Synthesis of 2-(carbamoyloxy)-N,N,N-trimethylethane-1-aminium salt

Abstract

This disclosure is directed to a synthetic process for preparing and purifying 2-(carbamoyloxy)-N,N,N-trimethylethane-1-aminium salt and its pharmaceutical compositions.

Description

[Background technology]

[0001] Background of the Invention Carbachol, also known as 2-(carbamoyloxy)-N,N,N-trimethylethane-1-aminium chloride, is a cholinergic agent that binds to and activates acetylcholine receptors.

[0002] Carbachol can be prepared through a two-step process starting with 2-chloroethanol and urea. The intermediate, 2-chloroethyl-carbamate, is then reacted with trimethylamine to form a quaternary ammonium product. While carbachol can be produced from this process, it cannot be efficiently scaled up. Furthermore, current synthetic methods rely on the use of undesirable solvents and / or reactants, which have adverse environmental impacts. Therefore, a more efficient and / or environmentally conscious method is needed to prepare carbachol while avoiding costly and undesirable challenges. Because carbachol is useful as a pharmaceutical, it is particularly important to purify it to remove residual reagents. This invention relates to a novel synthetic method for preparing and purifying high-purity carbachol on an industrial scale. [Overview of the project]

[0003] This disclosure provides a reaction pathway suitable for the large-scale preparation of 2-(carbamoyloxy)-N,N,N-trimethylethane-1-aminium or a pharmaceutically acceptable salt thereof (e.g., carbachol chloride), starting with a choline salt.

[0004] Compounds of formula I: A method for preparing TIFF2026524826000001.tif17128, or a pharmaceutically acceptable salt thereof, To produce the compound of formula IV, or a salt thereof, according to scheme 1, the compound of formula II is dissolved in a solvent into the compound of formula III (wherein R 1 and R 2A method is provided herein that includes reacting with (each of which is a leaving group).

[0005] Scheme 1 TIFF2026524826000002.tif27128 formula, R 1 and R 2 The present invention, as well as its embodiments and formulas, are described below.

[0006] In some embodiments of the method, to obtain the compound of formula I or a pharmaceutically acceptable salt thereof, the compound of formula IV or a salt thereof is reacted with ammonia according to scheme 2.

[0007] Scheme 2 TIFF2026524826000003.tif18128 formula, R 1 The present invention, as well as its embodiments and formulas, are described below.

[0008] In some embodiments of the method, the solvent is an organic solvent. In some embodiments, the organic solvent is THF, DMF, siRNA, CH3CN, DMSO, CH2Cl2, EtOH, etc. In some embodiments, the organic solvent is dichloromethane, acetonitrile, or dimethyl sulfoxide.

[0009] In some aspects of the method, R 1 is -O-(4-nitrophenyl) or imidazoline, R 2 This is -Cl or imidazoline.

[0010] In some aspects of the method, 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.

[0011] In some embodiments of the method, ammonia is introduced as a gas into the solution of formula IV.

[0012] In certain embodiments of the method, during the addition of gaseous ammonia, the solution of Formula IV is stirred at a reaction temperature of about 0 °C to about 25 °C.

[0013] Some embodiments of the present disclosure include methods in which the compound of Formula III is carbonyldiimidazole, the reaction temperature is about 65 °C to about 70 °C, the solvent is acetonitrile, and gaseous ammonia reacts with the solution of Formula IV at a temperature of about 20 °C to about 25 °C.

[0014] In some embodiments of the method, the compound of Formula I is recrystallized in water, one or more alcohol solvents, or combinations thereof.

[0015] In some embodiments of the method, at least 15 kg of the compound of Formula I is synthesized by the method of the present disclosure. In some embodiments, at least 15 kg of the compound of Formula I is synthesized as a pharmaceutically acceptable chloride salt by the disclosed method. In some embodiments of the method, at least 100 kg of the compound of Formula I is synthesized by the method of the present disclosure. In some embodiments of the method, at least 150 kg of the compound of Formula I is synthesized by the method of the present disclosure. In any of these embodiments, the compound of Formula I is synthesized as a pharmaceutically acceptable chloride salt by the disclosed method.

[0016] A compound of Formula IV having the following structure: TIFF2026524826000004.tif18128 (where R 1 is a leaving group), or a tautomer, salt, or solvate thereof is also contemplated.

[0017] In some embodiments, R 1 is imidazoline.

[0018] In some embodiments, the compound of Formula IV is a chloride salt.

[0019] In some embodiments, the compound of Formula IV is 2-(trimethyl- λ 4-azaneil) ethyl 1H-imidazole-1-carboxylate chloride.

[0020] A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof is also intended to be prepared by the method of the present disclosure.

[0021] An additional embodiment of the present invention is a compound of formula IV: TIFF2026524826000005.tif20128.

[0022] In an additional aspect of this embodiment, the compound according to formula IV described above may be in an alternative salt form (i.e., Cl - ions substituted with different counterions).

[0023] In some aspects, the composition i) formula IV; ii) formula V TIFF2026524826000006.tif10128; iii) formula VI TIFF2026524826000007.tif11128; iv) a leaving group; and its salt further comprises at least one additional compound selected from the group consisting of.

[0024] In some aspects, the composition further comprises from 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 its salt.

Mode for Carrying Out the Invention

[0025] Details of the Invention Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. In case of any conflict, the definition included in this application shall prevail. Unless otherwise specified in the context, singular terms shall include plural forms, and plural terms shall include singular forms. All publications, patents, and other references referenced herein are incorporated by reference in whole for all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0026] Similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, but suitable methods and materials are listed below. The materials, methods and examples are illustrative and not intended to limit the scope. Other features and advantages of this disclosure will be apparent from the detailed description and the claims.

[0027] To further define this disclosure, the following terms and definitions are provided.

[0028] The singular forms “a,” “an,” and “the” include multiple referents unless the context otherwise explicitly indicates otherwise. The terms “a” (or “an”), as well as “one or more” and “at least one,” may be used interchangeably herein. In certain aspects, the terms “a” or “an” mean “single.” In other aspects, the terms “a” or “an” include “two or more” or “plural.”

[0029] The term "approximately" is used herein to mean roughly, roughly, about, or nearly. When the term "approximately" is used in conjunction with a numerical range, it modifies that range by extending the upper and lower boundaries of the numerical value being stated. Generally, in this specification, the term "approximately" is used to adjust the numerical values ​​above and below the stated value by a 10 percent variance (up or down).

[0030] As used herein, the term "and / or" should be interpreted as a specific disclosure in which each of two designated features or components may or may not be accompanied by the other feature or component. Accordingly, the term "and / or" as used in phrases such as "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 include each of the following embodiments: 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).

[0031] As used herein, the term "wrt" is an abbreviation for "with respect to," and the quantities described are relative to another substance disclosed.

[0032] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, formulation, and / or dosage form that is appropriate for use in contact with human and animal tissues, within the bounds of sound medical judgment, with a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reaction, or other problems or complications.

[0033] The term “pharmaceutically acceptable salt” includes, as recognized in the art, 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 listed in Berge, Bighley, and Monkhouse, J.pharm. Sci. (1977) 66, pp 1–19.

[0034] 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, phosphorous acid, and similar substances. 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, phenyl heteroatom-substituted alkanates, aliphatic and aromatic sulfuric acids. Therefore, pharmaceutically acceptable salts prepared from inorganic or organic acids include, but are not limited to, hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydroiodide, hydrofluoric acid, acetate, propionate, formate, oxalate, tartrate, citrate, lactate, p-toluenesulfonate, methanesulfonate, and maleate. Suitable pharmaceutically acceptable salts may also be formed by reacting the active ingredient with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine. Examples of pharmaceutically acceptable salts include those formed between a carboxylic acid group or sulfonic acid group, which may be found in part of the active ingredient, and an inorganic cation such as sodium, potassium, ammonium, or calcium, or an organic cation such as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium. All of these salts can be prepared from the active ingredient of the present invention by conventional means, for example, by reacting the active ingredient with a suitable acid or base.

[0035] As used herein, the terms “leaving group” or “LG” mean a chemical group that is readily substituted by a nucleophile or readily cleaved or hydrolyzed under basic or acidic conditions. In some embodiments, the leaving group is selected from halogen atoms (e.g., Cl, Br, I) or unstable heterocycles such as imidazolines or succinimides.

[0036] As used herein, the term “organic solvent” refers to a carbon-based liquid capable of dissolving or dispersing one or more other substances. Non-exclusive exemplary organic solvents include, but are not limited to, acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (ԅ), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, and chloroform, as well as combinations thereof.

[0037] As used herein, the term "phosgene-equivalent reagent" refers to an organic compound that reacts with a substrate in a manner similar to phosgene, thereby effectively adding carbonyl to the substrate molecule. Non-exclusive exemplary phosgene-equivalent reagents include, but are not limited to, diphosgene, triphosgene, disuccinimidyl carbonate, carbonyldiimidazole (CDI), 4-(nitrophenyl)chloroformate (4-NPCF), chlorosulfonyl isocyanate (CSI), and combinations thereof.

[0038] Generally, “agitation” or “to agitate” refers to forcing a fluid to flow within a container, either in a circulating or otherwise patterned manner, by mechanical means. As used herein, the term “sparging” refers to the process of injecting a gas through a diffuser into a liquid phase.

[0039] As used herein, the terms "wt%" or "w / w" refer to the ratio of two components by volume. For example, 5 wt% ethanol in an aqueous solution represents a solution containing 5 g of ethanol in 100 mL (i.e., 100 g) of water.

[0040] The term “excipient” refers to any substance that is not a therapeutic agent itself but can be used in a composition to deliver an active therapeutic agent to a target, or can be combined with an active therapeutic agent to improve its handling or storage properties, or to allow or facilitate the formation of dose units of the composition (for example, to make a pharmaceutical composition). Excipients may be inert, inactive, and / or non-pharmaceutically active substances.

[0041] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” or “therapeutic effective dose” refer to the amount or quantity of a drug or pharmaceutically active substance sufficient to elicit the required or desired therapeutic response, in other words, sufficient to induce a substantial biological response when administered to a patient.

[0042] "Administering" or "to administer" means the step of giving (i.e., providing) a pharmaceutical composition to a subject. Pharmaceutical compositions disclosed herein can be "administered topically," that is, administered to or near the site where a therapeutic outcome or result is desired. For example, topical administration of a pharmaceutical composition can be performed directly to the eye of a subject to treat an eye condition such as corneal pain; this is an example of topical administration.

[0043] Detailed explanation This disclosure relates to compounds of formula I: A method for preparing TIFF2026524826000008.tif17128, or a pharmaceutically acceptable salt thereof, To produce the compound of formula IV, or a salt thereof, according to scheme 3, the compound of formula II is dissolved in a solvent into the compound of formula III (wherein R 1 and R 2 The present invention provides a method comprising reacting with (each of which is a leaving group).

[0044] Scheme 3 TIFF2026524826000009.tif27128R 1 and R2 The present invention, as well as its embodiments and formulas, are described below.

[0045] In some aspects of the method, the salt and / or pharmaceutically acceptable salt is an acetate, bicarbonate, tartrate, citrate, bromide, chloride, dihydrogen citrate, hydroxide, or hydrogen tartrate. In some aspects of the method, the leaving group is a halogen atom (e.g., Cl, Br, I). In some aspects of the method, the leaving group is a chloride. In some aspects of the method, the leaving group is a heterocycle such as imidazoline or succinimide. In some aspects, the compound of formula III is a phosgene equivalent reagent. In some aspects, the compound of formula III is diphosgene, triphosgene, disuccinimidyl carbonate, carbonyldiimidazole (CDI), 4-(nitrophenyl)chloroformate (4-NPCF), chlorosulfonyl isocyanate (CSI), or a combination thereof. In some aspects, the compound of formula III is carbonyldiimidazole.

