition does not contain compound VI.

[0159] In some respects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also contains about 0.01% by weight to about 5% by weight of a leaving group or a pharmaceutically acceptable salt thereof.In some aspects, the pharmaceutical composition comprises leaving groups or pharmaceutically acceptable salts thereof in amounts of: about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 1.5 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 2.5 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 3.5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 4.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 1.5 wt%, about 0. 1 wt% to about 2 wt%, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 3.5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 1. 5 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 5 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 5 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% % to about 4 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 5 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 5 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 5 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.5 wt%, about 4 wt% to about 5 wt%, or about 4.5 wt% to about 5 wt%.

[0160] In some aspects, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition further comprises about 5% by weight of a leaving group or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition comprises the following amounts of a leaving group or a pharmaceutically acceptable salt thereof: about 4.5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.01% by weight.

[0161] In some respects, the pharmaceutical composition does not contain leaving groups.

[0162] In some aspects, the total concentration of the pharmaceutical composition of compound IV or a pharmaceutically acceptable salt thereof, compound V or a pharmaceutically acceptable salt thereof, compound VI or a pharmaceutically acceptable salt thereof, and / or leaving group or a pharmaceutically acceptable salt thereof is less than 1% by weight. In some aspects, the total concentration of the pharmaceutical composition of compound IV or a pharmaceutically acceptable salt thereof, compound V or a pharmaceutically acceptable salt thereof, compound VI or a pharmaceutically acceptable salt thereof, and / or leaving group or a pharmaceutically acceptable salt thereof is less than 0.5% by weight, less than 0.1% by weight, less than 0.05% by weight, less than 0.01% by weight, or less than 0.005% by weight.

[0163] In some aspects, the solubility of components in a pharmaceutical composition may be enhanced by surfactants or other suitable co-solvents in the composition. Such co-solvents include polysorbate 20, polysorbate 60, and polysorbate 80, Pluronic F68, F-84, and P-103, cyclodextrin, or other agents known to those skilled in the art. In some aspects, the concentration of the co-solvent is from 0.01% by weight to about 2% by weight.

[0164] In some aspects, the pharmaceutical composition comprises one or more polyols. As used herein, the term "polyol" includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms, said two carbon atoms not being in the trans configuration of each other. Polyols can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, provided that the resulting complex is water-soluble and pharmaceutically acceptable. Examples of such compounds include sugars, sugar alcohols, sugar acids, and uronic acids. Preferred polyols are sugars, sugar alcohols, and sugar acids, including but not limited to mannitol, glycerol, xylitol, sorbitol, and propylene glycol. It is contemplated that a polyol may comprise two or more different polyols.

[0165] In some respects, the pharmaceutical composition comprises one or more anti-aggregation additives. Anti-aggregation additives enhance the stability of the pharmaceutical composition by reducing the rate of protein aggregation. Anti-aggregation additives include, but are not limited to, urea, guanidine hydrochloride, simple amino acids (such as glycine or arginine), sugars, polyols, polysorbates, polymers (such as polyethylene glycol and dextran), alkyl sugars (such as alkyl glycosides), and surfactants.

[0166] In some respects, the pharmaceutical composition comprises one or more antioxidants. Antioxidants include, but are not limited to, ascorbic acid, methionine, sodium thiosulfate, sodium metabisulfite, and combinations thereof. Metal chelators, thiol-containing compounds, and other general stabilizers may be acceptable antioxidants.

[0167] In some respects, the pharmaceutical composition comprises one or more osmotic agents. Osmotic agents include, but are not limited to, salts, especially sodium chloride or potassium chloride; organic compounds, such as propylene glycol, mannitol, sorbitol, dextran, and glycerol.

