Processes and intermediates for large-scale preparation of compounds hemisuccinates and acetates

Abstract

Embodiments of the present invention provide methods and intermediates for the large scale preparation of 2, 4, 6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl] benzamide hemisuccinate, as well as formulations and product forms prepared by these methods. Embodiments of the present invention further provide for the preparation of lamidetan acetate (2, 4, 6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl] benzamide acetate) and / or a pharmaceutical composition thereof, and / or the use of lamidetan acetate and formulations thereof in subcutaneous drug delivery.

Description

[0001] This application is a divisional application. The application number of the original application is 202080049829.4, the application date is July 6, 2020, the priority date is July 9, 2019, and the name of the invention is "Methods and intermediates for large-scale preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate and preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate".

[0002] Embodiments of the present invention relate to the fields of medicinal chemistry and synthetic organic chemistry, and provide methods and intermediates for the large-scale synthesis of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate (5-HT1F receptor agonist), as well as preparations and product forms prepared by these methods, and relate to the preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate and its use in parenteral preparations and for the treatment of migraine.

[0003] Lasmiditan is a selective and highly potent 5-HT 1F A 50 mg or 100 mg acetaminophen agonist, now approved in the United States as a 50 mg or 100 mg tablet for the emergency, on-demand treatment of migraine (see, e.g., Rubio-Beltrán et al., Pharmacol Ther 2018; 186: 88-97, and Lasmiditan for the Treatment of Migraine, Capi, M et al., Expert Opinion Investigational Drugs, (2017), Vol. 26, No. 2, 227-234). Lasmiditan (COL 144, LY 573144, CAS Reg. No. 439239-90-4) can be chemically described as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide. U.S. Patent No. 7,423,050 and U.S. Publication No. 20080300407 describe the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide having the following structural formula:

[0004]

[0005] Methods for preparing lasmiditan and salts thereof, certain polymorphic forms, formulations and dosage forms are known to those skilled in the art and are described, for example, in WO 2003 / 084949, WO 2011 / 123654 and WO 2018 / 106657.

[0006] As used herein, useful forms of lasmiditan include pharmaceutically acceptable salts thereof, including, but not limited to, 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide monohydrochloride and 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. A synthetic route for preparing the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide has been previously disclosed as shown in Scheme A below. Starting from commercially available piperidine 4-carboxylic acid, the overall yield of lasmiditan over all nine steps is approximately 10-46% via the route described in Scheme A below. Improving the synthesis of lasmiditan could provide numerous and diverse benefits, particularly for large-scale production.

[0007] Process A

[0008]

[0009] Synthetic chemistry process routes can be redesigned or modified with the goal of achieving various advantages, including, for example, improving yield, obtaining a crystalline product, reducing the impurity profile, utilizing commercially available intermediates, minimizing the number of synthetic steps required, reducing the amount of input required and / or the amount of by-products produced, or any useful combination of these improvements, to achieve important practical results, including reducing costs, providing a less resource-intensive process, and facilitating efficient production. There is a need for improved methods for preparing lasmiditan that can achieve one or more of these objectives, particularly for large-scale synthesis.

[0010] In addition, migraine is one of the most common presenting symptoms in emergency rooms. When lasmiditan is used for patients who are difficult to administer tablets due to nausea and / or vomiting, the current method for alleviating headaches in emergency room settings may need to rely on preparing a diluted formulation of about 1 mg / ml lasmiditan, which is delivered intravenously over an extended period of time, for example, within about 20-60 minutes. In clinical studies, lasmiditan was delivered intravenously at a dose of about 1-60 mg, which was delivered as a 60 ml infusion within 20 minutes (see U.S. Patent Application Publication No. 2010 / 0256187). For patients who cannot administer tablets, the safe and effective treatment of migraine with lasmiditan will become possible through the availability of high-concentration parenteral dosage forms. The present disclosure also addresses this need. SUMMARY OF THE INVENTION

[0011] Embodiments of the present invention provide methods for preparing lasmiditan hemisuccinate (2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate) and / or compositions thereof, and / or particularly useful intermediates for these methods. Embodiments of the present invention further provide the preparation of lasmiditan acetate (2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate) and / or compositions thereof, and / or the use of lasmiditan acetate and its formulations in subcutaneous drug delivery.

[0012] In one embodiment, the present invention provides a method for preparing the compound of the following formula, referred to as Route 1:

[0013]

[0014] The following steps are involved:

[0015] i.) treating piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water, followed by treatment with aqueous HCl, followed by water distillation and addition of acetonitrile, and repeating the dilution / distillation until the water content does not exceed 0.2% by Karl-Fischer analysis to provide solid 1-methylpiperidine-4-carboxylic acid hydrochloride;

[0016] ii.) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to give 1-methylpiperidine-4-carbonyl chloride;

[0017] iii.) treating 1-methylpiperidine-4-carbonyl chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by alkaline washing, and then treating with aqueous HCl in isopropanol to give solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride;

[0018] iv.) treating N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrochloride hydrate with an inorganic base such as aqueous NaOH in a nonpolar solvent such as methyl tert-butyl ether, followed by water washing, phase separation, and distillation of the organic solvent until the water content, as determined by Karl Fischer analysis, does not exceed 0.1% by weight to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide;

[0019] v.) subsequently treating N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a nonpolar organic solvent such as methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and repeated distillation of the organic solvent until the water content does not exceed 0.2% by weight as determined by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone;

[0020] vi.) treating (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr solution, followed by extraction with n-butanol, and then repeatedly distilling the organic solvent until the water content does not exceed 0.3% by Karl-Fischer analysis to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide;

[0021] vii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidinyl)methanone hydrobromide with a solution of NH in ethylene glycol in the presence of a CuO catalyst at about 80° C. for about 2 hours, followed by washing with water, saturated aqueous NaCl, and 20% aqueous NaOH, followed by extraction with a nonpolar aprotic solvent such as methyl tert-butyl ether, phase separation, and treating the organic phase with 5 wt% carbon;

[0022] viii.) filtering the mixture, diluting it with a suitable polar alcoholic solvent, such as isopropyl alcohol, repeatedly distilling the organic solvent until the water content by Karl-Fischer analysis is no more than 0.2%, then treating the resulting residue with isopropyl alcohol, water, and 20 wt % HCl to obtain a slurry having a water concentration of at least 2%, filtering the resulting slurry, and drying it under vacuum at 40° C. for 16-24 hours to obtain (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride as a solid;

[0023] ix.) treating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6% w / w aqueous NaOH at about 54° C. for about 30 minutes, followed by phase separation and vacuum distillation of the aqueous solution to provide (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone;

[0024] x.) (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone is then treated with 2,4,6-trifluorobenzoyl chloride in chlorobenzene at about 100° C. for about 4 hours, followed by cooling, addition of acetonitrile and heating the resulting slurry to 80° C. for about 1 hour, followed by collection of the resulting solid by filtration to provide solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hydrochloride;

[0025] xi.) treating 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride in methyl tert-butyl ether with saturated aqueous Na2CO3 solution;

[0026] xii.) treating the mixture from step xi above with SiO2, followed by filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation until the water content does not exceed 1% by Karl-Fischer analysis to provide 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

[0027] xiii.) 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in ethanol is treated with 0.5 equivalents of succinic acid in ethanol at about 55°C for not less than 3 hours at room temperature, followed by collection of the solid by filtration to give solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

[0028] In the above-mentioned process of route 1, it is preferred to use a batch process to carry out the reaction. In one embodiment, the batch of route 1 is produced at a process scale. In one embodiment, the batch of route 1 is produced at least 1 kilogram. In one embodiment, the batch of route 1 is produced at least 10 kilograms. In one embodiment, the batch of route 1 is produced at least 100 kilograms.

[0029] In the process of Route I above, the use of chlorobenzene avoids the degradation that occurs in other processes, such as THF, which reacts with the acid chloride on a large scale (e.g., 100 kg), resulting in essentially no production of the acid chloride.

[0030] In another embodiment, the present invention provides a method for preparing the compound of the following formula, referred to as Route II:

[0031]

[0032] The following steps are involved:

[0033] i.) treating piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water, followed by treatment with aqueous HCl, followed by water distillation and addition of acetonitrile, and repeating the dilution / distillation until the water content does not exceed 0.2% by Karl-Fischer analysis to provide solid 1-methylpiperidine-4-carboxylic acid hydrochloride;

[0034] ii.) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to give 1-methylpiperidine-4-carbonyl chloride;

[0035] iii.) treating 1-methylpiperidine-4-carbonyl chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by alkaline washing, and then treating with aqueous HCl in isopropanol to give solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride;

[0036] iv.) treating N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrochloride hydrate with an inorganic base such as aqueous NaOH in a nonpolar solvent such as methyl tert-butyl ether, followed by water washing, phase separation, and distillation of the organic solvent until the water content, as determined by Karl Fischer analysis, does not exceed 0.1% by weight to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide;

[0037] v.) subsequently treating N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a nonpolar organic solvent such as methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and repeated distillation of the organic solvent until the water content does not exceed 0.2% by weight as determined by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone;

[0038] vi.) treating (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr solution, followed by extraction with n-butanol, and then repeatedly distilling the organic solvent until the water content does not exceed 0.3% by Karl-Fischer analysis to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide;

[0039] vii.) treating (6-bromo-2-pyridinyl-1-methyl-4-piperidinyl)methanone hydrobromide with solid KOH in a two-phase mixture of water and toluene for about 3 hours, followed by separation of the organic layer and evaporation of the solvent to provide (6-bromo-2-pyridinyl-1-methyl-4-piperidinyl)methanone;

[0040] viii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing KCO, water, Pd(OAc), and Xantphos at about 70° C. for about 12 hours until the (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone content is no more than 0.1% as determined by HPLC, followed by dilution of the reaction mixture with water and EtOAc and subsequent treatment with thiourea-modified silica gel at 60° C. for about 8 hours followed by filtration to provide a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

[0041] ix.) A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in EtOAc was treated with about 0.5 equivalents of succinic acid in EtOH at 55° C. for about 3 hours, followed by cooling to room temperature over about 10 hours and collecting the resulting solid by filtration to provide solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

[0042] In the method of above-mentioned route II, it is preferred to use batch process method to carry out reaction.In one embodiment, the batch of route II is produced at process scale.In one embodiment, the batch of route II is produced at least 1 kilogram.In one embodiment, the batch of route II is produced at least 10 kilograms.In one embodiment, the batch of route II is produced at least 100 kilograms.