[0046] In some embodiments, approximately 0.1 to 5 equivalents of the compound of formula III are used relative to the compound of formula II. In some embodiments, approximately 0.5 to 3 equivalents of the compound of formula III are used relative to the compound of formula II. In some embodiments, approximately 1 to 2 equivalents of the compound of formula III are used relative to the compound of formula II. In some embodiments, 1.2 equivalents of the compound of formula III are used relative to the compound of formula II.

[0047] In some embodiments, formulas II and III are combined with a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the organic solvent is acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (siRNA), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, chloroform, or a combination thereof. In some embodiments, the organic solvent is acetonitrile.

[0048] In some embodiments, the reaction between Equation II and Equation III is stirred.

[0049] In some embodiments, about 3 to about 20 equivalents of an organic solvent are used for the compound of formula II. In some embodiments, about 5 to about 15 equivalents of an organic solvent are used for the compound of formula II. In some embodiments, about 7 to about 12 equivalents of an organic solvent are used for the compound of formula II. In some embodiments, about 8 to about 10 equivalents of an organic solvent are used for the compound of formula II. In some embodiments, about 6 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 7 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 8 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 9 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 10 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 11 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 12 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 13 equivalents of a solvent are used for the compound of formula II. In some embodiments, about 14 equivalents of solvent are used for the compound of formula II. In some embodiments, about 15 equivalents of solvent are used for the compound of formula II. In some embodiments, about 6 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 7 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 8 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 9 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 10 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 11 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 12 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 13 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 14 equivalents of acetonitrile are used for the compound of formula II. In some embodiments, about 15 equivalents of acetonitrile are used for the compound of formula II.

[0050] In a further embodiment of the method, to obtain the compound of formula I or a pharmaceutically acceptable salt thereof, the compound of formula IV or a salt thereof is reacted with ammonia according to scheme 4.

[0051] Scheme 4 TIFF2026524826000010.tif18128 in formula, R 1 and R 2 The present invention, as well as its embodiments and formulas, are described below.

[0052] One embodiment involves a compound of formula IV: The filename is TIFF2026524826000011.tif22128.

[0053] In one aspect of this embodiment, the compound of formula IV has a salt form different from the chloride described above.

[0054] In some embodiments of this method, the salt of formula IV is an acetate, bicarbonate, tartrate, citrate, bromide, chloride, dihydrogenate, hydroxide, or hydrogen tartrate.

[0055] In some embodiments, the solvent is an organic solvent. In some embodiments, the organic solvent is dichloromethane, acetonitrile, or dimethyl sulfoxide. In some embodiments, the organic solvent is acetonitrile.

[0056] In some embodiments, the solvent for the reaction of the compound of formula IV with ammonia is the same as the solvent used for the reactions of the compounds of formula II and formula III. In some embodiments, the solvent for the reaction of the compound of formula IV with ammonia is different from the solvent used for the reactions of the compounds of formula II and formula III.

[0057] In some embodiments, about 3 to about 20 equivalents of an organic solvent are used for the compound of formula IV. In some embodiments, about 5 to about 15 equivalents of an organic solvent are used for the compound of formula IV. In some embodiments, about 7 to about 12 equivalents of an organic solvent are used for the compound of formula IV. In some embodiments, about 8 to about 10 equivalents of an organic solvent are used for the compound of formula IV. In some embodiments, about 6 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 7 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 8 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 9 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 10 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 11 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 12 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 13 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 14 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 15 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 16 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 17 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 18 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 19 equivalents of solvent are used for the compound of formula IV. In some embodiments, about 20 equivalents of solvent are used for the compound of formula IV.

[0058] In some embodiments, the solvent is acetonitrile. In some embodiments, about 6 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 7 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 8 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 9 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 10 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 11 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 12 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 13 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 14 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 15 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 16 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 17 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 18 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 19 equivalents of acetonitrile are used for the compound of formula IV. In some embodiments, about 20 equivalents of acetonitrile are used for the compound of formula IV.

[0059] In some aspects of the methods disclosed herein, R 1 is -O-(4-nitrophenyl) or imidazoline, and R 2 is -Cl or imidazoline. In some embodiments, R 1 and R 2 These are the same leaving group. In some embodiments, R 1 and R 2 They are not identical. In some embodiments, the leaving group is a halogen atom (e.g., Cl, Br, I). In some embodiments of the method, the leaving group is a chloride.

[0060] In some embodiments, the reaction between formula II and formula III is carried out at a temperature of approximately 15°C to approximately 90°C. In some embodiments, the reaction between formula II and formula III is carried out at a temperature of approximately 15°C to approximately 85°C. In some embodiments, the reaction between formula II and formula III is carried out at a temperature of approximately 15°C to approximately 80°C. In some embodiments, the reaction between formula II and formula III is carried out at a temperature of approximately 45°C to approximately 70°C. In some embodiments, the reaction between formula II and formula III is carried out at a temperature at which the organic solvent refluxes.

[0061] In some embodiments, about 0.1 to about 5.0 equivalents of the compound of formula III are used relative to the compound of formula II. In some embodiments, about 1.0 to about 2.0 equivalents of the compound of formula III are used relative to the compound of formula II. In some embodiments, about 1.1 to about 1.5 equivalents of the compound of formula III are used relative to the compound of formula II. In some further embodiments, about 1.1 equivalents of the compound of formula III are used relative to the compound of formula II. In some further embodiments, about 1.2 equivalents of the compound of formula III are used relative to the compound of formula II. In some further embodiments, about 1.3 equivalents of the compound of formula III are used relative to the compound of formula II. In some further embodiments, about 1.4 equivalents of the compound of formula III are used relative to the compound of formula II. In some further embodiments, about 1.5 equivalents of the compound of formula III are used relative to the compound of formula II.

[0062] In some embodiments, a salt of the compound of formula III is used. In some embodiments, about 0.1 to about 5.0 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.0 to about 2.0 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.1 to about 1.5 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.1 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.2 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.3 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.4 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form. In some embodiments, about 1.5 equivalents of a salt of the compound of formula III is used relative to the compound of formula II or its salt form.

[0063] In some embodiments, the salt of the compound of formula III is a chloride. In some embodiments, about 0.1 to about 5.0 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form. In some embodiments, about 1.0 to about 2.0 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form. In some embodiments, about 1.1 to 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. In some embodiments, about 1.1 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form. In some embodiments, about 1.2 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form. In some embodiments, about 1.3 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form. In some embodiments, about 1.4 equivalents of the chloride salt of the compound of formula III are used relative to the compound of formula II or its salt form. In some embodiments, about 1.5 equivalents of the chloride salt of the compound of formula III is used relative to the compound of formula II or its salt form.

[0064] In some embodiments, the compound of formula IV is isolated and / or purified before the addition of ammonia. In certain embodiments, the compound of formula IV is isolated and / or purified by distillation, filtration, and / or washing with an organic solvent. In some embodiments, the compound of formula IV is filtered through a portable robotic filter (PRF). In some embodiments, the compound of formula IV is filtered through a PRF under reduced pressure. In certain embodiments, the compound of formula IV is filtered through a PRF under reduced pressure and nitrogen. In some embodiments, the compound of formula IV is isolated and / or purified by filtering the reaction mixture and subsequently washing the filter cake with an organic solvent. In some embodiments, the compound of formula IV is purified and / or isolated by filtering the reaction mixture and subsequently washing the filter cake with a mixture containing two or more organic solvents. In some embodiments, the compound of formula IV is isolated by filtering the reaction mixture and subsequently washing the filter cake with ACN. In some further embodiments, the compound of formula IV is isolated from solution and redissolved in an organic solvent before the addition of ammonia.

[0065] In some embodiments, ammonia is introduced as a gas into the solution of formula IV. In some embodiments, ammonia is introduced as a gas into a purified solution of formula IV. In some embodiments, gaseous ammonia is introduced into a solution of formula IV in which the compound of formula IV has been isolated and redissolved in an organic solvent. In some embodiments, ammonia is introduced via direct sparging of undiluted gaseous ammonia. In some embodiments, ammonia is introduced as a gas via subsurface sparging. In some embodiments, ammonia is diluted with a carrier gas. In some further embodiments, the carrier gas is nitrogen. In some embodiments, ammonia is introduced into the solution of formula IV while the reaction is maintained at atmospheric pressure. In some embodiments, ammonia is introduced into the solution of formula IV while the reaction is maintained at positive pressure relative to the atmosphere.

[0066] In some embodiments, ammonia is introduced into the solution of formula IV as a solution in a solvent. In some embodiments, ammonia is introduced into the solution of formula IV as a solution in an organic solvent. In some embodiments, the solvent is acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (siRNA), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, chloroform, or a combination thereof. In some embodiments, ammonia is in a solution of methanol. In some further embodiments, ammonia is present in methanol in a solution of about 4 M. In some further embodiments, ammonia is present in methanol in a solution of about 5 M. In some further embodiments, ammonia is present in methanol in a solution of about 6 M. In some further embodiments, ammonia is present in methanol in a solution of about 7 M. In some further embodiments, ammonia is present in methanol in a solution of about 8 M.

[0067] In some embodiments, ammonia is introduced in the form of a saturated solution in a solvent. In some embodiments, ammonia is introduced in the form of a saturated solution in an organic solvent. In some embodiments, ammonia is introduced in the form of a saturated solution in acetone, acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (ԅ), toluene, benzene, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, methanol (MeOH), ethanol (EtOH), isopropanol, chloroform, or a combination thereof. In some further embodiments, ammonia is introduced in the form of a saturated solution in acetonitrile.

[0068] In some embodiments, ammonia is introduced in solution form and cooled to about 0°C to about 5°C. In some embodiments, a saturated ammonia solution is prepared in situ by passing gaseous ammonia through a solvent, to which the solution of formula IV is then added.

[0069] In some embodiments, the solution of formula IV is stirred during the addition of gaseous ammonia at a reaction temperature of approximately 0°C to approximately 25°C. In certain embodiments, the solution of formula IV is stirred during the addition of gaseous ammonia at a reaction temperature of approximately 20°C to approximately 25°C. In some embodiments, the pH of the solution of formula IV is monitored during the addition of ammonia. In some embodiments, the pH of the solution of formula IV is adjusted before the addition of ammonia. In some embodiments, the pH of the solution of formula IV is maintained by adding an acid or base during the addition of ammonia. In some embodiments, ammonia is continuously added throughout the reaction by gently aerating the gas through the reactor. In some embodiments, ammonia is gently aerated throughout the reactor with moderate stirring. In some embodiments, ammonia is introduced as a single addition and the reaction vessel is sealed. In some embodiments, ammonia is manually added by the operator as a function of mass, temperature, or pressure values ​​observed by the operator. In some embodiments, ammonia is added by an electronically controlled valve as a function of mass, temperature, or pressure values ​​observed by a sensor. In some embodiments, ammonia is added manually or automatically as a function of the proportion of product observed by inline NMR monitoring. In some embodiments, ammonia is added as a function of the proportion of product observed after sampling and analysis of a portion of the reaction mixture.

[0070] In some embodiments, the compound of formula III is carbonyldiimidazole, the reaction temperature is about 65°C to about 70°C, the solvent is acetonitrile, and gaseous ammonia reacts with the solution of formula IV at a temperature of about 20°C to about 25°C.

[0071] In some embodiments, the compound of formula I is recrystallized in water, one or more alcoholic solvents, or a combination thereof. In some embodiments, the compound of formula I is recrystallized in a mixture of water and ethanol. In some embodiments, the solution containing the compound of formula I is heated during recrystallization. In some embodiments, the solution containing the compound of formula I is heated under reflux during recrystallization. In some embodiments, the solution containing the compound of formula I is heated to about 60°C to about 90°C during recrystallization. In some embodiments, the solution containing the compound of formula I is heated to about 60°C to about 80°C during recrystallization. In certain embodiments, the solution containing the compound of formula I is heated and cooled two or more times during recrystallization. In some embodiments, the solution containing the compound of formula I is concentrated by distillation. In some embodiments, the solution containing the compound of formula I is concentrated by distillation under nitrogen. In some embodiments, the compound of formula I is filtered, washed, and / or dried under heat and / or reduced pressure before recrystallization. In some embodiments, the solution is reduced to about 8 to about 10 parts of the compound of formula I. In some embodiments, the solution is reduced to about 8.5 to about 9.5 parts of the compound of formula I. In some embodiments, the solvent is reduced to about 9 parts of the compound of formula I by distillation under nitrogen at 1 atmosphere at about 77°C to about 79°C.