[0168] In some respects, the osmotic pressure of the pharmaceutical composition is about 260 to about 365 mOsm / kg. In some aspects, the osmotic pressure of the pharmaceutical composition is about 285 mOsm / kg to about 295 mOsm / kg, about 285 mOsm / kg to about 305 mOsm / kg, about 285 mOsm / kg to about 315 mOsm / kg, about 285 mOsm / kg to about 325 mOsm / kg, about 285 mOsm / kg to about 335 mOsm / kg, about 285 mOsm / kg to about 345 mOsm / kg, about 285 mOsm / kg to about 355 mOsm / kg, about 285 mOsm / kg to about 365 mOsm / kg, about 295 mOsm / kg to about 305 mOsm / kg, about 295 mOsm / kg to about 315 mOsm / kg, about 295 mOsm / kg to about 32 ... mOsm / kg to about 335 mOsm / kg, about 295 mOsm / kg to about 345 mOsm / kg, about 295 mOsm / kg to about 355 mOsm / kg, about 295 mOsm / kg to about 365 mOsm / kg, about 305 mOsm / kg to about 315 mOsm / kg, about 305 mOsm / kg to about 325 mOsm / kg, about 305 mOsm / kg to about 335 mOsm / kg, about 305 mOsm / kg to about 345 mOsm / kg, about 305 mOsm / kg to about 355 mOsm / kg, about 305 mOsm / kg to about 365 mOsm / kg, about 315 mOsm / kg to about 325 mOsm / kg, about 315 mOsm / kg to about 335 mOsm / kg mOsm / kg, about 315 mOsm / kg to about 345 mOsm / kg, about 315 mOsm / kg to about 355 mOsm / kg, about 315 mOsm / kg to about 365 mOsm / kg, about 325 mOsm / kg to about 335 mOsm / kg, about 325 mOsm / kg to about 345 mOsm / kg, about 325 mOsm / kg to about 355 mOsm / kg, about 325 mOsm / kg to about 365 mOsm / kg, about 325 mOsm / kg to about 345 mOsm / kg, about 325 mOsm / kg to about 365 mOsm / kg, about 335 mOsm / kg to about 345 mOsm / kg, about 335 mOsm / kg to about 355 mOsm / kg, about 34 ... mOsm / kg to about 365 mOsm / kg, about 355 mOsm / kg to about 365 mOsm / kg, about 260 mOsm / kg to about 265mOsm / kg, about 260 mOsm / kg to about 275 mOsm / kg, about 260 mOsm / kg to about 285 mOsm / kg, about 260 mOsm / kg to about 295 mOsm / kg, about 260 mOsm / kg to about 305 mOsm / kg, about 260 mOsm / kg to about 315 mOsm / kg, about 260 mOsm / kg to about 325 mOsm / kg, about 260 mOsm / kg to about 335 mOsm / kg, about 260 mOsm / kg to about 345 mOsm / kg, about 260 mOsm / kg to about 355 mOsm / kg, about 260 mOsm / kg to about 365 mOsm / kg, about 265 mOsm / kg to about 275 mOsm / kg, about 265 mOsm / kg to about 285 mOsm / kg, about 265 mOsm / kg to about 295 mOsm / kg, about 265 mOsm / kg to about 305 mOsm / kg, about 265 mOsm / kg to about 315 mOsm / kg, about 265 mOsm / kg to about 325 mOsm / kg, about 265 mOsm / kg to about 335 mOsm / kg, about 265 mOsm / kg to about 345 mOsm / kg, about 265 mOsm / kg to about 355 mOsm / kg, about 265 mOsm / kg to about 365 mOsm / kg, about 275 mOsm / kg to about 285 mOsm / kg, about 275 mOsm / kg to about 295 mOsm / kg, about 275 mOsm / kg to about 305 mOsm / kg mOsm / kg, about 275 mOsm / kg to about 315 mOsm / kg, about 275 mOsm / kg to about 325 mOsm / kg, about 275 mOsm / kg to about 335 mOsm / kg, about 275 mOsm / kg to about 345 mOsm / kg, about 275 mOsm / kg to about 355 mOsm / kg, about 275 mOsm / kg to about 365 mOsm / kg.

[0169] In some respects, the osmotic pressure of the pharmaceutical composition is about 260 mOsm / kg, about 265 mOsm / kg, about 275 mOsm / kg, about 285 mOsm / kg, about 295 mOsm / kg, about 305 mOsm / kg, about 315 mOsm / kg, about 325 mOsm / kg, about 335 mOsm / kg, about 345 mOsm / kg, about 355 mOsm / kg, about 365 mOsm / kg, about 370 mOsm / kg, or about 375 mOsm / kg.

[0170] In some respects, the pharmaceutical composition is isotonic. In some respects, the pharmaceutical composition is hypotonic. In some respects, the pharmaceutical composition is hypertonic.

[0171] In some respects, a pharmaceutical composition may include a variety of additional ingredients. Such ingredients include, but are not limited to, additional therapeutic agents, additional or alternative antimicrobial agents, suspending agents, surfactants, additional or alternative tension agents, additional or alternative buffers, antioxidants, additional or alternative viscosity modifiers, chelating agents, or any combination thereof.

[0172] Example

[0173] In the following embodiments, the compound of formula I is...