[0043] In the process of Route II above, the use of chlorobenzene avoids the degradation that occurs in other processes, such as THF, which reacts with the acid chloride on a large scale (e.g., 100 kg), resulting in essentially no production of the acid chloride.

[0044] In another embodiment, the present invention provides:

[0045]

[0046] It can be named (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride. Preferably, the compound is crystalline. (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride is particularly suitable for preparing 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and methods using (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride can provide advantageous process characteristics, including but not limited to the purity of the intermediate and / or final material. (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride is believed to be a new stable hydrated form of 6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone. The method for isolating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride described herein provides improved impurity removal and an improved controlled crystallization method. Various morphological and chemical stability studies indicate that (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride is generally stable, and various drying studies indicate that overdrying to remove the water of hydration is difficult, even under intensive conditions. Use of this intermediate advantageously provides a high-purity product in the desired yield.

[0047] In another embodiment, the present disclosure provides lasmiditan acetate, which can be represented by the following formula:

[0048]

[0049] In another embodiment, the present invention provides a crystalline form of lasmiditan acetate, and further provides a crystalline form of lasmiditan acetate characterized by an X-ray powder diffraction pattern using CuKα irradiation, wherein the X-ray powder diffraction pattern has a strong peak at a diffraction angle 2θ of 26.2° and one or more peaks selected from 20.4°, 14.0°, and 17.9° (±0.2°, respectively). In another embodiment, the present invention provides a pharmaceutical composition comprising lasmiditan acetate according to the above embodiment and one or more pharmaceutically acceptable carriers, diluents, or excipients. Preferably, the pharmaceutical composition comprises acetic acid. Preferably, the pharmaceutical composition comprises acetic acid and is for subcutaneous administration.

[0050] In another embodiment, the present invention provides a method of treating a migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of lasmiditan acetate. In another embodiment, the present invention provides a method of treating a migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of lasmiditan acetate in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients. In another embodiment, the present invention provides a method of treating a migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of lasmiditan acetate in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients, wherein the composition comprises acetic acid.

[0051] In another embodiment, the present invention provides lasmiditan acetate for use in therapy. In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate and one or more pharmaceutically acceptable carriers, diluents, or excipients for use in therapy. In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate and one or more pharmaceutically acceptable carriers, diluents, or excipients for use in therapy, wherein the composition comprises acetic acid.

[0052] In another embodiment, the present invention provides lasmiditan acetate for use in treating migraine. In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate for use in treating migraine and one or more pharmaceutically acceptable carriers, diluents, or excipients. In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate for use in treating migraine and one or more pharmaceutically acceptable carriers, diluents, or excipients, wherein the composition comprises acetic acid.

[0053] In another embodiment, the present disclosure provides lasmiditan acetate, and pharmaceutical compositions comprising high concentrations of lasmiditan acetate (e.g., about 10-200 mg / ml free-base equivalent) in an aqueous carrier. In embodiments, the pharmaceutical composition comprises about 10-200 mg / ml free-base equivalent of lasmiditan in a buffered aqueous solution. In embodiments, the buffered aqueous solution has a pH of 6.0-7.5 at 37° C. In embodiments, the buffered aqueous solution comprises acetic acid.

[0054] In addition to an aqueous carrier (preferably sterile deionized distilled water), the pharmaceutical compositions described herein may also contain one or more pharmaceutically acceptable excipients or cosolvents. The term "pharmaceutically acceptable" refers to excipients and cosolvents that are suitable for use in contact with human tissue without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Pharmaceutical compositions and methods for their preparation are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy (A. Gennaro et al., eds., 21st ed., Mack Publishing Co., 2005)).

[0055] The pharmaceutical composition of lasmiditan acetate can be provided in bulk or in dosage unit form. It is particularly advantageous to formulate the pharmaceutical composition of lasmiditan acetate in unit dosage form for ease of administration and consistency of dosage. As used herein, the term "dosage unit form" refers to a physically discrete unit suitable as a unit dosage for an individual to be treated; each unit contains a predetermined amount of the active compound lasmiditan calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. The dosage unit form can be, for example, an ampoule, a vial, or a syringe.

[0056] In an embodiment, the present disclosure provides a pharmaceutical composition comprising an amount of lasmiditan acetate as described herein, wherein the amount is 10 mg to 200 mg per dose. In an embodiment, the present disclosure provides a pharmaceutical composition comprising an amount of lasmiditan acetate as described herein, wherein the amount is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg or 200 mg per dose. The above dosages are based on an adult of average weight. For individuals with lighter weight, such as the elderly or children, smaller doses are acceptable. Therefore, in an embodiment, the pharmaceutical composition may comprise a smaller dose, such as 5, 10 or 15 mg.

[0057] As described herein, the high concentration aqueous solution of lasmiditan acetate enables administration of a single therapeutically effective dose by injection of the high concentration aqueous solution of lasmiditan (eg, by intravenous, subcutaneous, or intramuscular routes).

[0058] In embodiments, the present disclosure provides a high-concentration aqueous solution of lasmiditan acetate. In embodiments, the high-concentration aqueous solution of lasmiditan acetate is formulated as a parenteral dosage form. In embodiments, the high-concentration aqueous solution contains 10-200 mg / ml of lasmiditan in free base equivalents. In embodiments, the high-concentration aqueous solution of lasmiditan acetate is in the form of a parenteral dosage form. In embodiments, the parenteral dosage form is a buffered aqueous solution of 10-200 mg / ml of lasmiditan in free base equivalents. In embodiments, the parenteral dosage form is a buffered aqueous solution of 10, 20, 30, 40, 50, 100, or 200 mg / ml of lasmiditan in free base equivalents. In embodiments, the parenteral dosage form is suitable for subcutaneous or intramuscular injection. Preferably, the parenteral dosage form is for subcutaneous injection. In embodiments, the pH of the buffered solution is between pH 6.0 and 7.5 at 37°C.

[0059] In embodiments, the buffered aqueous solution comprises an organic acid-based buffer system. In embodiments, the organic acid is a dicarboxylic acid or a tricarboxylic acid. In embodiments, the dicarboxylic acid or tricarboxylic acid is selected from acetic acid and citric acid. In embodiments, the organic acid is succinic acid. In embodiments, the buffer is an acetic acid buffer. In embodiments, the buffered aqueous solution is free of an organic solvent. In embodiments, the buffered aqueous solution is free of an organic solvent and a surfactant. In preferred embodiments, the buffered aqueous solution comprises lasmiditan acetate, acetic acid, and sodium hydroxide, and the pH is adjusted to 6.0-7.5 at 37°C.

[0060] In an embodiment, the parenteral dosage form of lasmiditan acetate is provided in the form of a prefilled syringe suitable for administration by subcutaneous route. In an embodiment, the prefilled syringe contains 10-50 mg / ml free base equivalents of lasmiditan. In an embodiment, the prefilled syringe contains 10, 20, 30, 40, 50 or 100 mg / ml free base equivalents of lasmiditan. In an embodiment, lasmiditan is provided in a buffered aqueous solution having a pH of 6.0-7.5 at 37°C. In an embodiment, the prefilled syringe is suitable for home use, for example, for those migraine patients who may face extreme and rapid onset of headaches. In an embodiment, the prefilled syringe is contained in a package with instructions for parenteral administration, preferably subcutaneous administration. In an embodiment, the prefilled syringe is in the form of an automatic syringe with instructions for subcutaneous injection.

[0061] In an embodiment, the parenteral dosage form of lasmiditan acetate is provided in a vial containing 10-50 mg / ml of free base equivalents of lasmiditan. In an embodiment, the parenteral dosage form of lasmiditan acetate is provided in a vial containing 10, 20, 30, 40, 50 or 100 mg / ml of free base equivalents of lasmiditan. In an embodiment, lasmiditan is provided in a buffered aqueous solution having a pH of 6.0-7.5 at 37°C.

[0062] The present disclosure also provides a method for the acute treatment of a migraine attack, the method comprising administering a therapeutically effective dose of lasmiditan acetate as described herein. In embodiments, the parenteral solution is administered by subcutaneous injection. In embodiments, the parenteral solution comprises 10-50 mg / ml free base equivalents of lasmiditan acetate in a buffered aqueous solution having a pH of 6.0-7.5 at 37°C. In embodiments, the parenteral solution comprises 10, 20, 30, 40, 50 or 100 mg / ml free base equivalents of lasmiditan. In embodiments, the method comprises administering a single therapeutically effective dose of less than or equal to 1 ml, such as about 0.5 to 1 ml volume of lasmiditan acetate, for example, by a single subcutaneous injection. In embodiments, the injection volume is about 1 ml. In embodiments, the injection volume is about 0.5 ml.

[0063] The present invention provides a method for treating migraine in a patient in need thereof, the method comprising administering to the patient 20-200 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier. The present invention provides a method for treating migraine in a patient in need thereof, the method comprising administering to the patient 20 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier. The present invention provides a method for treating migraine in a patient in need thereof, the method comprising administering to the patient 50 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier. The present invention provides a method for treating migraine in a patient in need thereof, the method comprising administering to the patient 75 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier. The present invention provides a method for treating migraine in a patient in need thereof, comprising administering to the patient 100 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier. The present invention provides a method for treating migraine in a patient in need thereof, the method comprising administering to the patient 150 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier. The present invention provides a method for treating migraine in a patient in need thereof, the method comprising administering to the patient 200 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier.