[0072] In some embodiments, the compound of formula I is recrystallized in a solution of ethanol and water, with water present in an amount less than 10 w / v% or v / v% relative to ethanol. In some embodiments, the compound of formula I is recrystallized in a solution of ethanol and water, with water present in an amount of about 0.1 to about 20 w / v% or v / v% relative to ethanol. In some embodiments, water present in an amount of about 1 to about 15 w / v% or v / v% relative to ethanol. In some embodiments, water present in an amount of about 1 to about 10 w / v% or v / v% relative to ethanol. In some embodiments, water present in an amount of about 0.1 to about 5 w / v% or v / v% relative to ethanol. In some embodiments, water present in an amount of about 0.1 to about 3 w / v% or v / v% relative to ethanol. In some embodiments, water present in an amount of about 1 to about 3 w / v% or v / v% relative to ethanol. In some embodiments, water present in an amount of about 2 to about 4 w / v% or v / v% relative to ethanol. In some embodiments, the recrystallization solvent is approximately 97.5 w / v% or v / v% ethanol, with the remainder being water.

[0073] In some embodiments, the total amount of recrystallization solvent is about 5 to about 15 parts relative to the compound of formula I. In some embodiments, about 3 to about 20 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 5 to about 15 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 7 to about 12 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 8 to about 10 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 6 equivalents of solvent are used relative to the compound of formula IV. In some embodiments, about 7 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 8 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 9 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, about 10 equivalents of recrystallization solvent are used relative to the compound of formula IV. In some embodiments, approximately 11 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 12 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 13 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 14 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 15 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 16 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 17 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 18 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 19 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 20 equivalents of recrystallization solvent are used for the compound of formula IV. In some embodiments, approximately 6 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 7 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 8 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 9 equivalents of 94 v / v% ethanol are used for the compound of formula IV.In some embodiments, approximately 10 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 11 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 12 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 13 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 14 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 15 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 16 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 17 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 18 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 19 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, approximately 20 equivalents of 94 v / v% ethanol are used for the compound of formula IV. In some embodiments, the compound of formula I is heated under reflux until a clear solution is formed. In some embodiments, the compound of formula I is heated under reflux until a clear solution is formed after approximately 2 hours. In some embodiments, the compound of formula I is recrystallized two or more times. In some embodiments, the compound of formula I is recrystallized one or more times after purity analysis. In some embodiments, the cooling rate during recrystallization is controlled or limited by temperature control. In some embodiments, the product suspension is stirred and cooled before collecting the product by filtration. In some embodiments, recrystallization is facilitated by inserting seed crystals into the solution during the cooling step. In some embodiments, the recrystallized solution is purified using a 1 μm TFE FC (Teflon filter cartridge). In some embodiments, the solution is cooled to approximately 20°C to approximately 25°C over approximately 5 hours. In some embodiments, the product suspension is stirred and cooled to about 0°C to about 5°C before the product is collected by filtration. In some embodiments, the product suspension is stirred for about 1 to about 3 hours and cooled to about 0°C to about 5°C before the product is collected by filtration.In some embodiments, the product suspension is stirred for about 1 to 2 hours and cooled to about 0°C to about 5°C before the product is collected by filtration.

[0074] In some embodiments, the filtration cake is washed with a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the filtration cake is washed with anhydrous ethanol. In some embodiments, the filtration cake is washed twice with anhydrous ethanol. In some embodiments, the filtration cake is washed twice with 2 equivalents of a compound of formula I containing anhydrous ethanol. In some embodiments, the filtration cake is dried in a vacuum oven. In some embodiments, the filtration cake is dried in a vacuum oven at about 50°C.

[0075] In one embodiment of the method, as shown in Scheme 5, 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 reacts with the solution of formula IV at a temperature of about 20°C to about 25°C, and the compound of formula I is recrystallized in a combination of ethanol and water.

[0076] Scheme 5 TIFF2026524826000012.tif85128 A non-restrictive reaction sequence for producing the chloride salt of the compound of formula I from choline chloride, CDI, and ammonia.

[0077] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt form thereof, is filtered, washed, and / or dried under reduced pressure after recrystallization to obtain a purified compound of formula I, or a pharmaceutically acceptable salt form thereof. In some embodiments, the conversion and / or purity of the compound of formula I, or a pharmaceutically acceptable salt form thereof, before or after recrystallization is measured by ion chromatography (IC), high-performance liquid chromatography (HPLC), ultra-high-performance liquid chromatography with a charged aerosol detector (UPLC-CAD), and / or liquid chromatography-mass spectrometry (LC-MS).

[0078] In some embodiments, at least 15 kg of the compound of formula I, or a pharmaceutically acceptable salt form thereof, is synthesized. In some embodiments, at least 15 kg of the compound of formula I is in chloride salt form. In some embodiments, at least 100 kg of the compound of formula I, or a pharmaceutically acceptable salt form thereof, is synthesized. In some embodiments, at least 150 kg of the compound of formula I, or a pharmaceutically acceptable salt form thereof, is synthesized. In any of the above embodiments, the compound of formula I is in chloride salt form.

[0079] This disclosure relates to a compound of formula IV having the following structure: TIFF2026524826000013.tif18128 (in the formula, R 1 R is a leaving group), or a tautomer thereof, salt, or solvate. In some embodiments of this method, the salt of formula IV is an acetate, bicarbonate, tartrate, citrate, bromide, chloride, dihydrogenate, hydroxide, or hydrogen tartrate. In some embodiments, R 1 is imidazoline or succinimide. In some embodiments, R 1 These are halogen atoms (e.g., Cl, Br, I).

[0080] In some embodiments, the compound of formula IV is a chloride salt.

[0081] In certain embodiments, the compound of formula IV is 2-(trimethyl-λ4-azanail)ethyl 1H-imidazole-1-carboxylate chloride or an alternative salt form thereof.

[0082] Pharmaceutical composition This disclosure includes pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, prepared by the method described herein.

[0083] In some embodiments, the pharmaceutical composition, i) Equation IV; ii) Formula V TIFF2026524826000014.tif10128; iii) Formula VI TIFF2026524826000015.tif10128; iv) Leaving groups; and The pharmaceutically acceptable salt It further comprises at least one additional compound selected from the group consisting of the following:

[0084] In some embodiments, the composition may further contain 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 embodiments, the composition may further contain 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 embodiments, the composition may further contain 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 embodiments, the composition may further contain 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 embodiments, the composition further comprises about 0.001 w / w% to about 1.0 w / w% of one or more of formulas IV, V, VI, or leaving groups, or pharmaceutically acceptable salts thereof.

[0085] In some embodiments, 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 viscous agents, and about 0.05% to about 1% by weight of one or more buffers.

[0086] In some embodiments, the pharmaceutical composition is approximately 0.25% to approximately 0.5% by weight, approximately 0.25% to approximately 0.75% by weight, approximately 0.25% to approximately 1% by weight, approximately 0.25% to approximately 1.25% by weight, approximately 0.25% to approximately 1.5% by weight, approximately 0.25% to approximately 1.75% by weight, approximately 0.25% to approximately 2% by weight, approximately 0.25% to approximately 2.25% by weight, approximately 0.25% to approximately 2.5% by weight, approximately 0.25% to approximately 2.75% by weight, approximately 0.25% to approximately 3% by weight, approximately 0.25% to approximately 3.25% by weight, approximately 0.25% to approximately 3.5% by weight, approximately 0.25% to approximately 3.75 wt%, about 0.25 wt% to about 4 wt%, about 0.25 wt% to about 4.25 wt%, about 0.25 wt% to about 4.5 wt%, about 0.25 wt% to about 4.75 wt%, about 0.25 wt% to about 5 wt%, about 0.5 wt% to about 0.75 wt%, about 0.5 wt% to about 1 wt%, about 0 .5% to about 1.25% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 1.75% by weight, about 0.5% to about 2% by weight, about 0.5% to about 2.25% by weight, about 0.5% to about 2.5% by weight, about 0.5% to about 2.75% by weight, about 0.5% 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% About 5% by weight, about 0.75% to about 1% by weight, about 0.75% to about 1.25% by weight, about 0.75% to about 1.5% by weight, about 0.75% to about 1.75% by weight, about 0.75% to about 2% by weight, about 0.75% to about 2.25% by weight, about 0.75% to about 2.5% by weight, About 0.75 weight% to about 2.75 weight%, about 0.75 weight% to about 3 weight%, about 0.75 weight% to about 3.25 weight%, about 0.75 weight% to about 3.5 weight%, about 0.75 weight% to about 3.75 weight%, about 0.75 weight% to about 4 weight%, about 0.75 weight% to about 4.25 weight%, about 0.75 Weight% to about 4.5%, about 0.75% to about 4.75%, about 0.75% to about 5%, about 1% to about 1.25%, about 1% to about 1.5%, about 1% to about 1.75%, about 1% to about 2%, about 1% to about 2.25%, about 1% to about 2.Compounds of formula I in amounts of 5 wt%, approximately 1 wt% to approximately 2.75 wt%, approximately 1 wt% to approximately 3 wt%, approximately 1 wt% to approximately 3.25 wt%, approximately 1 wt% to approximately 3.5 wt%, approximately 1 wt% to approximately 3.75 wt%, approximately 1 wt% to approximately 4 wt%, approximately 1 wt% to approximately 4.25 wt%, approximately 1 wt% to approximately 4.5 wt%, approximately 1 wt% to approximately 4.75 wt%, approximately 1 wt% to approximately 5 wt%, approximately 1.25 wt% to approximately 1.5 wt%, approximately 1.25 wt% to approximately 1.75 wt%, approximately 1.25 wt% to approximately 2 wt%, approximately 1.25 wt% to approximately 2.25 wt%, approximately 1.25 wt% to approximately 2.5 wt%, approximately 1.25 wt% to approximately 2.7 5% by weight, approximately 1.25% to approximately 3% by weight, approximately 1.25% to approximately 3.25% by weight, approximately 1.25% to approximately 3.5% by weight, approximately 1.25% to approximately 3.75% by weight, approximately 1.25% to approximately 4% by weight, approximately 1.25% to approximately 4.25% by weight, approximately 1.25% to approximately 4.5% by weight, approximately 1.25% to about 4.75% by weight, about 1.25% to about 5% by weight, about 1.5% to about 1.75% by weight, about 1.5% to about 2% by weight, about 1.5% to about 2.25% by weight, about 1.5% to about 2.5% by weight, about 1.5% to about 2.75% by weight, about 1.5% 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% About 5% by weight, about 1.75% to about 2% by weight, about 1.75% to about 2.25% by weight, about 1.75% to about 2.5% by weight, about 1.75% to about 2.75% by weight, about 1.75% to about 3% by weight, about 1.75% to about 3.25% by weight, about 1.75% to about 3.5% by weight, about 1.75 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 Weight%, about 2% to about 2.75%, about 2% to about 3%, about 2% to about 3.25%, about 2% to about 3.5%, about 2% to about 3.75%, about 2% to about 4%, about 2% to about 4.25%, about 2% to about 4.5%, about 2% 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% %, approximately 2.5% by weight to approximately 3.5% by weight, approximately 2.5% by weight to approximately 3.75% by weight, approximately 2.5% by weight to approximately 4% by weight, approximately 2.5% by weight to approximately 4.25% by weight, approximately 2.5% by weight to approximately 4.5% by weight, approximately 2.5% by weight to approximately 4.75% by weight, approximately 2.5% by weight to approximately 5% by weight, approximately 2.75% by weight to approximately 3% by weight, approximately 2.75% by weight to approximately 3.25% by weight, approximately 2.75% by weight to approximately 3.5% by weight, approximately 2.75% by weight to approximately 4% by weight, approximately 2.75% by weight to approximately 4.25% by weight, approximately 2.75% by weight to approximately 4.5% by weight, approximately 2.75% by weight to approximately 4.75% by weight Approximately 2.75% to 5% by weight, approximately 3% to 3.25% by weight, approximately 3% to 3.5% by weight, approximately 3% to 3.75% by weight, approximately 3% to 4% by weight, approximately 3% to 4.25% by weight, approximately 3% to 4.5% by weight, approximately 3% to 4.75% by weight, approximately 3% to 5% by weight, approximately 3.25% to 3.5% by weight, approximately 3.25% to 3.75% by weight, approximately 3.25% to 4% by weight, approximately 3.25% to 4.25% by weight, approximately 3.25% to 4.5% by weight, approximately 3.25% to 4.75% by weight, approximately 3.25% to 5% by weight, approximately 3.5% by weight. % by weight ~ approx. 3.75% by weight, approx. 3.5% by weight ~ approx. 4% by weight, approx. 3.5% by weight ~ approx. 4.25% by weight, approx. 3.5% by weight ~ approx. 4.5% by weight, approx. 3.5% by weight ~ approx. 4.75% by weight, approx. 3.5% by weight ~ approx. 5% by weight, approx. 3.75% by weight ~ approx. 4% by weight ~ approx. 4.25% by weight, approx. 4% by weight ~ approx. 4.5% by weight, approx. 4% by weight ~ approx. 4.75% by weight, approx. 4% by weight ~ approx. 5% by weight, approx. 4.25% by weight ~ approx. 4.5% by weight, approx. 4.The composition contains a compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount of 25% to approximately 4.75% by weight, approximately 4.25% to approximately 5% by weight, approximately 4.5% to approximately 4.75% by weight, approximately 4.5% to approximately 5% by weight, or approximately 4.75% to approximately 5% by weight. In some embodiments, the pharmaceutical composition contains a compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount of approximately 2% to approximately 4% by weight.