[0174] ,

[0175] Compound II is choline chloride, compound III is 1,1-carbonyldiimidazole (CDI), and compound IV is...

[0176] .

[0177] Example 1: Preparation of a 2.5 kg batch of Formula I compound

[0178] Step 1: React compound II and compound III to form compound IV.

[0179] 2.500 kg of compound II, 3.484 kg of compound III (1.2 equivalents of CDI relative to compound II), and 19.650 kg of ACN (10 parts relative to compound II) were charged into a 50 L reactor dried under N2. The resulting mixture was then incubated at 20°C–25°C. o Vigorously stir at C. While stirring vigorously, heat the suspension to 65°C-70°C and stir for 1.25 hours (set point 1-2 hours). Warm and stir the reaction mixture until only the residual amount of compound II relative to compound IV is detected by NMR. After meeting the analytical requirements, cool the batch to 20°C-25°C over 1 hour and 20 minutes. o C (Set point minimum 1 hour). Cool the batch to 0°C-5°C with moderate stirring and stir overnight (total 19 hours) (Set point – cool to 0°C-5°C within a minimum 1 hour). oC, and stirred for at least 2 hours). The batch was filtered under reduced pressure in nitrogen through a portable robotic filter (PRF). The reactor was washed with 2 × 4 kg ACN (2 × 4 parts relative to compound II) pre-cooled at 0-5°C. The filter cake was dried on a filter under a stream of N2 at ambient temperature for about 20 hours. The yield was 90.7%, producing 3.799 kg of product as a grayish-white solid. QNMR analysis confirmed that compound IV was produced with a purity of 96.2% w / w.

[0180] Step 2: React compound IV with ammonia to form compound I.

[0181] 1,800 kg of compound IV and 14.07 kg of ACN (10 parts relative to compound II) were charged into a reactor under N2 conditions. The resulting mixture was incubated at 20°C–25°C. o Stir gently at C to form a thick white suspension. Cool the batch to approximately 17°C-18°C while stirring gently. Cooling the batch is intended to accommodate the slightly exothermic addition of ammonia via bubbling. Gently bubble anhydrous NH3 gas into the suspension while stirring gently, maintaining the batch temperature at 15°C-20°C (the batch temperature is approximately 18°C). o C). At 15℃-20℃ (batch temperature at approximately 18℃) o C) Continue ammonia bubbling for 3 hours with moderate stirring. In the batch, after 3 hours of bubbling, add approximately 555 kg of ammonia. In the batch, obtain a sample of the reaction mixture after 2 hours and analyze it, showing approximately 2.6% of Formula IV relative to the compound of Formula I. A sample obtained after 3 hours of bubbling shows approximately 0.6% of Formula IV relative to the compound of Formula I under gentle ammonia bubbling. After meeting the analytical requirements, stop ammonia bubbling and spray the suspension with nitrogen (to remove ammonia) at 20-25°C for 2.5 hours (set point – minimum 1 hour). Filter the batch under nitrogen using a portable robotic filter (PRF). Wash the reactor with 2 × 2.814 kg ACN (2 × 2 parts relative to the compound of Formula II). Dry the filter cake on a filter under a nitrogen flow for 23 hours. The recovered product weighed 1.310 kg and was a grayish-white solid of formula IV compound with a yield of 93.1% and an NMR purity of 90.2% w / w.

[0182] Step 3: Preparation of recrystallization solvent

[0183] Under N2, viaA stainless steel SCART filter was used to charge a 50 L reactor with 30.771 kg of anhydrous EtOH (15.9 parts relative to the crude compound of Formula I) and 0.938 kg of HPLC-grade water (0.382 parts relative to the crude compound of Formula I). ​​The mixture was then incubated at 20°C–25°C. o Stir gently at temperature C for 5 minutes. Stop stirring and drain the solution into a new PE container.