[0064] In some embodiments, a "patient" is a person who has been diagnosed with a condition or disorder that is in need of prevention using a pharmaceutical composition described herein. In some embodiments, a patient is a person who is characterized as being at risk for a condition or disorder for which administration of a pharmaceutical composition described herein is indicated. In the case of disorders that are known to be treatable by the methods of the present invention through established and accepted classifications, such as migraine, episodic headaches, chronic headaches, chronic cluster headaches, and / or episodic cluster headaches, their classifications can be found in a variety of sources. For example, currently, the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, DC) provides diagnostic tools for identifying many of the disorders described herein. In addition, the International Classification of Diseases, Tenth Revision (ICD-10) provides classifications for many of the disorders described herein. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-IV and ICD-10, and that terminology and classification systems evolve as medical science advances. Migraine patients can be further diagnosed as having migraines with aura (1.1 and 1.2) as defined in the International Headache Society (IHS) International Classification of Headache Disorders, Third Edition, (ICHD-3) beta version (The International Classification of Headache Disorders, Third Edition (beta version), Cephalalgia 2013; 33: 629-808). In some embodiments, the human patient has been diagnosed with episodic migraines prior to receiving long-term administration (preferably nighttime) of lasmiditan for migraine prophylaxis. In some embodiments, the human patient has been diagnosed with chronic migraines prior to receiving the antibody. In some embodiments, the human patient's migraine headaches are preceded by aura. In some embodiments, the human patient's migraine headaches are not preceded by aura.

[0065] As used herein, "migraine" includes, but is not limited to, a migraine attack. As used herein, "migraine attack" refers to the following description. Symptoms may overlap during the various stages of a migraine attack, and not all patients experience the same clinical presentation. During the prodromal phase, most patients experience pre-monitoring symptoms, which may precede the headache phase by up to 72 hours. These include changes in mood and activity, irritability, fatigue, food urges, repetitive yawning, neck stiffness, and high-pitched fear. These symptoms may persist well into the aura, headache, and even post-headache phases. Some patients experience a prodromal phase, with approximately one-third experiencing transient neurological deficits during the attack. The ICHD-3 defines an aura as one or more transient, fully reversible neurological deficits, at least one of which must be unilaterally localized, occurring over a period of 5 minutes or longer, and each deficit lasting 5 to 60 minutes. A visual aura is present in over 90% of cases at this time, which may manifest as positive (flash scotomas), negative (scotomas), or both, with sensory, motor, speech, brainstem, and retinal aura symptoms also present, most commonly with deficits. Transient waves of depolarization of cortical neurons are believed to be the pathophysiological brain mechanism behind the clinical phenomenon of migraine aura. During the headache phase, the headache attack may last from 4 to 72 hours and is accompanied by nausea, photophobia, fear of loud sounds, or both. The headache is characterized by being unilateral, pulsating, moderate or severe, and exacerbated by physical activity; two of these characteristics are sufficient to meet the diagnostic criteria. During the post-headache phase, characteristic symptoms mirror those observed in the pre-monitoring phase. Typical post-headache symptoms include tiredness, difficulty concentrating, and neck stiffness. It is unclear whether these symptoms begin in the pre-monitoring phase and continue throughout the headache phase and into the post-headache phase, or whether they may also begin during the headache phase, or even appear after the headache phase has ended.

[0066] As used herein, a "migraine headache" is a headache lasting ≥30 minutes with or without aura that has the following two required features (A and B): A) at least two of the following headache characteristics: 1) unilateral location, 2) pulsating quality, 3) moderate or severe pain intensity, and 4) aggravated by or causing avoidance of daily physical activities; and B) during the headache, at least one of the following conditions is present: a) nausea and / or vomiting, and / or b) photophobia and phobia of loud sounds. As used herein, a "possible migraine headache" is a headache lasting greater than 30 minutes with or without aura, but lacks one of the migraine features in the International Headache Society ICHD-3 definition.

[0067] The term "effective amount" or "therapeutically effective amount" refers to the amount or dosage of lasmiditan acetate in a pharmaceutical composition, such as the total dose administered during administration, which, when administered to a patient in a single dose or multiple doses, provides the patient with the desired pharmacological effect, such as the ability to activate 5-HT 1F In a preferred embodiment, an "effective amount" refers to an amount of lasmiditan acetate that, upon acute administration, renders the patient free of migraine attacks following administration. A "dose" refers to a predetermined amount of lasmiditan acetate calculated to produce the desired therapeutic effect in the patient. As used herein, "mg" refers to milligrams. As used herein, a dose expressed in mg refers to the free base mass equivalent of the active pharmaceutical ingredient lasmiditan, e.g., a "100 mg" dose refers to 100 mg of the active pharmaceutical ingredient lasmiditan as a free base equivalent. As used herein, a given dose can be interpreted as describing a dose of approximately the amount shown, i.e., a dose that is up to ten percent higher or lower than the dose shown should also be understood to provide a useful regimen in a manner similar to the dose shown. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 :Lasmiditan acetate containing maleic acid (internal standard) 1 Graphic representation of H NMR spectrum (400 MHz, DMSO-d6). Detailed Description of the Invention

[0069] The reactions described herein can be carried out by standard techniques known to those skilled in the art using conventional glassware, or can be carried out on a pilot scale and / or process scale in equipment designed for such transformations. In addition, each of the reactions described can be performed by a batch process or, where applicable, by a flow reaction process. The term "batch process" as used herein refers to a process in which the raw materials are combined in a reactor or vessel and the product is removed at the end of the reaction.

[0070] In addition, some intermediates described in the following preparations may contain one or more nitrogen protecting groups. The variable protecting groups may be the same or different at each occurrence, depending on the specific reaction conditions and the specific transformation to be performed. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis", 4th edition, Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0071] When used in this document, the following abbreviations are defined as follows: =Angstrom. “ACN” means acetonitrile. “AcOH” means acetic acid. “Bn” means benzyl; “nBuLi” means n-butyllithium. “CAS No.” means Chemical Abstracts Service registration number. “DCM” means dichloromethane. “DMF” means N,N-dimethylformamide. “DIPEA” means diisopropylethylamine. “DMSO” means dimethyl sulfoxide (perdeuterated [d6] if used for NMR). “EtOAc” means ethyl acetate. “EtOH” means ethanol. “HBTU” means (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. “HPLC” means high performance liquid chromatography. “HTRF” means homogeneous time-resolved fluorescence. “hr” or “h” means hour. “IPA” means isopropyl alcohol. “IPC” means in-process control. control). “LAH” means lithium aluminum hydride. “LCMS” means liquid chromatography mass spectrometry. “LDA” means lithium diisopropylamide. “Me” as a substituent in a structural representation of a compound means methyl. “MeOH” means methanol. “min” means minute. “MS” means mass spectrometry or mass spectrum. “MTBE” means methyl tert-butyl ether. “NMR” means nuclear magnetic resonance. “NMT” means not more than. “OAc” means acetate. “psig” means pounds per square inch gauge. “PyBOP” means (benzotriazol-1-yl-oxytripyrrolidin-1-ylphosphonium hexafluorophosphate). “RT” means room temperature / ambient temperature. “sec” as a time unit means seconds. “TBS-Cl” means tert-butyldimethylchlorosilane. “TEA” means triethylamine. “THF” means tetrahydrofuran. “tR” means retention time. “w / w” means weight to weight ratio.

[0072] Improved routes for preparing lasmiditan are provided below, as Schemes I and / or II, as well as other additional methods provided below.

[0073] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic and organic salts or salts of the compounds of the present invention. Those skilled in the art will appreciate that the compounds of the present invention are capable of forming salts. Some of the compounds of the present invention contain basic heterocycles and, therefore, react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and conventional methods for preparing them are well known in the art. See, for example, P. Stahl et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2008); S.M. Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0074] "Process-scale" synthesis refers to the preparation of 500 mg to 1000 kg or more of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. Preferably, the "process-scale" synthesis is carried out under good manufacturing process (GMP) or similar conditions required for the commercial production of pharmaceutical products for human consumption. Preferably, "process-scale" in the methods of Routes I and / or II above refers to batches produced in quantities of at least 1 kg, and / or batches produced in quantities of at least 10 kg, and / or batches produced in quantities of at least 100 kg.