[0087] In some embodiments, the pharmaceutical composition includes one or more viscous agents. Non-limiting examples of viscous agents include hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other acceptable viscous agents 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), ceratonia, chitin, carboxymethylated chitosan, chondrus, dextrose, ferceleran, gelatin, ghati gum, guar gum, and hectorum. Examples include sugar, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, araya gum, zanthang gum, tragacanth gum, ethylcellulose, ethyl hydroxyethylcellulose, ethyl methylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygerin, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin, and sucralose) and combinations thereof.

[0088] In some embodiments, the pharmaceutical composition comprises hydroxypropyl methylcellulose or carboxymethylcellulose.

[0089] In some embodiments, the pharmaceutical composition contains one or more viscous agents in amounts of about 0.05% to about 0.1% by weight, about 0.05% to about 0.25% by weight, about 0.05% to about 0.5% by weight, about 0.05% to about 0.75% by weight, about 0.05% to about 1% by weight, about 0.1% to about 0.25% by weight, about 0.1% to about 0.5% by weight, about 0.1% to about 0.75% by weight, about 0.1% to about 1% by weight, about 0.25% to about 0.5% by weight, about 0.25% to about 0.75% by weight, about 0.25% to about 0.75% by weight, about 0.25% to about 1% by weight, about 0.5% to about 0.75% by weight, about 0.5% to about 1% by weight, or about 0.75% to about 1% by weight. In some embodiments, the pharmaceutical composition contains one or more viscous agents in an amount of about 0.05% to about 1% by weight.

[0090] In some embodiments, the pharmaceutical composition contains one or more viscous agents in an amount of 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 embodiments, the pharmaceutical composition contains 0.2% by weight of a viscous agent. In the Multiplette, the viscosity of the pharmaceutical composition is approximately 1 cPs to 5 cPs, 1 cPs to 10 cPs, 1 cPs to 15 cPs, 1 cPs to 20 cPs, 1 cPs to 30 cPs, 1 cPs to 40 cPs, 1 cPs to 50 cPs, 1 cPs to 60 cPs, 1 cPs to 80 cPs, 1 cPs to 100 cPs, 1 cPs to 125 cPs, 1 cPs to 150 cPs, 1 cPs to 175 cPs, 1 cPs to 200 cPs, and 1 cPs to 400 cPs. Ps, about 5 cPs to about 10 cPs, about 5 cPs to about 15 cPs, about 5 cPs to about 20 cPs, about 5 cPs to about 30 cPs, about 5 cPs to about 40 cPs, about 5 cPs to about 50 cPs, about 5 cPs to about 60 cPs, about 5 cPs to about 80 cPs, about 5 cPs~about 100cPs, about 5cPs~about 125cPs, about 5cPs~about 150cPs, about 5cPs~about 175cPs, about 5cPs~about 200cPs, about 5cPs~about 400cPs, about 10cPs~about 15cPs, about 10cPs~about 20cPs , about 10 cPs - about 30 cPs, about 10 cPs - about 40 cPs, about 10 cPs - about 50 cPs, about 10 cPs - about 60 cPs, about 10 cPs - about 80 cPs, about 10 cPs - about 100 cPs, about 10 cPs - about 125 cPs, about 10 cPs - Approx. 150cPs, Approx. 10cPs ~ Approx. 175cPs, Approx. 10cPs ~ Approx. 200cPs, Approx. 10cPs ~ Approx. 400cPs, Approx. 15cPs ~ Approx. 20cPs, Approx. 15cPs ~ Approx. 30cPs, Approx. 15cPs ~ Approx. 40cPs, Approx. 15cPs ~ Approx. 50cPs, Approx. 15cPs~Approx. 60cPs, Approx. 15cPs~Approx. 80cPs, Approx. 15cPs~Approx. 100cPs, Approx. 15cPs~Approx. 125cPs, Approx. 15cPs~Approx. 150cPs, Approx. 15cPs~Approx. 175cPs, Approx. 15cPs~Approx. 200cPs, Approx. 15cPs ~400cPs, 20cPs~30cPs, 20cPs~40cPs, 20cPs~50cPs, 20cPs~60cPs, 20cPs~80cPs, 20cPs~100cPs, 20cPs~125cPs,Approx. 20cPs~Approx. 150cPs, Approx. 20cPs~Approx. 175cPs, Approx. 20cPs~Approx. 200cPs, Approx. 20cPs~Approx. 400cPs, Approx. 30cPs~Approx. 40cPs, Approx. 30cPs~Approx. 50cPs, Approx. 30cPs~Approx. 60cPs, Approx. 30cPs~Approx. 80 cPs, about 30cPs to about 100cPs, about 30cPs to about 125cPs, about 30cPs to about 150cPs, about 30cPs to about 175cPs, about 30cPs to about 200cPs, about 30cPs to about 400cPs, about 40cPs to about 50cPs, about 40c Ps ~ about 60cPs, about 40cPs - about 80cPs, about 40cPs - about 100cPs, about 40cPs - about 125cPs, about 40cPs - about 150cPs, about 40cPs - about 175cPs, about 40cPs - about 200cPs, about 40cPs - about 400cP s, about 50cPs to about 60cPs, about 50cPs to about 80cPs, about 50cPs to about 100cPs, about 50cPs to about 125cPs, about 50cPs to about 150cPs, about 50cPs to about 175cPs, about 50cPs to about 200cPs, about 50cPs to about Approx. 400cPs, Approx. 60cPs~Approx. 80cPs, Approx. 60cPs~Approx. 100cPs, Approx. 60cPs~Approx. 125cPs, Approx. 60cPs~Approx. 150cPs, Approx. 60cPs~Approx. 175cPs, Approx. Approx. 80cPs~Approx. 100cPs, Approx. 80cPs~Approx. 125cPs, Approx. 80cPs~Approx. 150cPs, Approx. 80cPs~Approx. 175cPs, Approx. 80cPs~Approx. 200cPs, Approx. 80cPs~Approx. 400cPs, Approx. 100cPs~Approx. 125cPs, Approx. 100cPs The viscosity ranges from approximately 10 cPs to 175 cPs, 100 cPs to 200 cPs, 100 cPs to 400 cPs, 125 cPs to 150 cPs, 125 cPs to 175 cPs, 125 cPs to 200 cPs, 125 cPs to 400 cPs, 150 cPs to 175 cPs, 150 cPs to 200 cPs, 150 cPs to 400 cPs, 175 cPs to 200 cPs, or 200 cPs to 400 cPs. In several embodiments, the viscosity of the composition is approximately 10 cPs to 30 cPs.

[0091] In some embodiments, the composition has a viscosity of about 1 cPs, about 5 cPs, about 10 cPs, about 15 cPs, about 20 cPs, about 30 cPs, about 40 cPs, about 50 cPs, about 60 cPs, about 80 cPs, about 100 cPs, about 125 cPs, about 150 cPs, about 175 cPs, about 200 cPs, or about 400 cPs. In some embodiments, the composition has a viscosity of about 30 cPs.

[0092] In some embodiments, the composition comprises one or more buffers. Non-limiting examples of buffers include acetate buffer, borate buffer, citrate borate buffer, citrate buffer, lactate buffer, phosphate buffer, succinate buffer, borate-polyol complex buffer, carbonate buffer, organic buffer, amino acid buffer, and combinations thereof. In some embodiments, the pharmaceutical composition comprises one or more buffers, which are phosphate buffers.

[0093] In some embodiments, the phosphate buffer comprises phosphoric acid, alkali metal phosphates such as disodium hydrogen phosphate, monobasic sodium phosphate monohydrate, sodium dihydrogen phosphate, dibasic sodium 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 embodiments, the phosphate buffer comprises one or more anhydrous compounds. In some embodiments, the phosphate buffer comprises one or more hydrate compounds.

[0094] Organic buffers include Good's buffers, such as 2-(N-morpholino)ethanesulfonic acid (MES), N-(2-acetamide)iminodiacetic acid, N-(carbamoylmethyl)iminodiacetic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES), N-(2-acetamide)-2-aminoethanesulfonic acid (ACES), β-hydroxy-4-morpholinepropanesulfonic acid, and 3-morpholino-2-hydroxypropanesulfonic acid (MOP). SO), coramine 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-piperazineethanesulfonic acid (HEPES), 3-(N,N-bis[2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid (D Examples of amino acid buffers include, but are not limited to, IPSO, acetamidoglycine, 3-{[1,3-dihydroxy-2-(hydroxymethyl)-2-propanyl]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), tricine, glycinamide, bicine, or sodium N-tris(hydroxymethyl)methyl-3-aminopropanesulfonate (TAPS), glycine, diethanolamine (DEA); and combinations thereof. Examples of amino acid buffers include, but are not limited to, taurine, aspartic acid and its salts (e.g., potassium salts), ε-aminocaproic acid, and combinations thereof.

[0095] In some embodiments, the pharmaceutical composition comprises one or more buffers in amounts of about 0.05% to about 0.1% by weight, about 0.05% to about 0.25% by weight, about 0.05% to about 0.5% by weight, about 0.05% to about 0.75% by weight, about 0.1% to about 0.25% by weight, about 0.1% to about 0.5% by weight, about 0.1% to about 0.75% by weight, about 0.1% to about 1% by weight, 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 0.3% to about 0.4% by weight, about 0.3% to about 0.35% by weight, about 0.5% to about 0.75% by weight, about 0.5% to about 1% by weight, or about 0.75% to about 1% by weight. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 1% by weight of one or more buffers.

[0096] In some embodiments, the pharmaceutical composition contains one or more buffers in 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 0.4% by weight, about 0.45% by weight, about 0.5% by weight, about 0.55% by weight, about 0.6% by weight, about 0.65% by weight, about 0.7% by weight, about 0.75% by weight, about 0.8% by weight, about 0.85% by weight, about 0.9% by weight, about 0.95% by weight, or about 1% by weight. In some embodiments, the pharmaceutical composition contains one or more buffers in about 0.3% by weight. In some embodiments, the pharmaceutical composition contains one or more buffers in about 0.35% by weight.