[0184] Step 4: Recrystallization of Compound I

[0185] 2.45 kg of the crude compound of formula I was added to the reactor under N2, followed by 25.48 kg of 97.5% v / v EtOH obtained from step 3 (13 parts relative to the crude compound of formula I). ​​The resulting suspension was stirred moderately. The batch was heated to reflux under moderate stirring to form a clear solution (approximately 1.5 hours). The batch was cooled to approximately 70°C under moderate stirring. The batch was passed through a 1 m TFE FC (Teflon cartridge filter) clarified to reactor (maintained at approximately 70°C) o In step C), the reactor is forward flushed with 0.98 kg of 97.5% v / v EtOH (0.5 parts relative to the crude compound of Formula I). ​​The batch is heated to reflux under moderate stirring to obtain a clear solution. The batch is concentrated to a target volume of about 9 parts relative to the crude compound of Formula I (setpoint 8.5-9.5 parts) by distillation under N2 at about one atmosphere under vigorous stirring. The batch is cooled to 20°C-25°C over a period of about 5 hours (setpoint – minimum 2 hours) under vigorous stirring. The batch is stirred at 20°C-25°C for 10 hours (setpoint – minimum 2 hours) under vigorous stirring. The batch is cooled to 0°C-5°C over a period of 1.5 hours (setpoint – minimum 1 hour) under vigorous stirring and stirred at 0°C-5°C for 3 hours (setpoint – minimum 3 hours). The batch is filtered through a portable robotic filter (PRF) under nitrogen. Used in the reactor at 0℃-5 o The filter cake was washed with 2 × 3.866 kg of anhydrous EtOH (2 × 2 parts relative to the crude compound of Formula I) pre-cooled at C. The filter cake was dried on a filter under a stream of N2 for approximately 69 hours. The yield of the compound of Formula I was 84%.

[0186] Example 2:

[0187] Intermediate compound IV was synthesized as described in Example 1. The suspension of compound IV in ACN was treated with ammonia for 2 hours (instead of 3 hours) and then stopped. Approximately 410 g of ammonia was partitioned into the reaction mixture. The resulting mixture was stirred for 1 hour and then sampled. The conversion (approximately 1% molar of compound IV relative to compound I) was determined by NMR. The crude compound I, as a grayish-white solid, was isolated in 95% yield (1.345 kg).

[0188] Examples 3-10:

[0189]

[0190] Example 11: 10 ACNs and time intervals

[0191]

[0192] Under the described conditions, compounds of type IV were separated by filtering the reaction mixture and then washing the filter cake with ACN, yielding high-quality material (NMR purity > 95%) in a yield typically of about 90%.

[0193] Examples 12-17: ≥50 g scale conversion of compound IV to compound I

[0194] In Examples 12-17, the compound of Formula III is CDI.

[0195]

[0196]

[0197] Example 18: Reaction of compound IV with NH3 solution

[0198] The diimidazole derivative of Formula IV was reacted with ammonia in a 7 M solution of MeOH to produce the expected carbamate compound of Formula I as the major product, along with a minor methyl carbonate product (10%–15% as determined by NMR). The reaction was complete, with almost no detectable byproducts. Formula IV showed good reactivity to ammonia to produce the desired product of Formula I.

[0199] Example 19: Reaction of compound IV with NH3 solution

[0200] Using nitrogen as the carrier gas, at approximately 15 oAmmonia gas was introduced (subsurface injection) into a stirred suspension of compound IV (1.5 g) in ACN (20 parts relative to compound IV) at C. After 15 minutes, the reaction mixture was analyzed by NMR to show that almost no reaction had occurred. No compound I was detected. The experiment was continued, in which ammonia gas was injected directly into the suspension containing compound IV (without nitrogen) for an additional 30 minutes. NMR analysis of the reaction mixture indicated that the level of compound IV decreased to approximately 1% relative to compound I. Ammonia injection was stopped, and the reaction mixture was incubated at 20°C–25°C. o Stir at C for another 3 hours (to allow ammonia to evaporate). Filter the suspension and wash the filter cake with ACN, then dry in a vacuum oven (approximately 50°C). o C) Drying. The yield of compound I was 87%. NMR analysis of the isolated compound I showed high purity, with trace amounts of byproducts also visible in the spectrum. NMR analysis of the residue from the filtrate primarily indicated the presence of compound I, with compound II as a minor component.

[0201] Example 20: Reaction of compound IV with NH3 solution

[0202] Example 19 was repeated using different modes of ammonia introduction. The experimental setup was "sealed" with balloons, and ammonia was fed into the top space of the setup to maintain a slight positive pressure, which was located at approximately 15... o Compound of formula IV was held above the suspension in ACN at C. The suspension was stirred, and the reaction progress was monitored by NMR analysis. Interestingly, the level of compound of formula IV relative to compound of formula I was found to decrease to approximately 1% after stirring for 30 minutes. The reaction was essentially complete.