[0075] general chemistry

[0076] Process 1

[0077]

[0078] Scheme 1 describes a process-scale synthesis of lasmiditan hemisuccinate compound I. N-methylation of commercially available piperidine 4-carboxylic acid 1 can be accomplished under various reducing conditions identifiable to one skilled in the art. Specifically, treatment of the secondary amine with approximately 1.3 equivalents of formaldehyde in excess formic acid affords N-methylpiperidine 2. Formation of diethylamide 3 can be accomplished using conventional amide coupling reagents such as benzotriazole, HBTU, or PyBOP, or by converting the carboxylic acid to an acid chloride using reagents well known in the art such as oxalyl chloride or thionyl chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 can be converted to an acid chloride by treatment with approximately 1.2 equivalents of thionyl chloride at approximately 50°C for 1 hour, at which point the reaction mixture can be cooled to approximately 0°C and 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine added. The free base is stirred with HCl to afford the diethylamide hydrochloride hydrate 3. One skilled in the art will recognize that pyridyl ketone 4 can be obtained by treating diethylamide 3 with lithiated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium can be formed by treating 2,6-dibromopyridine with n-BuLi at about -58°C. Separately, piperidine-4-diethylamide hydrochloride hydrate 3 can be treated with about 2 equivalents of NaOH, and the resulting free base is added to the lithiate at about -58°C. The resulting mixture can be treated with HBr to form pyridyl bromide hydrobromide 4. Amination of pyridyl bromide hydrobromide 4 can be achieved using transition metal catalysis well known to those skilled in the art. More specifically, to pyridyl bromide 4 are added about 0.075 equivalents of Cu2O, about 28 equivalents of NH3 in ethylene glycol, and stirred to about 80°C. The reaction is cooled to room temperature, quenched with H2O, washed with 20% aqueous NaOH, and slurried with 20% HCl in IPA and a small amount of H2O to provide aminopyridine dihydrate dihydrochloride 5 as a crystalline solid. Pyridylbenzamide hydrochloride 6 can be prepared by treating the free base of aminopyridine 5 with the acid chloride 5a. More specifically, aminopyridine dihydrate dihydrochloride 5 can be treated with 6% aqueous NaOH to provide the free base. Alternatively, 2,4,6-trifluorobenzoic acid can be treated with thionyl chloride and the above-described free base 5 at about 100°C to provide pyridylbenzamide hydrochloride 6. The hemisuccinate I can be prepared by treating the hydrochloride 6 with about 2 equivalents of NaHCO3 followed by about 0.55 equivalents of succinic acid to provide lasmiditan hemisuccinate compound I.

[0079] Process 2

[0080]

[0081] Scheme 2 describes the synthesis of (6-amino-2-pyridinyl)-(1-methyl-4-piperidinyl)methanone dihydrate hydrochloride 5. Amination of pyridinyl bromide hydrobromide 4 can be achieved as described in Scheme 1 using transition metal catalysis well known to those skilled in the art. More specifically, about 0.075 equivalents of CuO, about 28 equivalents of NH in ethylene glycol are added to pyridinyl bromide 4 and stirred at about 80° C. The reaction is cooled to room temperature, quenched with H O, washed with 20% aqueous NaOH, and slurried with 20% HCl in IPA and a small amount of H O to provide aminopyridine dihydrate hydrochloride 5.

[0082] Process 3

[0083]

[0084] Scheme 3 illustrates an improved method for the synthesis of lasmiditan hemisuccinate I. N-methylation of commercially available piperidine 4-carboxylic acid 1 can be accomplished under various reducing conditions identifiable to one skilled in the art. Specifically, treatment of the secondary amine with approximately 1.3 equivalents of formaldehyde in excess formic acid affords N-methylpiperidine 2. Formation of diethylamide 3 can be accomplished using conventional amide coupling reagents such as benzotriazole, HBTU, or PyBOP, or by converting the carboxylic acid to an acid chloride using reagents well known in the art such as oxalyl chloride or thionyl chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 can be converted to an acid chloride by treatment with approximately 1.2 equivalents of thionyl chloride at approximately 50°C for 1 hour, at which point the reaction mixture can be cooled to approximately 0°C and 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine added. The free base is stirred with HCl to afford the diethylamide hydrochloride hydrate 3. One skilled in the art will recognize that pyridyl ketone 4 can be obtained by treating diethylamide 3 with lithiated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium can be formed by treating 2,6-dibromopyridine with n-BuLi at about -58°C. Separately, piperidine-4-diethylamide hydrochloride hydrate 3 can be treated with about 2 equivalents of NaOH, and the resulting free base is added to the lithiate at about -58°C. The resulting mixture can be treated with HBr to form pyridyl bromide hydrobromide 4. Amination of pyridyl bromide hydrobromide 4 to afford amide 6 can be achieved using transition metal catalysis well known to those skilled in the art. Specifically, as is well known in the literature, pyridyl ketone 4 can be converted to its corresponding free base form with a suitable inorganic base and subjected to Buchwald-type coupling conditions. More specifically, the free base of compound 4 can be stirred in a suitable aprotic solvent such as toluene or xylene, containing about 1-5% by weight of water, about 1.1 equivalents of commercially available 2,4,6-trifluorobenzamide (CAS# 82019-50-9), about 1.5 equivalents of potassium carbonate, about 0.005 to about 0.015 equivalents of a suitable palladium catalyst, such as palladium (II) acetate, and about 0.01 to 0.02 equivalents of a suitable phosphine ligand compound such as Xaphos, XPhos or DPEpHos. The resulting mixture can be heated at about 70°C for about 12-24 hours. The reaction mixture can be diluted with a suitable mixture of water and an organic solvent such as DCM or EtOAc, and the organic layer can be treated with a suitable palladium scavenger such as thiourea-modified silica gel at about room temperature to about 65°C for about 8-24 hours. The resulting mixture can be cooled, filtered, treated with activated carbon, filtered, and concentrated under reduced pressure. The resulting residue can be dissolved in a suitable alcoholic solvent, such as ethanol, and slowly treated with a solution of about 0.5 equivalents of succinic acid dissolved in ethanol at about 55° C. The resulting mixture can be cooled to room temperature over about 10 hours, and the resulting slurry can be slurry-milled by treating it under a series of thermal cycles of heating to 60° C. and cooling back to room temperature over 4 hours.The resulting solid can be collected by filtration, dried at about 40°C for about 4 hours, and optionally jet milled to obtain lasmiditan hemisuccinate I.

[0085] Experimental procedures

[0086] The preparation of the following method intermediates further illustrates the present invention and represents a typical synthesis of various compounds. Reagents and starting materials are easily available or can be easily synthesized by those of ordinary skill in the art. It should be understood that the preparations and examples are provided by way of illustration, and that those of ordinary skill in the art may make various modifications.

[0087] LC-ES / MS The results were obtained on an HP1100 liquid chromatography system. Electrospray mass spectrometry (acquired in positive and / or negative mode) was performed on a quadrupole mass spectrometer with a mass selective detector connected to an HP1100 HPLC. LC-MS conditions (low pH): Column: NX C18 2.1 mm × 50 mm, 3.0 μm; Gradient: 5-100% B in 3 minutes, then 100% B in 0.75 minutes, Column temperature: 50°C ± 10°C; Flow rate: 1.2 mL / min; Solvent A: Deionized water containing 0.1% HCOOH; Solvent B: ACN containing 0.1% formic acid; Wavelength: 214 nm. Alternative LC-MS conditions (high pH): Column: MS C18 columns 2.1×50 mm, 3.5 μm; gradient: 5% solvent A for 0.25 min, 5%-100% solvent B over 3 min, 100% solvent B for 0.5 min, or 10%-100% solvent B over 3 min and 100% solvent B for 0.75 min; column temperature: 50°C±10°C; flow rate: 1.2 mL / min; solvent A: 10 mM NH4HCO3, pH 9; solvent B: ACN; wavelength: 214 nm.

[0088] NMR spectra were performed on a Bruker AVIII HD 400 or 500 MHz NMR spectrometer, obtained as solutions in CDCl or (CD)SO, and reported in ppm using residual solvent [CDCl, 7.26 ppm; (CD)SO, 2.05 ppm] as a reference standard. When reporting peak multiplicities, the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broad singlet), dd (doublet), dt (doublet or triplet). Coupling constants (J), when reported, are reported in Hertz (Hz).

[0089] Chloride Analysis in ESA Plus instrument, which is equipped with (Electrified aerosol detector) - HPLC, Acclaim Trinity P1 (100 x 3.0 mm, 3 um), mobile phase: 50 mM ammonium acetate, pH ~5 in ACN.

[0090] The compounds described herein can be prepared by general methods known to those skilled in the art or by methods described herein. Suitable reaction conditions for the steps of these processes are well known in the art, and appropriate substitutions of solvents and co-reagents are known to those skilled in the art. Similarly, it will be understood by those skilled in the art that synthetic intermediates can be separated and / or purified as needed or desired by various known techniques, and generally, various intermediates can be used directly in subsequent synthetic steps with little or no purification. In addition, it will be understood by those skilled in the art that, in some cases, the order in which the structural moieties are introduced is not critical.

[0091] Preparation 1

[0092] 1-Methylpiperidine-4-carboxylic acid hydrochloride

[0093]

[0094] Scheme 1, Step A: To a jacketed reactor, piperidine-4-carboxylic acid (10.0 g, 77.5 mmol) and deionized water (40 mL) were added. The mixture was heated to reflux (95-100° C.). Formic acid (13.9 g, 302 mmol) was added over 30 minutes. 37% aqueous formaldehyde (8.1 g, 101 mmol) was added dropwise to the mixture over at least 30 minutes. Water (0.3 mL) was used as a line rinse into the reactor. The mixture was stirred at reflux (95-100° C.) for 4 hours and sampled for IPC analysis by HPLC (NMT 0.5% piperidine-4-carboxylic acid). If the amount of piperidine-4-carboxylic acid was above 0.5%, the mixture was stirred for an additional 2 hours. If within specifications, the solution was concentrated under vacuum until a residual volume of ~20 mL remained, and the residue was cooled to 45-50°C. 33% aqueous HCl (12.8 g, 116 mmol) was added to the cooled solution over a period of not less than 30 minutes. Water (0.3 mL) was used as a line rinse into the reactor. Water was removed by vacuum distillation until a residual volume of ~20 mL remained. ACN (42.4 mL) was added to the concentrate at 45-50°C, and the mixture was concentrated at atmospheric pressure to a residual volume of ~40 mL. ACN (20.4 mL) was added to the concentrate at 45-50°C, and the mixture was concentrated at atmospheric pressure to a residual volume of ~40 mL. The dilution / concentration operation was repeated until the process control for moisture content by Karl-Fischer analysis was NMT 0.2%; a slurry formed during these operations. To the slurry was added ACN (10.2 mL) at 45-50°C, cooled to 20°C over 1 hour, and stirred for an additional 2 hours. The resulting solid was isolated by filtration, and the filter cake was rinsed with ACN (10.2 mL). The wet filter cake was dried at 40°C under nitrogen and atmospheric pressure to give the title compound (12.1 g, 87% yield). MS (m / z): 144 (M+H).