[0097] In some embodiments, the pharmaceutical composition has a pH of 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, 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 7.2 to about 8, about 7.4 to about 7.6, about 7.4 to about 7.8, about 7.4 to about 8, or about 7.6 to about 7.8. In some embodiments, the pharmaceutical composition has a pH of about 7 to about 7.6.

[0098] In some embodiments, the pharmaceutical composition has a pH of about 6, about 6.5, about 7, about 7.2, about 7.6, or about 8. In some embodiments, the pharmaceutical composition has a pH of about 7.4.

[0099] In some embodiments, the pH of a pharmaceutical composition is adjusted by a strong acid or 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 embodiments, the strong acid or strong base is HCl or NaOH.

[0100] In some embodiments, the pharmaceutical composition includes a preservative. Non-limiting examples of preservatives include benzalkonium chloride, stabilized oxychloro complex (Purite®), phenylmercury acetate, chlorobutanol, benzyl alcohol, parabens, EDTA, and thimerosal.

[0101] In some embodiments, the pharmaceutical composition does not contain preservatives.

[0102] In some embodiments, the pharmaceutical composition does not contain ethylenediaminetetraacetic acid (EDTA).

[0103] In some embodiments, the pharmaceutical composition includes a permeation enhancer. Non-limiting examples of permeation enhancers include benzalkonium chloride, laurocaprum (azon), bile acids and their alkali metal salts, chenodeoxycholic acid, cholic acid, taurocholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid or ursodeoxycholic acid, glycocholic acid, n-dodecyl-β-D-maltoside, sucrose dodecanoate, octyl maltoside, decyl maltoside, tridecyl maltoside, tetradecyl maltoside, hexamethylene lauramide, hexamethylene octanamide, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, methylsulfonylmethane, sodium fusidate, saponins, or any combination thereof. In some embodiments, the pharmaceutical composition includes benzalkonium chloride.

[0104] In some embodiments, the pharmaceutical composition is approximately 0.0025% to approximately 0.005% by weight, approximately 0.0025% to approximately 0.0075% by weight, approximately 0.0025% to approximately 0.01% by weight, approximately 0.0025% to approximately 0.0125% by weight, approximately 0.0025% to approximately 0.02% by weight, approximately 0.005% to approximately 0.0075% by weight, and approximately 0.005% to approximately 0. The composition contains a permeation accelerator in amounts of 0.01% by weight, about 0.005% to about 0.0125% by weight, about 0.005% to about 0.02% by weight, about 0.0075% to about 0.01% by weight, about 0.0075% to about 0.02% by weight, about 0.01% to about 0.0125% by weight, about 0.01% to about 0.02% by weight, or about 0.0125% to about 0.02% by weight. In some embodiments, the pharmaceutical composition contains about 0.0075% to about 0.0125% by weight of a permeation accelerator.

[0105] In some embodiments, the pharmaceutical composition contains 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 of a permeation enhancer. In some embodiments, the pharmaceutical composition contains about 0.01% by weight of a permeation enhancer.

[0106] In some embodiments, the pharmaceutical composition is approximately 0.0025% to approximately 0.005% by weight, approximately 0.0025% to approximately 0.0075% by weight, approximately 0.0025% to approximately 0.01% by weight, approximately 0.0025% to approximately 0.0125% by weight, approximately 0.0025% to approximately 0.02% by weight, approximately 0.005% to approximately 0.0075% by weight, and approximately 0.005% to approximately 0.01% by weight. The composition contains benzalkonium chloride in amounts of approximately 0.005% by weight to approximately 0.0125% by weight, approximately 0.005% by weight to approximately 0.02% by weight, approximately 0.0075% by weight to approximately 0.01% by weight, approximately 0.0075% by weight to approximately 0.02% by weight, approximately 0.01% by weight to approximately 0.0125% by weight, approximately 0.01% by weight to approximately 0.02% by weight, or approximately 0.0125% by weight to approximately 0.02% by weight. In some embodiments, the pharmaceutical composition contains approximately 0.0075% by weight to approximately 0.0125% by weight of benzalkonium chloride.

[0107] In some embodiments, the pharmaceutical composition contains 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 of benzalkonium chloride. In some embodiments, the pharmaceutical composition contains about 0.01% by weight of benzalkonium chloride.

[0108] In some embodiments, the pharmaceutical composition does not contain a permeation enhancer.

[0109] In some embodiments, the pharmaceutical composition does not contain benzalkonium chloride.

[0110] In some embodiments, the pharmaceutical composition includes one or more stabilizers. The 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 ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In some embodiments, amide analogs of the stabilizers are also used. In some embodiments, the selected stabilizers alter the hydrophobicity of the formulation, improve the mixing of various components in the formulation, control the water level in the formulation, or control the phase mobility.

[0111] In some embodiments, 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 analogs, divalent cations such as magnesium and zinc, or combinations thereof.

[0112] In some embodiments, the pharmaceutical composition does not contain ethylenediaminetetraacetic acid (EDTA).

[0113] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition contains about 0.01% to about 5% by weight of the compound of formula IV or a pharmaceutically acceptable salt thereof.In some embodiments, the pharmaceutical composition is approximately 0.01% to approximately 0.1% by weight, approximately 0.01% to approximately 0.5% by weight, approximately 0.01% to approximately 1% by weight, approximately 0.01% to approximately 1.5% by weight, approximately 0.01% to approximately 2% by weight, approximately 0.01% to approximately 2.5% by weight, approximately 0.01% to approximately 3% by weight, approximately 0.01% to approximately 3.5% by weight, approximately 0.01% to approximately 4% by weight, approximately 0.01% to approximately 4.5% by weight, approximately 0.1% to approximately 0.5% by weight, approximately 0.1% to approximately 1% by weight, approximately 0.1% to approximately 1.5% by weight, approximately 0.1% to approximately 2% by weight, approximately 0.1% About 2.5% by weight, about 0.1% to about 3% by weight, about 0.1% to about 3.5% by weight, about 0.1% to about 4% by weight, about 0.1% to about 4.5% by weight, about 0.1% to about 5% by weight, about 0.5% to about 1% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 2% by weight %, about 0.5% to about 2.5%, about 0.5% to about 3%, about 0.5% to about 3.5%, about 0.5% to about 4%, about 0.5% to about 4.5%, about 0.5% to about 5%, about 1% to about 1.5%, about 1% to about 2%, about 1% by weight About 2.5% by weight, about 1% to about 3% by weight, about 1% to about 3.5% by weight, about 1% to about 4% by weight, about 1% to about 4.5% by weight, about 1% to about 5% by weight, about 1.5% to about 2% by weight, about 1.5% to about 2.5% by weight, about 1.5% to about 3% by weight, about 1.5% by weight ~3.5% by weight, 1.5% to 4%, 1.5% to 4.5%, 1.5% to 5%, 2% to 2.5%, 2% to 3%, 2% to 3.5%, 2% to 4%, 2% to 4.5%, 2% by weight Contains compounds of formula IV or pharmaceutically acceptable salts thereof in amounts of approximately 5% by weight, approximately 2.5% to approximately 3% by weight, approximately 2.5% to approximately 3.5% by weight, approximately 2.5% to approximately 4% by weight, approximately 2.5% to approximately 4.5% by weight, approximately 2.5% to approximately 5% by weight, approximately 3% to approximately 3.5% by weight, approximately 3% to approximately 4% by weight, approximately 3% to approximately 4.5% by weight, approximately 3% to approximately 5% by weight, approximately 3.5% to approximately 4% by weight, approximately 3.5% to approximately 4.5% by weight, approximately 3.5% to approximately 5% by weight, approximately 4% to approximately 4.5% by weight, approximately 4% to approximately 5% by weight, or approximately 4.5% to approximately 5% by weight.

[0114] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprises about 5% by weight of the compound of formula IV or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 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 of the compound of formula IV or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the pharmaceutical composition does not contain the compound of formula IV.

[0116] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprises about 0.01% to about 5% by weight of the compound of formula V or a pharmaceutically acceptable salt thereof.In some embodiments, the pharmaceutical composition is approximately 0.01% to approximately 0.1% by weight, approximately 0.01% to approximately 0.5% by weight, approximately 0.01% to approximately 1% by weight, approximately 0.01% to approximately 1.5% by weight, approximately 0.01% to approximately 2% by weight, approximately 0.01% to approximately 2.5% by weight, approximately 0.01% to approximately 3% by weight, approximately 0.01% to approximately 3.5% by weight, approximately 0.01% to approximately 4% by weight, approximately 0.01% to approximately 4.5% by weight, approximately 0.1% to approximately 0.5% by weight, approximately 0.1% to approximately 1% by weight, approximately 0.1% to approximately 1.5% by weight, approximately 0.1% to approximately 2% by weight, approximately 0.1% About 2.5% by weight, about 0.1% to about 3% by weight, about 0.1% to about 3.5% by weight, about 0.1% to about 4% by weight, about 0.1% to about 4.5% by weight, about 0.1% to about 5% by weight, about 0.5% to about 1% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 2% by weight Amount %, about 0.5% to about 2.5% by weight, about 0.5% to about 3% by weight, about 0.5% to about 3.5% by weight, about 0.5% to about 4% by weight, about 0.5% to about 4.5% by weight, about 0.5% to about 5% by weight, about 1% to about 1.5% by weight, about 1% to about 2% by weight, about 1% by weight ~2.5% by weight, approximately 1% to approximately 3% by weight, approximately 1% to approximately 3.5% by weight, approximately 1% to approximately 4% by weight, approximately 1% to approximately 4.5% by weight, approximately 1% to approximately 5% by weight, approximately 1.5% to approximately 2% by weight, approximately 1.5% to approximately 2.5% by weight, approximately 1.5% to approximately 3% by weight, approximately 1.5% by weight % to about 3.5% by weight, about 1.5% to about 4% by weight, about 1.5% to about 4.5% by weight, about 1.5% to about 5% by weight, about 2% to about 2.5% by weight, about 2% to about 3% by weight, about 2% to about 3.5% by weight, about 2% to about 4% by weight, about 2% to about 4.5% by weight, about 2% by weight The compounds of formula V, or pharmaceutically acceptable salts thereof, are present in amounts of approximately 5% by weight, approximately 2.5% by weight to approximately 3% by weight, approximately 2.5% by weight to approximately 3.5% by weight, approximately 2.5% by weight to approximately 4% by weight, approximately 2.5% by weight to approximately 4.5% by weight, approximately 2.5% by weight to approximately 5% by weight, approximately 3% by weight to approximately 3.5% by weight, approximately 3% by weight to approximately 4% by weight, approximately 3% by weight to approximately 4.5% by weight, approximately 3% by weight to approximately 5% by weight, approximately 3.5% by weight to approximately 4% by weight, approximately 3.5% by weight to approximately 4.5% by weight, approximately 3.5% by weight to approximately 5% by weight, approximately 4% by weight to approximately 4.5% by weight, or approximately 4.5% by weight to approximately 5% by weight.

[0117] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprises about 5% by weight of the compound of formula V or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 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 of the compound of formula V or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the pharmaceutical composition does not contain the compound of formula V.