[0203] Example 21: Reaction of compound IV with saturated NH3 solution

[0204] 300 mL of ACN (10 parts relative to Formula IV compound) was charged into a 500 mL RBF equipped with a top stirrer. Ammonia was gently bubbled into the ACN for approximately 50 minutes with moderate stirring at 0-5°C, and then stopped. The weight of the contents of the flask increased by approximately 18.55 g (approximately 8.5 equivalents relative to Formula IV compound). 30 g of Formula IV compound was added to the ammonia solution in a single batch (in solid form). No change in batch temperature was observed. The apparatus was then “sealed” with a balloon (to confirm a slight positive pressure in the headspace). The reaction mixture was stirred at 0-5°C for 40 minutes. Aliquots of the reaction mixture were obtained for IPC analysis (NMR), and approximately 2% of Formula IV compound (relative to Formula I compound) remained. The reaction was considered complete. The reaction mixture was then warmed to 20-25°C under an NH3 atmosphere.o C and stirred for 1 hour. The batch was filtered and the filter cake was washed with ACN, then dried overnight in a vacuum oven at about 50°C to give 22.72 g of compound I (about 97% yield). NMR analysis of the product showed the presence of 2.19% (w / w) of compound II and 2.44% (w / w) of imidazole.

[0205] Example 22: Reacting compound IV under direct bubbling of ammonia

[0206] A suspension of 10 parts of ACN solution containing compound IV (15 g) was prepared and incubated at 20°C-25°C. o Stir gently under nitrogen atmosphere for about 5 minutes at temperature C. Close the nitrogen inlet and gently bubble anhydrous ammonia (from the tank) into the suspension. Observe a slight increase in batch temperature, and maintain the temperature of the reaction mixture at 20°C-25°C using a cold water bath. o C. Ammonia consumption is very rapid at the start of ammonia application, creating negative pressure in the apparatus. Bubbling of ammonia is stopped after 50 minutes, and a small sample of the reaction mixture is taken for NMR. Approximately 1.4% of compound IV (relative to compound I) is present. The reaction is considered complete. The reaction mixture is placed under a N2 atmosphere and stirred at 20-25°C for approximately 2 hours. The product is filtered, washed, and dried in a vacuum oven at approximately 50°C. o Drying at C gave 10.7 g of compound I (91% yield). NMR analysis of the isolated product showed the presence of approximately 2.2% (w / w) of compound II.

[0207] Examples 23-27: Reproducibility of the reaction between compound IV and ammonia

[0208]

[0209]

[0210]

[0211] Examples 28-37: Recrystallization of compound I (1g)

[0212]

[0213]

[0214] Example 38: Recrystallization of compound I (30g)

[0215] A suspension of the crude compound of formula I (30 g) in 95% EtOH (15 parts, containing about 5% water v / v) was heated to reflux to produce a clear solution. The solution was then cooled to about 65°C. o C, then filter. Forward flush the equipment with 1 part 95% EtOH. Heat the combined filtrate and flushing solution to reflux (to regenerate the solution), then gradually cool to 0°C–5°C. o C. Stir overnight. Filter the crystalline compound of Formula I, wash (4 parts 95% EtOH), and dry in a vacuum oven at 40°C to give 25.3 g (84.3% yield) of a grayish-white solid. NMR analysis indicated the absence of Formula II in the recrystallized material (approximately 1.5 mol / mol was present in the crude compound of Formula I). ​​Evaporate the combined filtrate and washings to dryness to give 3.94 g of solid residue, which, according to NMR, mainly contained the compounds of Formula I, Formula II, and imidazole.

[0216] Example 39 AB: Recrystallization of compound I (50g)

[0217] The crude compound of Formula I (50 g / experiment) was dissolved under reflux in 95% EtOH (15 parts, containing approximately 5% water prepared by the chemist, v / v). The solution was cooled to 60°C-65°C. o C. Filter. Rinse the equipment forward with 1 part 95% EtOH. Heat the rinse solution and filtrate to reflux, then gradually cool to 0°C-5°C. o C. Stir overnight. Filter the suspension and treat the filter cake with 95% EtOH (4 parts, at 0℃-5℃). o Pre-cooling and washing were performed at C. The separated solids were dried in a vacuum oven at 40°C to obtain a grayish-white solid. The solid was analyzed by NMR, and the results are shown in the table below. The filtrate and washings were combined and concentrated to dryness to obtain a solid residue, which was also dried in a vacuum oven at 40°C. o Drying at C.