[0095] Preparation 2

[0096] N,N-Diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride

[0097]

[0098] Scheme 1, Step B: To a jacketed reactor were added 1-methylpiperidine-4-carboxylic acid hydrochloride (30.0 g, 167 mmol), chlorobenzene (240 mL) and DMF (0.61 g, 8.35 mmol), and the resulting mixture was heated to 50°C. To the hot suspension was added thionyl chloride (24.2 g, 200.4 mmol) over a period of 1 hour. Chlorobenzene (13.5 mL) was used as a line flush into the reactor. After the thionyl chloride addition was complete, the mixture was stirred for 5 hours. The solution was then cooled to 0 to 10°C. A solution prepared from diethylamine (17.7 g, 12.5 mmol) and TEA (50.7 g, 25 mmol) was added to the cold reaction mixture over a period of 3 hours. Chlorobenzene (13.5 mL) was used as a line flush into the reactor. After the amine mixture was completely added, the mixture was stirred for 2 hours. The reactant was treated with a 20 wt % NaOH aqueous solution (180.3 g, 902 mmol) and stirred at room temperature for 2 hours. Water (3 mL) was used as the pipeline flushing liquid entering the reactor. The mixture was allowed to settle for 2 hours and the aqueous phase was removed. The remaining organic phase was placed under vacuum. The heated mixture was used to evaporate the residual amine and most of the chlorobenzene. After collecting about ten volumes of distillate, nitrogen was used to evacuate the reactor to atmospheric pressure. The remaining solution was cooled to between 10 ℃ and 30 ℃, and THF (120 mL) and water (4.54 g, 252 mmol) were added to the reactor. At room temperature, the reaction mixture was precipitated with the desired product by adding a 20 wt % HCl isopropanol solution (30.4 g, 167 mmol). THF (5.4 mL) was used as the pipeline flushing liquid entering the reactor. After HCl was fully added, the suspension was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and washed with THF (75.0 mL). The collected solid was dried under vacuum at 40°C for 16 hours to give the title compound (35.5 g, 84% yield). MS (m / z): 199 (M+H).

[0099] Preparation 3

[0100] (6-Bromo-2-pyridyl)-(1-methyl-4-piperidinyl)methanone hydrobromide

[0101]

[0102] Scheme 1, Step C: A suspension of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride (21.5 g, 85.1 mmol) in MTBE (109 mL) was treated with a 20 wt% aqueous solution of NaOH (34.0 g, 170 mmol). The addition was completed by rinsing with water (1.94 mL). The mixture was stirred at room temperature for 30 minutes, the phases were allowed to settle, and the phases were separated. The aqueous phase was extracted with MTBE (43.7 mL), and the organic phases were combined. The organic phase was dried by distillation at atmospheric pressure until the process control for water content was less than 0.10 wt% by Karl-Fischer analysis. If the target analysis was not met, MTBE (43.7 mL) was added to the reaction and the distillation was repeated. Three distillations were typically required to achieve the target analysis for water. In a separate reactor, a mixture of 2,6-dibromopyridine (30.2 g, 128 mmol) and MTBE (105 mL) was added and cooled to below -58°C. To the cooled suspension was added a 2.5 M solution of n-BuLi in hexane (51.3 mL, 128 mmol) over 2 hours. The transfer was completed with a rinse of MTBE (4.5 mL). After the n-BuLi addition was complete, the mixture was aged while maintaining the temperature below -58°C for an additional 2 hours. After aging, a solution of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride in MTBE was added to the cold reaction over 45 minutes. The transfer was completed with a rinse of MTBE (13.5 mL). After the complete addition of the N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride in MTBE, the mixture was aged for at least 30 minutes. After aging, the reaction was warmed to 0°C over 1 hour. The cold reaction mixture was added to a 2.5 M aqueous HCl solution (146 mL, 366 mmol) at a rate to maintain the quench temperature at 30°C. The transfer is completed with a rinse of MTBE (13.5 mL). After the transfer is completed, the mixed solution is stirred for at least 30 minutes and each phase is allowed to settle. The phases are separated and the aqueous phase is retained. n-BuOH (54.8 mL) is added to the aqueous phase and the mixed solution is treated with a 20 wt % aqueous solution of NaOH (59.5 g, 298 mmol). Rinse with water (2.80 mL) to complete the transfer. The mixed solution is stirred for at least 30 minutes and each phase is allowed to settle. The phases are separated and the organic phase is retained. The aqueous phase is extracted with n-BuOH (54.8 mL). The combined organic phases are dried by vacuum distillation to obtain a process control of a water content of <0.20 wt % by Karl-Fischer analysis. If the target analysis is not met, n-BuOH (41.1 mL) is added and the distillation is repeated. Typically, two distillations are required to achieve the process control target analysis. The concentrated solution is clarified by filtration, rinsed with n-BuOH (89.6 mL) to complete the transfer, and the filter is rinsed.The clear solution was treated with a 48% by weight aqueous HBr solution (9.91 mL, 87.7 mmol) for 90 minutes. Rinse with n-butanol (13.8 mL) to complete the transfer. pH detection showed that the pH of the reaction mixture was ~1. The mixture was dried by distillation under atmospheric pressure to obtain a process control of a water content of <0.30% by weight by Karl-Fischer analysis. The mixture was concentrated to 172 mL. If the target analysis was not met, n-BuOH (54.8 mL) was added and the distillation was repeated. The mixture was cooled to 20 ° C and stirred for 12 hours. The resulting solid was collected by filtration and washed twice with n-BuOH (10.75 mL). The solid was dried in vacuo at 60 ° C to give the title compound (24.8 g, 80% yield). MS (m / z): 283, 285 (. 79 Br, 81 Br, M+H).

[0103] Preparation 4

[0104] (6-Amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrate dihydrochloride

[0105]

[0106] Scheme 1, Step D: A pressure reactor was charged with (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide (30 g, 82.9 mmol) and Cu2O (880 mg, 6.2 mmol). The headspace was exchanged three times with nitrogen / vacuum purge cycles. NH3 / ethylene glycol solution (273.5 g total, 39.1 g NH3, 2.33 mol; 210 mL ethylene glycol) was added to the solids, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was heated to 80°C, stirred for 10 hours, cooled to room temperature, and an in-process control sample of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide NMT 2% was taken. If the target analysis was not met, the reaction was stirred at 80°C for an additional 4 hours and sampled again. HO (90 mL) was added to the completed reaction, and the mixture was filtered. The filtrate is added to a NaCl aqueous solution (253.9g NaCl, 2.73mol, 13.7L / kg H2O), and the resulting mixed solution is stirred at room temperature for 10 minutes. To this mixture, a 20% NaOH aqueous solution (4.44 equivalents, 368mmol) is added, and the two-phase mixture is stirred at room temperature for 5 minutes. This mixed solution is extracted with MTBE (90mL) 4-5 times at room temperature. The combined MTBE layers are treated with 5% by weight carbon for 30 minutes and the carbon is removed by filtration. The organic filtrate is concentrated to ~150mL under vacuum. IPA (200mL) is added to the concentrated filtrate, and the solution is concentrated to ~150mL twice under vacuum. Repeat IPA distillation as needed to meet the target analysis for process control of water. Determine that the water content is no more than 0.2% by Karl-Fischer analysis. At room temperature, a solution (30g, 166mmol) and water (10.5mL) of 20% by weight HCl in IPA are added in another reactor at room temperature. The concentrated product mixture was added to an HCl solution over 90 minutes. The resulting slurry was stirred at room temperature for no less than 8 hours. The slurry was filtered, washed twice with a 95:5 mixture of IPA / H₂O (36 mL) at room temperature, and dried under vacuum at 40°C for 16-24 hours to afford the title compound (18.4 g, 68% yield). MS (m / z): 220 (M+H). 1H NMR(400MHz,D2O / DMSO-d6)δppm 1.74-1.88(m,2H),2.05(br d,J=14.9Hz,2H),2.73(s,3H),3.01(td,J=13.1,2.6Hz,2H),3.41-3.50(m,2H),3.55(tt,J=12 .0,3.5Hz,1H),7.14(dd,J=9.0,0.7Hz,1H),7.59(d,J=7.2Hz,1H),7.90(dd,J=9.0,7.2Hz,1H). 13 C NMR (101 MHz, D2O / / DMSO-d6) δ ppm 27.4, 40.7, 44.6, 54.6, 117.2, 121.1, 137.9, 145.2, 156.2, 196.3. Chloride analysis: 20.23% (n=2).

[0107] Crystalline forms by X-ray powder diffraction (XRPD)

[0108] The XRPD pattern of the crystalline solid was obtained on a Bruker D4 Dearter X-ray powder diffractometer equipped with a CuKα source and a Vantec detector, operated at 35 kV and 50 mA. The sample was scanned between 4 and 40 2θ° with a step size of 4 and 40 2θ° and a scan rate of 0.5 seconds per step, using a divergence of 1.0 mm, a fixed anti-scattering of 6.6 mm, and a detector slit of 11.3 mm. The dried powder was mounted on a quartz sample holder and a glass slide was used to obtain a smooth surface. The crystal diffraction pattern was collected at ambient temperature and relative humidity. In MDI-Jade, the crystal peak positions were determined after a complete pattern shift based on an internal NIST 675 standard, with peaks at 8.853 and 26.774 2θ°. It is well known in the art of crystallography that for any given crystalline form, the relative intensities of the diffraction peaks may vary due to preferred orientations caused by factors such as crystal morphology and habit. When there is the influence of preferred orientation, the peak intensity changes, but the characteristic peak position of the polymorph remains unchanged. See, for example, United States Pharmacopoeia #23, National Formulary #18, pages 1843-1844, 1995. In addition, it is also well known in the field of crystallography that for any given crystal form, the angular peak position can vary slightly. For example, the peak position may shift due to temperature changes of the analyzed sample, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variation of ±0.2 2θ° is considered to take into account these potential variations without hindering the clear identification of the indicated crystal form. A crystal form can be confirmed based on any unique combination of distinguishing peaks.