[0119] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprises about 0.01% to about 5% by weight of the compound of formula VI or a pharmaceutically acceptable salt thereof.In some embodiments, the pharmaceutical composition is approximately 0.01% to approximately 0.1% by weight, approximately 0.01% to approximately 0.5% by weight, approximately 0.01% to approximately 1% by weight, approximately 0.01% to approximately 1.5% by weight, approximately 0.01% to approximately 2% by weight, approximately 0.01% to approximately 2.5% by weight, approximately 0.01% to approximately 3% by weight, approximately 0.01% to approximately 3.5% by weight, approximately 0.01% to approximately 4% by weight, approximately 0.01% to approximately 4.5% by weight, approximately 0.1% to approximately 0.5% by weight, approximately 0.1% to approximately 1% by weight, approximately 0.1% to approximately 1.5% by weight, approximately 0.1% to approximately 2% by weight, approximately 0.1% About 2.5% by weight, about 0.1% to about 3% by weight, about 0.1% to about 3.5% by weight, about 0.1% to about 4% by weight, about 0.1% to about 4.5% by weight, about 0.1% to about 5% by weight, about 0.5% to about 1% by weight, about 0.5% to about 1.5% by weight, about 0.5% to about 2% by weight Amount %, about 0.5% to about 2.5% by weight, about 0.5% to about 3% by weight, about 0.5% to about 3.5% by weight, about 0.5% to about 4% by weight, about 0.5% to about 4.5% by weight, about 0.5% to about 5% by weight, about 1% to about 1.5% by weight, about 1% to about 2% by weight, about 1% by weight ~2.5% by weight, approximately 1% to approximately 3% by weight, approximately 1% to approximately 3.5% by weight, approximately 1% to approximately 4% by weight, approximately 1% to approximately 4.5% by weight, approximately 1% to approximately 5% by weight, approximately 1.5% to approximately 2% by weight, approximately 1.5% to approximately 2.5% by weight, approximately 1.5% to approximately 3% by weight, approximately 1.5% by weight % to about 3.5% by weight, about 1.5% to about 4% by weight, about 1.5% to about 4.5% by weight, about 1.5% to about 5% by weight, about 2% to about 2.5% by weight, about 2% to about 3% by weight, about 2% to about 3.5% by weight, about 2% to about 4% by weight, about 2% to about 4.5% by weight, about 2% by weight The compounds of formula VI, or pharmaceutically acceptable salts thereof, are present in amounts of approximately 5% by weight, approximately 2.5% by weight to approximately 3% by weight, approximately 2.5% by weight to approximately 3.5% by weight, approximately 2.5% by weight to approximately 4% by weight, approximately 2.5% by weight to approximately 4.5% by weight, approximately 2.5% by weight to approximately 5% by weight, approximately 3% by weight to approximately 3.5% by weight, approximately 3% by weight to approximately 4% by weight, approximately 3% by weight to approximately 4.5% by weight, approximately 3% by weight to approximately 5% by weight, approximately 3.5% by weight to approximately 4% by weight, approximately 3.5% by weight to approximately 4.5% by weight, approximately 3.5% by weight to approximately 5% by weight, approximately 4% by weight to approximately 4.5% by weight, or approximately 4.5% by weight to approximately 5% by weight.

[0120] In some embodiments, in addition to a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition contains about 5% by weight of a compound of formula VI or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 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 of a compound of formula VI or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the pharmaceutical composition does not contain the compound of formula VI.

[0122] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprises about 0.01% to about 5% by weight of a leaving group or a pharmaceutically acceptable salt thereof.In some embodiments, the pharmaceutical composition is approximately 0.01% to approximately 0.1% by weight, approximately 0.01% to approximately 0.5% by weight, approximately 0.01% to approximately 1% by weight, approximately 0.01% to approximately 1.5% by weight, approximately 0.01% to approximately 2% by weight, approximately 0.01% to approximately 2.5% by weight, approximately 0.01% to approximately 3% by weight, approximately 0.01% to approximately 3.5% by weight, approximately 0.01% to approximately 4% by weight, approximately 0.01% to approximately 4.5% by weight, approximately 0.1% to approximately 0.5% by weight, approximately 0.1% to approximately 1% by weight, approximately 0.1% to approximately 1.5% by weight, approximately 0.1% to approximately 2% by weight, and approximately 0.1% by weight. ~2.5% by weight, 0.1% to 3%, 0.1% to 3.5%, 0.1% to 4%, 0.1% to 4.5%, 0.1% to 5%, 0.5% to 1%, 0.5% to 1.5%, 0.5% to 2 Weight%, about 0.5% to about 2.5%, about 0.5% to about 3%, about 0.5% to about 3.5%, about 0.5% to about 4%, about 0.5% to about 4.5%, about 0.5% to about 5%, about 1% to about 1.5%, about 1% to about 2%, about 1% by weight Amount % to about 2.5% by weight, about 1% to about 3% by weight, about 1% to about 3.5% by weight, about 1% to about 4% by weight, about 1% to about 4.5% by weight, about 1% to about 5% by weight, about 1.5% to about 2% by weight, about 1.5% to about 2.5% by weight, about 1.5% to about 3% by weight, about 1.5 Weight % to about 3.5 weight %, about 1.5 weight % to about 4 weight %, about 1.5 weight % to about 4.5 weight %, about 1.5 weight % to about 5 weight %, about 2 weight % to about 2.5 weight %, about 2 weight % to about 3 weight %, about 2 weight % to about 3.5 weight %, about 2 weight % to about 4 weight %, about 2 weight % to about 4.5 weight %, about Contains leaving groups or pharmaceutically acceptable salts thereof in amounts of 2% to approximately 5% by weight, approximately 2.5% to approximately 3% by weight, approximately 2.5% to approximately 3.5% by weight, approximately 2.5% to approximately 4% by weight, approximately 2.5% to approximately 4.5% by weight, approximately 2.5% to approximately 5% by weight, approximately 3% to approximately 3.5% by weight, approximately 3% to approximately 4% by weight, approximately 3% to approximately 4.5% by weight, approximately 3% to approximately 5% by weight, approximately 3.5% to approximately 4% by weight, approximately 3.5% to approximately 4.5% by weight, approximately 3.5% to approximately 5% by weight, approximately 4% to approximately 4.5% by weight, approximately 4% to approximately 5% by weight, or approximately 4.5% to approximately 5% by weight.

[0123] In some embodiments, in addition to the compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprises about 5% by weight of a leaving group or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 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 of a leaving group or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the pharmaceutical composition does not contain leaving groups.

[0125] In some embodiments, the pharmaceutical composition has a total concentration of less than 1% by weight of the compound of formula IV or a pharmaceutically acceptable salt thereof, the compound of formula V or a pharmaceutically acceptable salt thereof, the compound of formula VI or a pharmaceutically acceptable salt thereof, and / or a leaving group or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition has a total concentration of 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 of the compound of formula IV or a pharmaceutically acceptable salt thereof, the compound of formula V or a pharmaceutically acceptable salt thereof, the compound of formula VI or a pharmaceutically acceptable salt thereof, a leaving group, or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the solubility of the components of the pharmaceutical composition may be enhanced by a surfactant or other suitable co-solvent in the composition. Such co-solvents include polysorbates 20, 60, and 80, Pluronic F68, F-84, and P-103, cyclodextrin, or other agents known to those skilled in the art. In some embodiments, the concentration of the co-solvent is 0.01% to about 2% by weight.

[0127] In some embodiments, the 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 that are not in trans configuration with respect to each other. Polyols can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, insofar as 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, but are not limited to, sugars, sugar alcohols, and sugar acids, including mannitol, glycerin, xylitol, sorbitol, and propylene glycol. It is intended that the polyol may consist of two or more different polyols.

[0128] In some embodiments, the composition comprises one or more anti-aggregation additives. The anti-aggregation additives enhance the stability of the composition by reducing the rate of protein aggregation. The anti-aggregation additives include, but are not limited to, urea, guanidinium chloride, simple amino acids such as glycine or arginine, sugars, polyalcohols, polysorbates, polymers such as polyethylene glycol and dextrans, alkyl sugars such as alkyl glycosides, and surfactants.

[0129] In some embodiments, the composition contains one or more antioxidants. Antioxidants include, but are not limited to, ascorbic acid, methionine, sodium thiosulfate, sodium metabisulfate, and combinations thereof. Metal chelating agents, thiol-containing compounds, and other common stabilizers may be acceptable antioxidants.

[0130] In some embodiments, the composition comprises one or more osmolality agents. The osmolality agents include, but are not limited to, salts, particularly sodium chloride or potassium chloride, organic compounds, such as propylene glycol, mannitol, sorbitol, dextrose, and glycerin.

[0131] In some embodiments, the pharmaceutical composition has an osmolality of about 260 to about 365 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of 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, and about 295 mOsm / kg to about 305 mOsm / kg. , about 295mOsm / kg to about 315mOsm / kg, about 295mOsm / kg to about 325mOsm / kg, about 295mOsm / kg to about 335mOsm / kg, about 295mOsm / kg to about 345mOsm / kg, about 295mOsm / kg to about 355mOs m / kg, about 295mOsm / kg to about 365mOsm / kg, about 305mOsm / kg to about 315mOsm / kg, about 305mOsm / kg to about 325mOsm / kg, about 305mOsm / kg to about 335mOsm / kg, about 305mOsm / kg to about 34 5mOsm / kg, about 305mOsm / kg to about 355mOsm / kg, about 305mOsm / kg to about 365mOsm / kg, about 315mOsm / kg to about 325mOsm / kg, about 315mOsm / kg to about 335mOsm / kg, about 315mOsm / kg ~345mOsm / kg, approximately 315mOsm / kg~355mOsm / kg, approximately 315mOsm / kg~365mOsm / kg, approximately 325mOsm / kg~335mOsm / kg, approximately 325mOsm / kg~345mOsm / kg, approximately 325mOs m / kg~about 355mOsm / kg, about 325mOsm / kg~about 365mOsm / kg, about 335mOsm / kg~about 345mOsm / kg, about 335mOsm / kg~about 355mOsm / kg, about 335mOsm / kg~about 365mOsm / kg, about 34 5mOsm / kg~about 355mOsm / kg, about 345mOsm / kg~about 365mOsm / kg, about 355mOsm / kg~about 365mOsm / kg, about 260mOsm / kg~about 265mOsm / kg, about 260mOsm / kg~about 275mOsm / kg,Approx. 260mOsm / kg~Approx. 285mOsm / kg, Approx. 260mOsm / kg~Approx. 295mOsm / kg, Approx. 260mOsm / kg~Approx. 305mOsm / kg, Approx. 260mOsm / kg~Approx. 315mOsm / kg, about 260mOsm / kg to about 325mOsm / kg, about 260mOsm / kg to about 335mOsm / kg, about 260mOsm / kg to about 345mOsm / kg, about 2 60mOsm / kg~Approx. 355mOsm / kg, Approx. 260mOsm / kg~Approx. 365mOsm / kg, Approx. 265mOsm / kg~Approx. 275mOsm / kg, Approx. 265mOsm / kg~Approx. 28 5mOsm / kg, about 265mOsm / kg to about 295mOsm / kg, about 265mOsm / kg to about 305mOsm / kg, about 265mOsm / kg to about 315mOsm / kg, about 265 mOsm / kg ~ approx. 325mOsm / kg, approx. 265mOsm / kg ~ approx. 335mOsm / kg, approx. 265mOsm / kg ~ approx. 345mOsm / kg, approx. 265mOsm / kg ~ approx. 355m Osm / kg, approximately 265mOsm / kg to approximately 365mOsm / kg, approximately 275mOsm / kg to approximately 285mOsm / kg, approximately 275mOsm / kg to approximately 295mOsm / kg, approximately 275mO It has osmotic pressures of approximately 305 mOsm / kg, 315 mOsm / kg, 325 mOsm / kg, 335 mOsm / kg, 345 mOsm / kg, 355 mOsm / kg, and 365 mOsm / kg.

[0132] In some embodiments, the pharmaceutical composition has an osmotic pressure of approximately 260 mOsm / kg, approximately 265 mOsm / kg, approximately 275 mOsm / kg, approximately 285 mOsm / kg, approximately 295 mOsm / kg, approximately 305 mOsm / kg, approximately 315 mOsm / kg, approximately 325 mOsm / kg, approximately 335 mOsm / kg, approximately 345 mOsm / kg, approximately 355 mOsm / kg, approximately 365 mOsm / kg, approximately 370 mOsm / kg, or approximately 375 mOsm / kg.

[0133] In some embodiments, the composition is isotonic. In some embodiments, the composition is hypotonic. In some embodiments, the composition is hypertonic.

[0134] In some embodiments, the pharmaceutical composition may contain a variety of additional components. Such components include, but are not limited to, additional therapeutic agents, additional or alternative antimicrobial agents, suspension agents, surfactants, additional or alternative isotonic agents, additional or alternative buffering agents, antioxidants, additional or alternative viscosity modifiers, chelating agents, or any combination thereof. [Examples]

[0135] In the following embodiments, the compound of formula I is TIFF2026524826000016.tif18128, the compound of formula II is choline chloride, the compound of formula III is 1,1-carbonyldiimidazole (CDI), and the compound of formula IV is The filename is TIFF2026524826000017.tif19128.