[0218]

[0219] Example 40: Recrystallization of compound I (30 g) with approximately 6% v / v water

[0220] A suspension of the crude compound of Formula I (30 g, a mixture of two different batches) in 94% EtOH (7 parts, containing approximately 6.3% w / v water) was heated to reflux to produce a solution. The solution was then cooled to 65°C. o C. Filter. Rinse the equipment with 0.5 parts of 94% EtOH. Heat the combined rinse and filtrate to 65-70°C. oC is used to regenerate the solution, which is then gradually cooled to 0℃-5℃. o C. Stir overnight. Filter the suspension and treat the filter cake with 94% EtOH (4 parts, at 0℃-5℃). o Pre-cooling and washing were performed at C. The separated solids were dried in a vacuum oven at 40°C to obtain 25.6 g of I as a grayish-white solid (85% yield). The filtrate and washings were evaporated to dryness to obtain 3.97 g of solid residue. Note that due to equipment malfunction, NMR analysis of the product was not performed.

[0221] Example 41 AB: Recrystallization of compound I (50 g) with approximately 6% v / v water

[0222] In two larger-scale recrystallization experiments, the procedure described in Example 40 was repeated using 50 g of the crude compound of Formula I, respectively:

[0223]

[0224] Examples 42-47: Recrystallization of Compound I under variable water content

[0225]

[0226] Example 48 AB: Recrystallization with 95% EtOH (containing 5% v / v water) at a reduced volume (9 parts)

[0227] In both embodiments, the crude compound of Formula I was readily soluble in 8.5 parts of 95% EtOH under reflux, and the process proceeded smoothly at 65-70 °C without problems. o Clarify the resulting hot solution at C. Then flush the equipment forward with 0.5 parts solvent. Gradually cool the solution to 0°C-5°C. o C and at 0℃-5 o The mixture was stirred at C and then separated by filtration. Details of the experiment are shown in the table below. As observed in previous experiments, the recrystallized compound of Formula I was of very high quality. No residual Formula II compound or imidazole was detected by NMR. However, the recovery rate (approximately 78%) was similar to the recovery rate previously achieved using 94% EtOH.

[0228]

[0229] Example 50: Recrystallization using a reduced volume (6 parts) of commercial 95% EtOH (containing 5% v / v water)

[0230] A suspension of compound I (10 g) in 9 parts of solvent was heated to reflux to form a clear solution. The batch was concentrated by distillation at atmospheric pressure to approximately 6 parts by volume (no solid precipitation was observed at this point). The concentrated solution was gradually cooled to 0-5 °C and stirred overnight. A resuspension was obtained, with some solid crust adhering to the sides of the flask. The crust was scraped off with a spatula. The solid was filtered and washed with cold EtOH (97.5%), then dried in a vacuum oven at 45 °C to give 8.48 g of compound I (84.8% yield). The analysis (NMR) of the obtained compound I indicated the absence of compound II and imidazole. However, trace amounts of other byproducts appeared to be present in the NMR spectrum (far below the quantitative power of NMR). After drying in a vacuum oven, the combined filtrate and washes were evaporated to give a 1.21 g solid residue.

[0231] Example 51: Recrystallization using 6 parts (5g) of 95% EtOH

[0232] Dissolve 5 g of compound I under reflux in 6 parts of 95% EtOH (from Greenfield) (at approximately 74 °C). o A clear solution is formed at temperature C. The hot solution is then gradually cooled to 20°C-25°C. o C, then stirred overnight to form a heavy suspension. A large amount of solid was observed adhering to the flask wall as a thick crust. The solid in the suspension was collected by filtration. The crust was removed from the wall with a scraper and suspended in the filtrate, then filtered. The total amount of compound I obtained was 4.26 g (85% yield).

[0233] Example 52: Recrystallization using 7 parts (5g) of 95% EtOH

[0234] The second experiment was performed in the same manner using 5 g of compound I and 7 parts of 95% EtOH. As observed in the previous experiment, a heavy suspension was formed in which a large amount of solid crust adhered to the flask wall. The solid crust was removed from the wall by vigorous initial stirring, and then the solid was filtered off and dried to give 4.19 g of compound I (84% yield). Evaporation of the filtrate gave 0.71 g of solid residue.

[0235] Examples 53-56: Recrystallization using an Easymax reactor and 9 parts of 95% EtOH

[0236] A series of recrystallizations were carried out using an Easymax reactor and 9 parts of 95% EtOH. In this series, 75 to 25... o The cooldown time for C is set to 2, 4, 5, and 6 hours. It reaches 25... oAfter C, the resulting suspension was further cooled to approximately 3°C. o C, and then stirred overnight before product separation. All three examples used the previously prepared crude compound of formula I.