[0109] The sample of Preparation 4, (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride, is characterized in that the XRD pattern using CuKα irradiation has the diffraction peaks (2θ values) described in Table 1 below, especially having a peak at 8.3° and one or more peaks selected from 16.6°, 23.5° and 33.7°, and the allowable error of the diffraction angle is 0.2°.

[0110] Table 1: X-ray powder diffraction peaks of the crystalline compound of Preparation 4; (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride

[0111]

[0112]

[0113] Preparation 5

[0114] 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride

[0115]

[0116] Scheme 1, Step E: To a suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrochloride dihydrate (10 g, 30.6 mmol) in chlorobenzene (65 mL) was added 6 w / w% aqueous NaOH solution (3 g, 75 mmol). The biphasic mixture was heated to 54°C with stirring for 30 minutes, the mixture was allowed to separate over 30 minutes, and the layers were separated at 54°C. The aqueous layer was back-extracted with chlorobenzene (45 mL) at room temperature. The organic layers were combined and distilled under vacuum to ~62 mL to provide a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. In a separate reactor were added 2,4,6-trifluorobenzoic acid (5.9 g, 1.1 equiv, 33.7 mmol), DMF (62 mg, 0.85 mmol) and chlorobenzene (32 mL), and the mixture was heated to 80°C. Thionyl chloride (4.37 g, 37 mmol) was added to the heated mixture at 80° C. over 4 hours. The mixture was stirred at 80° C. for at least 6 hours and heated to 100° C. for at least 6 hours to remove residual HCl gas. The acid chloride solution was cooled to room temperature and transferred to a separate reactor. The acid chloride solution was heated to 100° C. and (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl)methanone was added over 4 hours. The resulting slurry was stirred for another 3 hours at 100° C. and cooled to room temperature. ACN (100 mL) was added to the cooled slurry. The resulting slurry was heated to 80° C. for 1 hour and cooled to room temperature within 2 hours. The resulting slurry was stirred for another 1 hour at room temperature and filtered. The filter cake was washed with ACN (10 mL) at room temperature. The collected solid was dried at 100° C. under vacuum for 16 hours to obtain the title compound (10.7 g, 85% yield). MSm / z 378 (M+H).

[0117] Alternative method for preparation 5

[0118] To a suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrochloride dihydrate (10 g, 30.6 mmol) in chlorobenzene (65 mL) was added 6 w / w% aqueous NaOH solution (2.97 g, 74.4 mmol). The biphasic mixture was heated to 54°C with stirring for 30 minutes, and the layers were allowed to separate over 30 minutes. The layers were separated at 54°C, and the aqueous layer was back-extracted with chlorobenzene (45 mL) at room temperature. The organic layers were combined and distilled under vacuum to ~62 mL to provide a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. In a separate reactor, 2,4,6-trifluorobenzoic acid (5.9 g, 33.7 mmol), DMF (62 mg, 0.85 mmol), and chlorobenzene (32 mL) were added, and the mixture was heated to 80°C. Thionyl chloride (4.4 g, 37 mmol) was added to the heated mixture at 80° C. over 4 hours. The mixture was stirred at 80° C. for at least 6 hours and heated to 100° C. for at least 6 hours to remove residual HCl gas. The acid chloride solution was cooled to room temperature and transferred to a separate reactor. The acid chloride solution was heated to 100° C. and (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) ketone was added to the solution over 4 hours. The resulting slurry was stirred at 100° C. for another 3 hours and cooled to room temperature. ACN (100 mL) was added to the cooled slurry. The resulting slurry was heated to 80° C. for 1 hour and cooled to room temperature within 2 hours. The resulting slurry was stirred at room temperature for another 1 hour and the resulting solid was collected by filtration. The filter cake was washed with ACN (10 mL) at room temperature. The solid was dried at 100° C. under vacuum for 16 hours to obtain the title compound (10.7 g, 85% yield). MSm / z 378 (M+H).

[0119] Preparation 6

[0120] 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate

[0121]

[0122] Scheme 1, Step F: 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride (20 g, 48.4 mmol) and MTBE (202 mL) were added to a reactor. To the stirred slurry was added aqueous NaHCO₃ (8.13 g, 96.8 mmol NaHCO₃ in 200 mL of water) over 1 hour at room temperature. The two phases were separated and the aqueous layer was back extracted with MTBE (202 mL). The combined organic layers were distilled under vacuum to a final volume of ~200 mL. SiO₂ (2 g) was added to the distilled solution, and the resulting mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was rinsed with MTBE (10.8 mL). Carbon (340 mg; alternatively, the solution can be filtered through a carbon cartridge) was added to the filtrate, and the resulting mixture was stirred at room temperature for 30 minutes, filtered through a 1-5 μm filter, and then rinsed with MTBE (21.6 mL). The filtrate was distilled under vacuum to ~80 mL. Ethanol (114 mL) was added to the concentrate and the resulting solution was distilled under vacuum to ~84 mL. EtOH was added back and distilled until the water content did not exceed 1% by Karl-Fischer analysis to obtain a dry solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide. Succinic acid (3.03 g, 25.7 mmol) and EtOH (60 mL) were added to a separate reactor. The mixture was stirred and heated at 33°C until the succinic acid was completely dissolved.

[0123] A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide was heated to 55°C, and a portion of a solution of succinic acid in EtOH (about 1.0 L / kg) was added to the heated solution. The resulting solution was then seeded by adding 1 wt% of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate (200 mg). The resulting slurry was stirred for 30 minutes, and the remaining succinic acid in EtOH was added at a constant rate over 2 hours. The reactor contents were stirred for 30 minutes and linearly cooled to room temperature over 2.5 hours. The resulting slurry was stirred at room temperature for not less than 3 hours. The slurry was filtered and the collected solid was washed with EtOH (60 mL). The solid was dried under vacuum at 45°C for 16 hours to give the title compound (20.4 g, 85% yield). MS m / z 378 (M+H). 1H NMR(500MHz,DMSO-d6)δppm 1.59(d,J=12.1Hz,2H),1.84(d,J=12.8Hz,2H),2.08(t,J=11.4Hz,1H),2.38(s,2H),2.24(s,3H),2.89(d,J=13.1Hz,2H),3 .70(s,1H),7.40(dd,J=9.4,7.8Hz,2H),7.75(d,J=7.6Hz,1H),8.08(t,J=7.9Hz,1H),8.39(d,J=8.2Hz,1H),11.47(s,1H).

[0124] Alternative method for preparing 6

[0125] Scheme 3, Steps D, E, and F: To a jacketed reactor was added (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone (50 g, 137 mmol) and toluene (400 mL). Water (250 mL) was added, followed by KOH pellets (13.6 g, 206 mmol), and the mixture was stirred at room temperature for 3 hours. The contents of the reactor were filtered and returned to the reactor. The aqueous layer was drained and the organic layer was treated with activated carbon to remove color if necessary. The mixture was concentrated under reduced pressure at 50°C to ~150 mL. Toluene (225 mL) was added back to the reactor under a nitrogen atmosphere, KCO (28.5 g, 206 mmol), 2,4,6-trifluorobenzamide (26.5 g, 151 mmol), and water (2.5 mL) were added, and the contents were stirred at room temperature. Under a nitrogen atmosphere, toluene (20 mL), Pd(OAc)2 (154 mg, 0.68 mmol), and Xantphos (795 mg, 1.37 mmol) were added to a separate flask, and the contents were stirred at room temperature for 30 minutes. The resulting solution was transferred to a reactor, which was heated to 70°C with stirring. After 5 hours, the mixture was sampled for IPC HPLC analysis of NMT 0.1% (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone. If the amount of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone was not reached, the mixture was stirred for an additional 5 hours and sampled again. If the IPC was met, the mixture was stirred at 70°C for an additional 12 hours, after which the contents of the reactor were cooled to 45°C, water (250 mL) and EtOAc (250 mL) were added, and the mixture was stirred for 1 hour. Stirring was stopped, and the layers were allowed to separate. The aqueous layer was removed and discarded. Water (250 mL) was added and the resulting mixture was stirred for 1 hour. Stirring was stopped and the layers were separated. The aqueous layer was removed and discarded. Thiourea-modified silica gel (5 g) was added and the reactor was heated to 60° C. for 8 hours with stirring. The contents of the reactor were cooled to room temperature. The solution was filtered and returned to the reactor. The thiourea-modified silica gel filter cake was rinsed with EtOAc (150 mL) and the rinse was returned to the reactor. If necessary, activated carbon treatment can be performed to remove color. The solution was passed through a polish filter to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide.

[0126] 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide solution was concentrated under reduced pressure to 150 mL at 50 ° C. EtOH (250 mL, denatured with toluene) was added and the contents were concentrated under reduced pressure to 150 mL at 50 ° C. This process was repeated for a total of 3 cycles to achieve sufficient toluene removal before the last toluene feed reached a total of 250 mL. The resulting toluene mixture was heated to 55 ° C, and succinic acid (8.6 g, 73 mmol) and EtOH (200 mL, denatured with toluene) were added to another container. The contents of the stirring container were stirred until the succinic acid was completely dissolved. Approximately 30 mL of the succinic acid solution was transferred to the 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide solution, and the resulting solution was stirred at 55°C. 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate was added as a seed crystal either as a solid or as a slurry in toluene-denatured EtOH. The remaining succinic acid in toluene-denatured EtOH solution was transferred to the reactor over 1.5 hours. The contents of the reactor were cooled to room temperature over 10 hours. The resulting slurry can be milled to control the particle size. If the slurry is milled, the contents of the reactor can be subjected to a series of thermal cycles by heating to 60°C with stirring and cooling back to room temperature over 4 hours to further control the particle size distribution. The slurry was filtered, rinsed with EtOH (100 mL, denatured with toluene), and dried under reduced pressure at 40°C for 12 hours to afford the title compound (43.9 g, 73% yield).The dried solid can then be jet milled to further control particle size.