[0136] Example 1: Preparation of a 2.5 kg batch of compound of formula I Step 1: Reaction of compound II and compound III to form compound IV. Under N2 conditions, a dry 50 L reactor was packed with 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). The resulting mixture was vigorously stirred at 20–25°C. The suspension was heated to 65–70°C with vigorous stirring and stirred for 1.25 hours (setpoint, 1–2 hours). The reaction mixture was heated and stirred until no residual amount of compound II relative to compound IV was detected by NMR. Once the analytical requirements were met, the batch was cooled to 20–25°C over 1 hour and 20 minutes (setpoint, minimum 1 hour). The batch was cooled to 0–5°C with moderate stirring and stirred overnight (total 19 hours) (setpoint - cooling to 0–5°C over a minimum of 1 hour, stirring for a minimum of 2 hours). The batch was filtered through a portable robotic filter (PRF) under nitrogen and reduced pressure. The reactor was washed with 2 × 4 kg of ACN (2 × 4 parts relative to the compound of formula II) pre-cooled to 0–5°C. The cake was dried on a filter under N2 flow at ambient temperature for approximately 20 hours. The yield was 90.7%, producing 3.799 kg of product as a grayish-white solid. QNMR assay confirmed the formation of the compound of formula IV with a purity of 96.2% w / w.

[0137] Step 2: Reaction of compound IV with ammonia to form compound I. Under N2 conditions, 1,800 kg of the compound of formula IV and 14.07 kg of ACN (10 parts relative to the compound of formula II) were packed into the reactor. The resulting mixture was stirred moderately at 20–25°C to form a thick white suspension. The batch was cooled to approximately 17–18°C with moderate stirring. The purpose of cooling the batch was to address the gradual exothermic addition of ammonia by aeration. The batch temperature was set to 15–20°C (the batch temperature was approximately 18°C). °While maintaining the temperature at C, the suspension was gently aerated with dry NH3 gas under moderate stirring. Ammonia aeration was continued for 3 hours under moderate stirring at 15-20°C (batch temperature was approximately 18°C). In this batch, approximately 555 kg of ammonia gas was packed into the batch after 3 hours of aeration. In this batch, a sample of the reaction mixture was taken after 2 hours, and analysis showed that approximately 2.6% of compound IV remained relative to compound I. A sample taken after 3 hours of aeration showed approximately 0.6% of compound IV remaining relative to compound I, and was maintained under gentle ammonia gas aeration. Once the analytical requirements were met, ammonia aeration was stopped, and the suspension was sparged with nitrogen at 20-25°C for 2.5 hours (setpoint - minimum 1 hour) to remove ammonia. The batch was filtered through a portable robotic filter (PRF) under nitrogen. The reactor was washed with 2 × 2.814 kg of ACN (2 × 2 parts relative to the compound of formula II). The cake was dried on a filter under a nitrogen stream for 23 hours. The mass of the recovered product was 1.310 kg, with a purity of 90.2% w / w as determined by NMR, and the yield of the grayish-white solid of the compound of formula IV was 93.1%.

[0138] Step 3: Preparation of the recrystallization solvent Under N2 conditions, 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) were packed into a 50 L reactor via a stainless steel cartridge (SCART) filter. The mixture was stirred moderately at 20-25°C for 5 minutes. Stirring was stopped, and the solution was discharged into a new PE drum.

[0139] Step 4: Recrystallization of compound I Under N2 conditions, 2.45 kg of the crude compound of formula I obtained from step 3 was added to the reactor, followed by 25.48 kg of 97.5% v / v EtOH (13 parts relative to the crude compound of formula I). ​​The resulting suspension was stirred moderately. The batch was heated under reflux with moderate stirring (for about 1.5 hours) to form a clear solution. The batch was cooled to about 70°C with moderate stirring. The batch was clarified by passing it through a 1 μm TFE FC (Teflon filter cartridge) and then heated in the reactor (for about 70°C). ° The mixture was placed in a container (held in C). The reactor was rinsed with 0.98 kg of 97.5% v / v EtOH (0.5 parts relative to the crude compound of formula I). ​​The batch was heated under moderate stirring and refluxed to obtain a clear solution. The batch was concentrated by distillation under N2 at approximately 1 atm with vigorous stirring to a target volume of approximately 9 parts (set value, 8.5-9.5 parts) relative to the crude compound of formula I. The batch was cooled to 20-25°C over a period of approximately 5 hours with vigorous stirring (set value - minimum 2 hours). The batch was stirred at 20-25°C for 10 hours with vigorous stirring (set value - minimum 2 hours). The batch was cooled to 0-5°C over a period of 1.5 hours with vigorous stirring (set value - minimum 1 hour), and then stirred at 0-5°C for 3 hours (set value - minimum 3 hours). The batch was filtered under nitrogen through a portable robotic filter (PRF). The filtered cake was washed in the reactor at 0-5°C with 2 × 3.866 kg of pre-cooled anhydrous EtOH (2 × 2 parts relative to the crude compound of formula I). ​​The cake was dried on a filter under a flow of N2 for approximately 69 hours. The yield of the compound of formula I obtained was 84%.

[0140] Example 2 The intermediate compound of formula IV was synthesized as described in Example 1. A suspension of the compound of formula IV in ACN was treated with ammonia gas for 2 hours (instead of 3 hours) and stopped. Approximately 410 g of ammonia gas was poured into the reaction mixture. The resulting mixture was stirred for 1 hour and then sampled. The conversion was determined by NMR (approximately 1% mol / mol of the compound of formula IV relative to the compound of formula I). ​​The crude compound of formula I was isolated as a grayish-white solid in 95% yield (1.345 kg).

[0141] Examples 3-10: TIFF2026524826000018.tif96166

[0142] Example 11: ACN and time interval of 10 parts TIFF2026524826000019.tif35166

[0143] Under the conditions described, the compound of formula IV was obtained by simply filtering the reaction mixture, followed by washing the filtered cake with ACN, to obtain a material of good quality (purity by NMR, >95%) typically in about 90% yield.

[0144] Examples 12-17: Scale conversion of compound IV to compound I, ≥50g. In Examples 12-17, the compound of formula III was CDI. TIFF2026524826000020.tif213167

[0145] Example 18 Compound of formula IV reacted with NH3 solution The diimidazolide species of the compound of formula IV was reacted with a 7M solution of ammonia in MeOH to produce the expected urethane compound of formula I as the major product, along with a trace amount of methyl carbonate (10-15% by NMR). The reaction was remarkably clean, with almost no by-products detected. The compound of formula IV showed good reactivity with ammonia, producing the desired product of the compound of formula I.

[0146] Example 19 Compound of formula IV reacted with NH3 solution At approximately 15°C, ammonia gas was introduced (subsurface sparging) using nitrogen as a carrier gas to a stirred suspension of compound IV (1.5 g) (20 parts relative to compound IV) in ACN. After 15 minutes, the reaction mixture was analyzed by NMR, indicating that little reaction had occurred. No compound in the form of formula I was detected. The experiment was continued for another 30 minutes using direct sparging of ammonia gas into a suspension containing compound IV (without using nitrogen gas). NMR analysis of the reaction mixture showed that the level of compound IV had decreased to approximately 1% of the compound I. Sparging of ammonia was stopped, and the reaction mixture was stirred for a further 3 hours at 20-25°C (to allow evaporation of ammonia). The suspension was filtered, the filter cake was washed with ACN, and then dried in a vacuum oven (approximately 50°C). The yield of compound I was 87%. NMR analysis of the isolated compound of formula I showed high purity, and very small amounts of by-products were also detected in the spectrum. NMR analysis of the residue derived from the filtrate revealed the presence of mainly the compound of formula I, with the compound of formula II present as a trace component.

[0147] Example 20 Compound of formula IV reacted with NH3 solution Example 19 was repeated in a different manner, with ammonia being introduced. The experimental apparatus was "sealed" with a balloon and kept at approximately 15°C. Ammonia gas was supplied to the apparatus headspace above the suspension of compound IV in ACN, maintaining a slight positive pressure. The suspension was stirred, and the progress of the reaction was monitored by NMR analysis. Interestingly, the level of compound IV relative to compound I was found to have decreased to approximately 1% after 30 minutes of stirring. The reaction was substantially complete.

[0148] Example 21 Compound of formula IV reacted with saturated NH3 solution 300 mL (10 parts relative to the compound of formula IV) of ACN was packed into a 500 mL RBF equipped with an overhead stirrer. Ammonia gas was gently aerated into the ACN for approximately 50 minutes under moderate stirring at 0–5°C and then stopped. The weight of the contents in the flask increased by approximately 18.55 g (approximately 8.5 equivalents relative to the compound of formula IV). The compound of formula IV (30 g) was added to the ammonia solution in one batch (in solid form). No change in batch temperature was observed. The apparatus setup was then "sealed" with a balloon (a slight positive pressure in headspace was confirmed). The reaction mixture was stirred at 0–5°C for 40 minutes. Aliquots of the reaction mixture were taken for IPC analysis (NMR) and it was shown that approximately 2% of the compound of formula IV remained (relative to the compound of formula I). ​​The reaction was considered complete. The reaction mixture was heated to 20–25°C under an NH3 atmosphere and stirred for 1 hour. The batch was filtered, the filtered cake was washed with ACN, and then dried overnight in a vacuum oven at approximately 50°C to obtain 22.72 g of compound I (yield approximately 97%). NMR analysis of the product revealed the presence of 2.19% (w / w) of compound II and 2.44% (w / w) of imidazole.

[0149] Example 22 Compound of formula IV reacted by direct aeration with ammonia A suspension of compound IV (15 g) was prepared in ACN (10 parts) and moderately stirred under nitrogen at 20-25°C for about 5 minutes. The nitrogen inlet was shut off and dry ammonia gas was gently aerated into the suspension (from the tank). A slight rise in batch temperature was observed, and the temperature of the reaction mixture was maintained at 20-25°C using a cold water bath. At the start of ammonia loading, ammonia consumption was very rapid, and negative pressure was generated in the apparatus setup. Ammonia aeration was stopped after 50 minutes, and a small sample of the reaction mixture was taken for NMR. Approximately 1.4% of compound IV (relative to compound I) was present. The reaction was considered complete. The reaction mixture was placed under an N2 atmosphere and stirred at 20-25°C for about 2 hours. The product was filtered, washed, and dried in a vacuum oven at about 50°C to obtain 10.7 g of compound I (yield 91%). Analysis of the isolated product by NMR revealed the presence of approximately 2.2% (w / w) of the compound of formula II.

[0150] Examples 23-27: Reproducibility of the reaction between the compound of formula IV and ammonia gas. TIFF2026524826000021.tif236168

[0151] Examples 28-37: Recrystallization of compound (1g) of formula I TIFF2026524826000022.tif237167

[0152] Example 38: Recrystallization of compound I (30 g) A suspension of crude compound I (30 g) in 95% EtOH (containing approximately 5% water v / v, 15 parts) was heated under reflux to produce a clear solution. The solution was cooled to approximately 65°C and then filtered. The apparatus was rinsed with 1 part of 95% EtOH. The combined filtrate and rinse solution were heated under reflux (to regenerate the solution), then gradually cooled to 0-5°C and stirred overnight. The crystallized compound of formula I was filtered, washed (with 4 parts of 95% EtOH), and dried in a vacuum oven at 40°C to obtain 25.3 g (yield 84.3%) of a grayish-white solid. NMR analysis showed that compound II was not present in the recrystallized material (approximately 1.5% mol / mol was present in the crude compound of formula I). ​​The combined filtrate and wash solution were evaporated to dryness to obtain 3.94 g of solid residue, which NMR indicated mainly contained compound I, compound II, and imidazole.