[0237]

[0238] Used for product crust formation.

[0239] Example 57: Recrystallization using an Easymax reactor and 9 parts of 95% EtOH

[0240] 97.5% EtOH was prepared by adding 2.5% w / v water to anhydrous EtOH. This was achieved by heating to 75°C. o C. Dissolve 5 g of compound I in 97.5% EtOH (13 parts, water content 3.03% w / v). Consistent with data from the solubility curve, the solution was found to be approximately 65 g / mL. o A clear solution is formed at temperature C (when the hot solution is gradually cooled, at approximately 56°C). o Crystallization occurs at C. The solution is heated to reflux and the batch is concentrated by distillation at atmospheric pressure (under nitrogen) to approximately 7 parts of the batch volume. The batch is then cooled at 20°C-25°C over a 3-hour period. o C forms a heavy suspension, which is then incubated at 20°C-25°C. o Stirred overnight at C (sample with supernatant removed and water content determined to be 3.67% w / v by KFC). No crust formation was observed in the product. Filter the solids and cool 2×2 parts (0℃-5℃) o C) Wash with 97.5% EtOH and sterilize at 20℃-25℃. o The material was dried under vacuum at C for 48 hours. The recovery rate of compound I was approximately 87% (4.34 g). NMR analysis of the material showed the presence of compound I of excellent quality, while compound II and imidazole were not visible in the spectrum. The filtrate was evaporated to dryness to obtain a residue, which was dried in a vacuum oven to give 0.55 g (approximately 11%) of a yellow solid. NMR analysis of this solid revealed the presence of various byproducts, as well as compounds I and II. Evaporation of the combined washes yielded 0.22 g (approximately 4.4%) of a solid residue consisting of I and some minor byproducts (NMR).

[0241] Examples 57-59: Recrystallization with 97.5% EtOH

[0242] Examples 57-59 were prepared using the same procedure, but with different final batch volumes achieved through distillation (atmospheric pressure). 97.5% EtOH was prepared by mixing a calculated amount of water (2.5% v / v) with anhydrous EtOH.

[0243]

[0244] The water content of the resulting mixture was then determined by KFC titration before use. It is noteworthy that for experiments 57 and 58, the batches at the target concentration volumes (7 and 6 parts, respectively, relative to compound I) were optically suspended at reflux temperature. However, for experiment 59 (at 9 batch volumes), a clear solution was observed. Despite the different final batch volumes, the recovery rate of compound I was virtually identical for all three examples, which is excellent. Analysis of the products isolated from these three examples by NMR showed the presence of compound I of excellent quality. Imidazole and compound II were not visible in their NMR spectra. However, it should be noted that trace amounts of byproducts may be present (based on NMR spectral examination), but the levels of these byproducts are far below the quantitative capabilities of NMR.

[0245] Example 60: Recrystallization using 40g of compound of formula I

[0246] via Atmospheric distillation (under nitrogen) was performed by repeating the recrystallization process with approximately 9 batch volumes. The batch at this point was a clear solution (approximately 78...). o C). Stop heating and cool the batch. Note that when the batch temperature reaches approximately 75°C... o Crystallization occurs at C. The resulting suspension is cooled to room temperature, and then further cooled to 0°C-5°C. o C and stir for 2 hours. Filter the solids and use 4 parts cold (at 0°C-5°C). o (Pre-cooled at C) Washed with 100% EtOH, then at 40 o Drying at C in a vacuum oven for 3 hours yielded 35.58 g of I (89% yield). NMR analysis of compound I showed the absence of compound II and imidazole.

[0247]

[0248] Example 61: Preparation of 20 kg batch of Formula I compound

[0249] Step 1

[0250] Under a nitrogen atmosphere, 157 kg of acetonitrile, 20 kg of choline chloride (compound of formula II) and 27.9 kg of 1,1-carbonyldiimidazole (compound of formula III) were combined and heated to 65-70°C. o Stir at temperature C. After about 1-2 hours, reduce the heat to 40°C-45°C. o C. Sampling and analysis of the reactants. After meeting the analytical requirements, cool the reactants to 20°C-25°C for 1.5 hours. o C. Next, cool the reactants to 0°C-5°C. o C, and maintain for two hours with stirring. Filter the product (formula IV compound), wash with 3 × 63 kg ACN, and dry on the filter.