[0127] Description of the drug preparation method

[0128] In one embodiment, lasmiditan prepared by the methods provided herein can be further prepared into certain useful pharmaceutical product forms. In one embodiment, the pharmaceutical product forms can be oval-shaped 50 and 100 mg debossed, aqueous film-coated immediate-release tablets. The 50 mg tablet is a light gray, oval tablet with a debossed design of "4312" on one side and "L-50" on the other side. The 100 mg tablet is a light purple, oval tablet with a debossed design of "4491" on one side and "L-100" on the other side.

[0129] The following unit formula can be used to produce lasmiditan tablets. The ingredient naming convention is based on USP.

[0130] Table 2. Unit Formulations for Lasmiditan 50 mg and 100 mg Tablets

[0131]

[0132] Notes to Table 2:

[0133] a. Calculate the amount of lasmiditam hemisuccinate using a salt conversion factor of 0.86469. The amount of microcrystalline cellulose can be adjusted accordingly to maintain the target tablet weight.

[0134] b. Use purified water in the granulation operation. Most of the water is subsequently removed during the drying operation.

[0135] c. A small amount of residual water remains after the drying process, which may be in the form of free water or water of hydration associated with the drug substance.

[0136] d. Purified water is used for the coating unit operation. The coating suspension consists of 20% w / w solids. Sufficient coating is sprayed to achieve a 3% weight gain. This water is removed during the coating unit operation.

[0137] Tablet preparation:

[0138] Lasmiditam tablets were prepared using a high shear wet granulation process as described below. High shear wet granulation: Sodium lauryl sulfate was passed through a safety screen and added to purified water to form the granulation liquid. The lasmiditam drug substance and the excipients to be wet granulated (microcrystalline cellulose, pregelatinized starch, croscarmellose sodium) were passed through a safety screen and mixed in a granulator. The materials were mixed using the main impeller of the granulator before the granulation liquid was added. While the powders were mixing, the powder blend was granulated in the granulator by adding the granulation liquid. Upon completion of the liquid addition, the particles were wet agglomerated to facilitate liquid distribution. The particles were coarsely graded by a conical grinder before drying.

[0139] Fluid Bed Drying: Dry the granules in a fluid bed dryer until a moisture value of (50 mg and 100 mg: NMT 7%) is reached as measured by loss on drying or a scientifically sound equivalent method. The dried granules are passed through a cone mill and added to a tumble bin.

[0140] Final Blend - Extragranular Powder Blend and Final Blend Lubrication: Pass the extragranular croscarmellose sodium through a safety screen and add it to the dry-milled granules in the tumble hopper. Tumble mix the materials. Pass the extragranular magnesium stearate through a safety screen and add it to the tumble hopper. Tumble mix the materials.

[0141] Tablet Compression: The blended granules were compressed into tablets using a rotary tablet press. Compression parameters were selected at the start of a batch to achieve target mean (n=10) tablet weights (50 mg: 111.4 mg-123.2 mg, 100 mg: 222.8-246.2 mg) and mean (n=10) tablet crushing forces (50 mg: 4.1-13.7 kgf, 100 mg: 6.0-17.9 kgf). Mean (n=10) core weight, tablet crushing force, and tablet thickness were assessed during startup and throughout the compression unit operation. Tablet friability and tablet disintegration time were evaluated at the start of compression.

[0142] Film Coating of Tablet Cores: The color mixture (grey for 50 mg and purple for 100 mg) is passed through a safety screen and mixed with purified water to form a coating suspension. The tablets are film coated with the suspension using a spray gun in a perforated coating pan. The pan is rotated while the coating suspension is applied using pneumatic atomization at a controlled rate, with dry air passed over the tablet bed to produce an acceptable exhaust temperature. Sufficient coating is sprayed to achieve the desired coating percentage (50 mg and 100 mg: 2.0%-5.5%). After the coating step is completed, the film-coated tablets are inspected for visual quality. The film-coated tablets are discharged into bulk storage containers and can be sorted (optional).

[0143] Container Closure System - Unit Dose Blister:

[0144] Lasmiditant tablets are provided in individual blister cavities formed from a polychlorotrifluoroethylene (PCTFE) / polyvinyl chloride (PVC) laminate film and sealed with an aluminum foil laminate lidding material comprising a PVC-based heat seal coating.

[0145] Preparation and Description of 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate

[0146]

[0147] 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate (also known as lasmiditan acetate) was prepared by placing 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide (541 mg, 1.6 mmol) in isopropyl acetate (5 mL) while stirring at 1000 rpm at room temperature. Acetic acid (100 μL) was added. After stirring for about two minutes, a white solid precipitated from the solution. After 10 minutes, stirring was stopped and the white solid was collected by vacuum filtration on Whatman filter paper and dried in situ under air flow for 10 minutes to give the title compound (650 mg, 92% yield).

[0148] Counterion stoichiometry was measured by nuclear magnetic resonance using an Agilent 400-MHz spectrometer. Sample solutions were prepared by dissolving the prepared 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate (7.715 mg) and maleic acid (5.949 mg) used as an additional measurement standard in DMSO-d6 (approximately 0.75 mL). The following parameters were used to obtain a 0-12 ppm concentration of the sample: 13 C-decoupled 1 H spectrum: 90 degree excitation pulse, 64 scans, 25 second relaxation delay, and 4.5 second acquisition time. The resonance of acetate at approximately 1.9 ppm (3H) and the resonance of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide at approximately 7.8 ppm (1H) were integrated to give areas of 29094 and 9508, respectively. The molar ratio of acetate to 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide was calculated by taking the ratio of these areas, accounting for the difference in the resonance proton counts, to give an observed molar ratio of 29094 / (3 x 9508) = 1.02 acetate:2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide. See, for example, Figure 1 , which shows the concentration of lasmiditan acetate containing maleic acid (internal standard) 1 H NMR spectrum (400 MHz, DMSO-d6). This result provides experimental evidence that the preparation example of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate is a monoacetate.

[0149] X-ray Powder Diffraction (XRPD) of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate

[0150] The XRPD pattern of crystalline solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate was obtained on a Bruker D4 Dearter X-ray powder diffractometer equipped with a CuKα source and a Vantec detector, operating at 35 kV and 50 mA. The sample was scanned between 4 and 40 2θ° with a step size of 4 and 40 2θ° and a scan rate of 0.5 sec / step, using a divergence of 1.0 mm, a fixed anti-scatter of 6.6 mm, and a detector slit of 11.3 mm. The dry powder was mounted on a quartz sample holder and a glass slide was used to obtain a smooth surface. The crystal diffraction pattern was collected at ambient temperature and relative humidity. The crystal peak positions were determined in an MDI-Jade according to the internal NIST 675 standard after a complete pattern shift, with peaks at 8.853 and 26.774 2θ°. It is well known in the art of crystallography that for any given crystal form, the relative intensity of the diffraction peaks may vary due to preferred orientations caused by factors such as crystal morphology and habit. When there is an influence of preferred orientation, the peak intensity changes, but the characteristic peak positions of the polymorph remain unchanged. See, for example, United States Pharmacopoeia #23, National Formulary #18, pages 1843-1844, 1995. In addition, it is also well known in the art of crystallography that for any given crystal form, the angular peak positions may vary slightly. For example, the peak positions may shift due to temperature changes of the analyzed sample, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variation of ±0.2 2θ° is considered to take into account these potential variations without hindering the clear identification of the indicated crystal form. A crystal form can be confirmed based on any unique combination of distinguishing peaks.

[0151] The sample of the prepared crystalline acetate salt is characterized by an XRPD pattern using CuKa irradiation, which has diffraction peaks (2θ values) as described in Table 3 below, in particular having a peak at 26.2 and one or more peaks selected from 20.4, 14.0 and 17.9; the permissible error of the diffraction angle is 0.2 degrees.

[0152] Table 3. X-ray powder diffraction peaks of crystalline 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate

[0153]

[0154] Solubility of lasmiditan acetate and its use in subcutaneous injection formulations:

[0155] For the preparation of subcutaneous formulations, it was found that lasmiditan acetate was surprisingly superior to many alternative salt forms, delivering a dose of lasmiditan in a near-physiological fluid with a minimal volume. It was found that lasmiditan acetate was able to achieve the desired dose target of approximately 50 mg in a minimal volume of less than or equal to about 1 mL, while achieving the desired target pH close to neutral, and was also relatively isotonic and physically and chemically stable. Using lasmiditan hemisuccinate, it was experimentally determined that it was difficult to achieve a solubility of >50 mg / mL without the use of a cosolvent at near-neutral pH. To determine the solubility, a 10 mmol buffer was prepared with the corresponding acid and salt, and the pH was adjusted by varying the acid / salt ratio. The excess solid was equilibrated at room temperature overnight, the solution concentration was analyzed by HPLC, and the solid was characterized by XRPD. In contrast, for lasmiditan acetate, it was found that a solubility of >50 mg / mL could be achieved at near-neutral pH without adjusting the pH.

[0156] Table 4:

[0157] Solubility of lasmiditan acetate in acetate, citrate, or phosphate buffers. 10 mmol of buffer was prepared using the corresponding acid and salt, and the pH was adjusted by varying the acid / salt ratio. All added solutes went into solution, forming a viscous solution.