[0153] Examples 39A-B: Recrystallization of compound (50g) of formula I Crude compound I (50 g in each experiment) was dissolved under reflux in 95% EtOH (15 parts, containing approximately 5% water v / v, prepared by the chemist). The solution was cooled to 60-65°C and filtered. The apparatus was rinsed with 1 part of 95% EtOH. The rinse solution and filtrate were heated under reflux, then gradually cooled to 0-5°C and stirred overnight. The suspension was filtered, and the filtered cake was washed with 95% EtOH (4 parts, pre-cooled to 0-5°C). The isolated solid was 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 washing solution were combined, concentrated to dryness, and a solid residue was obtained, which was dried in a vacuum oven at 40°C. TIFF2026524826000023.tif41167

[0154] Example 40: Recrystallization of compound I (30 g) using approximately 6% v / v water. A suspension of crude compound I (30 g, mixture of two different lots) in 94% EtOH (containing approximately 6.3% w / v water, 7 parts) was heated under reflux to produce a solution. The solution was cooled to 65°C and filtered. The apparatus was rinsed with 0.5 parts of 94% EtOH. The combined rinse and filtrate were heated to 65-70°C to regenerate the solution, which was then gradually cooled to 0-5°C and stirred overnight. The suspension was filtered, and the filter cake was washed with 94% EtOH (4 parts, pre-cooled to 0-5°C). The isolated solid was dried in a vacuum oven at 40°C to obtain 25.6 g of I (yield 85%) as a grayish-white solid. The filtrate and washings were evaporated to dryness to obtain 3.97 g of solid residue. Note that NMR analysis was not performed due to equipment malfunction.

[0155] Examples 41A-B: Recrystallization of compound I (50g) using approximately 6% v / v water. The procedure described in Example 40 was repeated in two large-scale recrystallization experiments using 50 g of the crude compound of Formula I. TIFF2026524826000024.tif46167

[0156] Examples 42-47: Recrystallization of the compound of formula I at variable water content TIFF2026524826000025.tif88168

[0157] Examples 48A-B: The volume was reduced (to 9 parts), and recrystallization was performed using 95% EtOH (containing 5% v / v water). In both examples, the crude compound of formula I was readily dissolved in 8.5 parts of 95% EtOH under reflux, and clarification of the high-temperature solution obtained at 65–70°C proceeded smoothly without issue. The apparatus was then rinsed with 0.5 parts of solvent. The solution was gradually cooled to 0–5°C and stirred at 0–5°C before isolation by filtration. Details of the experiment are shown in the table below. As observed in previous experiments, the quality of the recrystallized compound of formula I was very high. Residual compounds of formula II and imidazole were not detected by NMR. However, the recovery rate (approximately 78%) was similar to that previously achieved using 94% EtOH. TIFF2026524826000026.tif41167

[0158] Example 50: The volume was reduced (to 6 parts), and recrystallization was performed using commercially available 95% EtOH (containing 5% v / v water). A suspension of compound I (10 g) in 9 parts solvent was heated under reflux to form a clear solution. The batch was concentrated by distillation under atmospheric pressure to a volume of approximately 6 parts (no solid precipitate was observed at this point). The concentrated solution was cooled to 0-5°C and stirred overnight. A concentrated suspension was obtained using some solid crust adhering to the side of the flask. The crust was scraped off with a spatula. The solid was filtered, washed with cold EtOH (97.5%), and subsequently dried in a vacuum oven at 45°C to obtain 8.48 g of compound I (yield 84.8%). Analysis (NMR) of the obtained compound I showed that compound II and imidazole were not present. However, the NMR spectrum indicated the possible presence of trace amounts of other by-products (far below the quantitative capability of NMR). After evaporation of the combined filtrate and washings and drying in a vacuum oven, 1.21 g of solid residue was obtained.

[0159] Example 51: Recrystallization with 6 parts of 95% EtOH (5g) 5 g of the compound of formula I was dissolved under reflux in 6 parts of 95% EtOH (sourced from Greenfield) (a clear solution was formed at approximately 74°C). The hot solution was gradually cooled to 20-25°C and then stirred overnight to form a concentrated suspension. A considerable 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 spatula, suspended in the filtrate, and then filtered. The total amount of the compound of formula I obtained was 4.26 g (85% yield).

[0160] Example 52 Recrystallization with 7 parts of 95% EtOH (5g) A second experiment was carried out in the same manner, using 5 g of the compound of formula I together with 7 parts of 95% EtOH. A concentrated suspension was formed with a considerable amount of solid crust adhering to the flask wall, as observed in the previous experiment. The solid crust was removed from the wall by beginning vigorous stirring, and the solid was then filtered and dried to obtain 4.19 g of the compound of formula I (yield 84%). Evaporation of the filtrate yielded 0.71 g of solid residue.

[0161] Examples 53-56: Recrystallization using an Easymax reactor and 9 parts 95% EtOH A series of recrystallizations were performed using an Easymax reactor and 9 parts of 95% EtOH. In this series, the cooling time from 75°C to 25°C was set to 2, 4, 5, and 6 hours. After reaching 25°C, the resulting suspension was further cooled to approximately 3°C and then stirred overnight before product isolation. In all three examples, the previously prepared crude compound of formula I was used. TIFF2026524826000027.tif86166 For product crusting.

[0162] Example 57 Recrystallization using an Easymax reactor and 9 parts 95% EtOH 97.5% EtOH was prepared by adding 2.5% w / v water to anhydrous EtOH. 5 g of compound I was dissolved in 97.5% EtOH (13 parts, water content 3.03% w / v) by heating to 75°C. Consistent with data from the solubility curve, a clear solution was formed at approximately 65°C (crystals formed at approximately 56°C when this hot solution was gradually cooled). This solution was heated under reflux, and the batch was concentrated by distillation under atmospheric pressure (under nitrogen) to a batch volume of approximately 7 parts. The batch was cooled at 20–25°C for 3 hours to form a concentrated suspension, which was stirred overnight at 20–25°C (a sample of the supernatant was taken, and the water content was measured to be 3.67% w / v by KFC). No product crusting was observed. The solid was filtered, washed with 2 × 2 parts of cold (0~5°C) 97.5% EtOH, and dried under vacuum at 20~25°C for 48 hours. The recovery rate of compound I was approximately 87% (4.34 g). NMR analysis of this substance showed that compound I was present in excellent quality, and compound II and imidazole were not detected in the spectrum. The filtrate was evaporated to dryness to obtain the residue, which was dried in a vacuum oven to obtain 0.55 g (approximately 11%) of yellow solid. NMR analysis of this solid revealed the presence of compound I and compound II, along with numerous by-products. The combined washing solution was evaporated to obtain 0.22 g (approximately 4.4%) of solid residue, which consisted of I and some by-products (NMR).

[0163] Examples 57-59: Recrystallization with 97.5% EtOH Examples 57-59 were prepared using the same procedure, but with different final batch volumes achieved by distillation (at atmospheric pressure). 97.5% EtOH was prepared by mixing the calculated amount of water (2.5% v / v) with anhydrous EtOH. TIFF2026524826000028.tif57167

[0164] Next, the water content of the resulting mixture was measured by KFC titration before use. It is noteworthy that for experiments 57 and 58, batches of the target concentration (7 and 6 parts relative to the compound of formula I, respectively) were mild suspensions at reflux temperature. On the other hand, in experiment 59 (with a batch volume of 9 parts), a clear solution was observed. Although the final batch volumes differed, the recovery of the compound of formula I was substantially identical for all three examples, which was good. NMR analysis of the products isolated from these three examples indicated the presence of the compound of formula I in good quality. Imidazole and the compound of formula II were not detected in their NMR spectra. However, it should be noted that (from the examination of the NMR spectra) trace amounts of by-products may be present, but the levels of these by-products were far below the quantitative capability of NMR.

[0165] Example 60 Recrystallization with 40 g of the compound of formula I The recrystallization procedure was repeated using a batch volume of approximately 9 parts via atmospheric distillation (under nitrogen). At this point, the batch was a clear solution (approximately 78°C). Heating was stopped and the batch was cooled. Crystallization was observed when the batch temperature reached approximately 75°C. The formed suspension was cooled to room temperature, then further cooled to 0-5°C, and stirred for 2 hours. The solid was filtered, washed with 4 parts of cold (pre-cooled to 0-5°C) 100% EtOH, and subsequently dried in a vacuum oven at 40°C for 3 hours to obtain 35.58 g of I (89% yield). Analysis of the obtained compound of formula I by NMR showed the absence of the compound of formula II and the imidazole. TIFF2026524826000029.tif31167

[0166] Example 61 Preparation of a 20 kg batch of compound I Step 1 157 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 mixed, heated, and stirred at 65-70°C under a nitrogen atmosphere. The temperature decreased to 40-45°C after about 1-2 hours. The reaction product was sampled and analyzed. After meeting the analytical requirements, the reaction product was cooled to 20-25°C over 1.5 hours. Next, the reaction product was cooled to 0-5°C and held for 2 hours with stirring. The product, compound of formula IV, was filtered, washed with 3 × 63 kg of ACN, and dried on the filter.

[0167] Step 2 263.1 kg of acetonitrile and 33.5 kg of the crude compound of formula IV were mixed and stirred under a nitrogen atmosphere at 15-20°C for approximately 15 minutes. Ammonia was added directly as a gas over 3 hours while stirring the reactants and maintaining the temperature at 15-20°C. 7.4 kg of ammonia was added to the reactants. After the addition of ammonia, the reaction temperature was adjusted to 20-25°C and held for 1 hour. The solution was analyzed by NMR to confirm that no additional ammonia was needed. Once the reaction passed the analytical requirements, the crude product, the compound of formula I, was filtered, washed twice with 52.6 kg of ACN per wash, dried on the filter, and confirmed by analytical testing.

[0168] Step 3 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 mixed and stirred in a reactor. The mixture was heated to 75°C and held until the compound of formula I was completely dissolved (approximately 1 to 1.5 hours). The temperature was then reduced to 70°C. The material was then filtered at 70°C and washed with 8 kg of 97.5% EtOH / water. After filtration, the temperature was adjusted to 79°C and the excess solvent was distilled off. Under reduced pressure, the temperature was adjusted to 20-25°C for 2 hours. The solution was then stirred at 20-25°C for 2 hours. The solution was then cooled to 0-5°C for 2 hours. It was then held at 0-5°C for 3 hours. Finally, the solid was filtered under nitrogen at 0-5°C, washed twice with 31.4 kg of EtOH, and dried on the filter.

Claims

1. Compound of formula I: or a method for preparing a pharmaceutically acceptable salt thereof, To produce the compound of formula IV, or a salt thereof, the compound of formula II is reacted with the compound of formula III in a solvent. (In the formula, R １ and R ２ (Each of these is an independent leaving group.) Methods that include...

2. To obtain the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound of formula IV, or a salt thereof, is reacted with ammonia. The method according to claim 1.

3. The method according to claim 1 or 2, wherein the solvent is an organic solvent.

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

5. R １ However, it is -O-(4-nitrophenyl) or imidazoline, R ２ The method according to any one of claims 1 to 4, wherein the other is -Cl or imidazoline.

6. The method according to any one of claims 1 to 5, wherein 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.

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

8. The method according to 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 while gaseous ammonia is added.

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

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

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

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

13. Compound of formula IV having the following structure: (In the formula, R １ (is a leaving group), or its tautomers, salts, or solvates.

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

15. The compound according to claim 13, which is a chloride salt.

16. 2-(trimethyl-λ) ４ The compound according to any one of claims 13 to 15, wherein the compound is (-azanail) ethyl 1H-imidazole-1-carboxylate chloride.

17. A compound of formula I prepared by the method of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing the above.

18. The composition is i) Equation IV; ii) Formula V ； iii) Formula VI ； iv) Leaving group; and The pharmaceutically acceptable salt The pharmaceutical composition according to claim 17, further comprising at least one additional compound selected from the group consisting of the following.

19. The pharmaceutical composition according to 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, the leaving group, or a pharmaceutically acceptable salt thereof.

Images