[0251] Step 2

[0252] 263.1 kg of acetonitrile and 33.5 kg of the crude compound of formula IV were combined and incubated under a nitrogen atmosphere at 15-20 °C. o Stir at C for approximately 15 minutes. Ammonia is added directly in gaseous form over a 3-hour process, while the reactants are stirred and the temperature is maintained at 15-20°C. o C. Add 7.4 kg of ammonia to the reactants. After the ammonia is added, adjust the reaction temperature to 20℃-25℃. o C and maintain for one hour. The solution was analyzed by NMR to determine that no additional ammonia was required. Once the reaction met analytical requirements, the crude product (compound of formula I) was filtered, washed twice with 52.6 kg ACN each time, dried on a filter, and confirmed by analytical testing.

[0253] Step 3

[0254] Under a nitrogen atmosphere, 20.0 kg of the crude compound of formula I and 208 kg of a 97.5% EtOH / water mixture were combined and stirred in a reactor. The mixture was heated to 75°C. o Hold at C until the compound of formula I is completely dissolved (approximately 1–1.5 hours). Then lower the temperature to 70°C. o C. Then the substance is at 70 o Filter at C and wash with 8 kg of 97.5% EtOH / water. Once filtered, adjust the temperature to 79°C. o C is used to distill off excess solvent. Once reduced, the temperature is adjusted to 20°C-25°C. o C, for two hours. Afterwards, the solution is kept at 20℃-25℃. o Stir at C for two hours. Then cool the solution to 0°C-5°C. o C, for two hours. Then at 0℃-5℃ oKeep at C for three hours. Finally, place the solid under nitrogen at 0°C-5°C. o Filter at C, wash twice with 31.4 kg EtOH, and dry on the filter.

Claims

1. A method of making a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the method comprises reacting a compound of Formula II with a compound of Formula III in a solvent, , wherein: , to yield a compound of Formula IV or a salt thereof. R 1 and R 2 each independently is a leaving group; 2. The method of claim 1, wherein the compound of Formula IV or a salt thereof is reacted with ammonia to yield the compound of Formula I: or a pharmaceutically acceptable salt thereof. , 3. The method of claim 1 or 2, wherein the solvent is an organic solvent.

4. The method of claim 3, wherein the organic solvent is dichloromethane, acetonitrile, or dimethyl sulfoxide.

6. The method of any one of claims 1 to 5, wherein the reaction between the compound of Formula I and the compound of Formula II is conducted at a temperature of about 15 °C to about 90 °C.

5. The method of any one of claims 1 to 4, wherein R 1 is -0-(4-nitrophenyl) or imidazoline, and R 2 is -CI or imidazoline.

7. The method of any one of claims 2 to 6, wherein the ammonia is introduced as a gas into a solution of Formula IV.

8. The method of any one of claims 2 to 7, wherein the solution of Formula IV is stirred at a reaction temperature of about 0 °C to about 25 °C during gaseous ammonia addition.

9. The method of any one of claims 2 to 8, wherein the compound of Formula III is carbonyl diimidazole, the reaction temperature is about 65 °C to about 70 °C, the solvent is acetonitrile, and gaseous ammonia is reacted with the solution of Formula IV at a temperature of about 20 °C to about 25 °C.

10. The method of any one of claims 1 to 9, wherein the compound of Formula I is recrystallized in water, one or more alcoholic solvents, or a combination thereof.

11. The method of any one of claims 1 to 10, wherein at least 15 kg of the compound of Formula I is synthesized.

12. The method of any one of claims 1 to 11, wherein the pharmaceutically acceptable salt or salt thereof is a chloride salt form.

13. A compound of Formula IV having the structure:

15. The compound of claim 13, wherein the compound is a chloride salt. , or a tautomer, salt, or solvate thereof, wherein R 1 is a leaving group.

14. The compound of claim 13, wherein R 1 is imidazoline.

17. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof made by the method of any one of claims 1 to 11.

16. The compound of any one of claims 13 to 15, wherein the compound is 1 H - imidazole-1-carboxylic acid 2-(trimethyl-λ 4 - azanyl)ethyl ester chloride.

18. The pharmaceutical composition of claim 17, wherein the composition further comprises at least one additional compound selected from the group consisting of: i) Formula IV; ii) Formula V; iii) Formula VI; , iv) a leaving group; and , pharmaceutically acceptable salts thereof.

19. The pharmaceutical composition of claim 18, wherein the composition further comprises about 0.001 w / w % to about 10.0 w / w % of one or more of Formula IV, Formula V, Formula VI, or the leaving group, or a pharmaceutically acceptable salt thereof. ​

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