[0158]

[0159]

[0160] It has been found that lasmiditan acetate surprisingly shows a combination of highly advantageous pharmaceutical properties. For the required unit dose, lasmiditan acetate can provide the required solubility to provide a high concentration formulation with a dose volume of less than or equal to about 1 mL, which is critical for clinical applications such as use in available automatic injector devices. In addition, the dissolution of lasmiditan acetate at 50 mg / mL results in a pH close to neutral (pH approximately 6.8), which is isotonic and remains stable for at least 2 months. Lasmiditan acetate shows a significantly higher solubility than lasmiditan hemisuccinate, which has the desired pH properties, making it possible to deliver the required unit dose in a volume of about 1 mL or less.

[0161] These results indicate that lasmiditan acetate enables aqueous solutions of lasmiditan to have surprisingly high concentrations, and has useful pharmaceutical properties for clinical parenteral administration, such as subcutaneous injection. The pharmacological activity of lasmiditan is well established (Curto, M et al., Profiling lasmiditan as a treatment option for migraine, Expert Opinion on Pharmacotherapy (2020), Vol. 21, No. 2, pp. 147-153). Preferably, subcutaneous injection is administered by prefilled syringe or automatic syringe, using a device known to the skilled person (see, for example, Stauffer VL et al., Comparison between prefilled syringe and autoinjector deviceson patient-reported experiences and pharmacokinetics in galcanezumabstudies., Patient Prefer Adherence. (2018) 12: 1785-1795 and van den Bemt BJF et al., A portfolio of biologic self-injection devices in rheumatology: how patient involvement in device design can improve treatment experience., Drug Deliv. (2019), 26 (1): 384-392). These forms provide a fixed dose without the need for patient measurement, providing dosage accuracy and safety while enabling patient autonomy. The use of lasmiditan acetate in a form such as an autoinjector for the acute treatment of migraine attacks provides an improved tool for institutional patients, such as in hospital emergency situations, where the use of tablets by patients is disrupted by migraine attacks and associated nausea and vomiting, and patients and / or providers prefer to have access to an improved injectable form of lasmiditan. The parenteral formulation of lasmiditan acetate is expected to provide immediate release, enabling a rapid onset of action, and when used as needed at the onset of a migraine attack, may preferably allow for a shorter onset of action relative to oral dosage forms.

[0162] Providing a lasmiditan formulation for injection at a neutral and physiological pH (about 6.0-7.5) and isotonic with physiological fluids (e.g., 280-300 mosm / kg) is clinically highly desirable and is believed to minimize the possibility of pain and / or tissue irritation upon injection, for example. Achieving an injection volume of about 1 ml or less enables the use of available syringe technology such as autoinjectors and provides an improved injection and delivery experience for patients, for example, in terms of injection time and / or pain upon injection. The ability to use pre-filled syringes, pens, and / or autoinjector technology is clinically important for migraine patients because these devices provide ease of use during a migraine attack, when patients are often in duress when the product is used. In addition, the ability to use pre-filled syringes, pens, and / or autoinjector technology is clinically important because they provide a portable medication at any time that can be easily obtained during daily life (migraine attacks can occur at any time).

[0163] The following unit formula can be used to produce lasmiditan solution for injection.

[0164] Table 5. Unit Formulation for Lasmiditan 50 mg Solution in Autoinjector

[0165]

[0166] The present invention also includes the following solutions:

[0167] 1. A method for preparing the compound of the formula:

[0168]

[0169] The following steps are involved:

[0170] i.) treating piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water, followed by treatment with aqueous HCl, followed by water distillation and addition of acetonitrile, and repeating the dilution / distillation until the water content does not exceed 0.2% by Karl-Fischer analysis to provide solid 1-methylpiperidine-4-carboxylic acid hydrochloride;

[0171] ii.) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to give 1-methylpiperidine-4-carbonyl chloride;

[0172] iii.) treating 1-methylpiperidine-4-carbonyl chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by alkaline washing, and then treating with aqueous HCl in isopropanol to give solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride;

[0173] iv.) treating N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrochloride hydrate with an inorganic base such as aqueous NaOH in a nonpolar solvent such as methyl tert-butyl ether, followed by water washing, phase separation, and distillation of the organic solvent until the water content, as determined by Karl Fischer analysis, does not exceed 0.1% by weight to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide;

[0174] v.) subsequently treating N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a nonpolar organic solvent such as methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and repeated distillation of the organic solvent until the water content does not exceed 0.2% by weight as determined by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone;

[0175] vi.) treating (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr solution, followed by extraction with n-butanol, and then repeatedly distilling the organic solvent until the water content does not exceed 0.3% by Karl-Fischer analysis to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide;

[0176] vii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidinyl)methanone hydrobromide with a solution of NH in ethylene glycol in the presence of a CuO catalyst at about 80° C. for about 2 hours, followed by washing with water, saturated aqueous NaCl, and 20% aqueous NaOH, followed by extraction with a nonpolar aprotic solvent such as methyl tert-butyl ether, phase separation, and treating the organic phase with 5 wt% carbon;

[0177] viii.) filtering the mixture, diluting it with a suitable polar alcoholic solvent, such as isopropyl alcohol, repeatedly distilling the organic solvent until the water content by Karl-Fischer analysis is no more than 0.2%, then treating the resulting residue with isopropyl alcohol, water, and 20 wt % HCl to obtain a slurry having a water concentration of at least 2%, filtering the resulting slurry, and drying it under vacuum at 40° C. for 16-24 hours to obtain (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride as a solid;

[0178] ix.) treating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6% w / w aqueous NaOH at about 54° C. for about 30 minutes, followed by phase separation and vacuum distillation of the aqueous solution to provide (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone;

[0179] x.) (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone is then treated with 2,4,6-trifluorobenzoyl chloride in chlorobenzene at about 100° C. for about 4 hours, followed by cooling, addition of acetonitrile and heating the resulting slurry to 80° C. for about 1 hour, followed by collection of the resulting solid by filtration to provide solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hydrochloride;

[0180] xi.) treating 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride in methyl tert-butyl ether with saturated aqueous Na2CO3 solution;

[0181] xii.) treating the mixture from step xi above with SiO2, followed by filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation until the water content does not exceed 1% by Karl-Fischer analysis to provide 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

[0182] xiii.) 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in ethanol is treated with 0.5 equivalents of succinic acid in ethanol at about 55°C for not less than 3 hours at room temperature, followed by collection of the solid by filtration to give solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

[0183] 2. Method for preparing the compound of the following formula:

[0184]

[0185] The following steps are involved:

[0186] i.) treating piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water, followed by treatment with aqueous HCl, followed by water distillation and addition of acetonitrile, and repeating the dilution / distillation until the water content does not exceed 0.2% by Karl-Fischer analysis to provide solid 1-methylpiperidine-4-carboxylic acid hydrochloride;

[0187] ii.) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to give 1-methylpiperidine-4-carbonyl chloride;

[0188] iii.) treating 1-methylpiperidine-4-carbonyl chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by alkaline washing, and then treating with aqueous HCl in isopropanol to give solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride;

[0189] iv.) treating N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrochloride hydrate with an inorganic base such as aqueous NaOH in a nonpolar solvent such as methyl tert-butyl ether, followed by water washing, phase separation, and distillation of the organic solvent until the water content, as determined by Karl Fischer analysis, does not exceed 0.1% by weight to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide;

[0190] v.) subsequently treating N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a nonpolar organic solvent such as methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and repeated distillation of the organic solvent until the water content does not exceed 0.2% by weight as determined by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone;

[0191] vi.) treating (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr solution, followed by extraction with n-butanol, and then repeatedly distilling the organic solvent until the water content does not exceed 0.3% by Karl-Fischer analysis to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide;

[0192] vii.) treating (6-bromo-2-pyridinyl-1-methyl-4-piperidinyl)methanone hydrobromide with solid KOH in a two-phase mixture of water and toluene for about 3 hours, followed by separation of the organic layer and evaporation of the solvent to provide (6-bromo-2-pyridinyl-1-methyl-4-piperidinyl)methanone;

[0193] viii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing KCO, water, Pd(OAc), and Xantphos at about 70° C. for about 12 hours until the (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone content is no more than 0.1% as determined by HPLC, followed by dilution of the reaction mixture with water and EtOAc and subsequent treatment with thiourea-modified silica gel at 60° C. for about 8 hours followed by filtration to provide a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

[0194] ix.) A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in EtOAc was treated with about 0.5 equivalents of succinic acid in EtOH at 55° C. for about 3 hours, followed by cooling to room temperature over about 10 hours and collecting the resulting solid by filtration to provide solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

[0195] 3. The method of embodiment 1 or 2, wherein the reaction is carried out using a batch process.

[0196] 4. The method of embodiment 3, wherein the batch produced is produced on a process scale.

[0197] 5. The method of embodiment 4, wherein the batch produced is at least 1 kg.

[0198] 6. The method of embodiment 4, wherein the batch produced is at least 10 kg.

[0199] 7. The method of embodiment 4, wherein the batch produced is at least 100 kg.

[0200] 8. A tablet prepared by the method of any one of embodiments 1 to 7, wherein the tablet comprises 50 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

[0201] 9. A tablet prepared by the method of any one of embodiments 1 to 7, wherein the tablet comprises 100 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

[0202] 10. Compounds of the formula:

[0203]

[0204] 11. The compound of embodiment 10, which is crystalline.

[0205] 12. The compound of embodiment 11, characterized in that it has an X-ray powder diffraction pattern using CuKα irradiation, wherein the X-ray powder diffraction pattern has a strong peak at a diffraction angle 2-θ of 8.3°, and one or more peaks selected from 16.6°, 23.5° and 33.7° (±0.2° respectively).

[0206] 13. Compounds of the formula:

[0207]

[0208] 14. A crystalline form of the compound according to embodiment 13.

[0209] 15. The compound of embodiment 14, characterized in that it has an X-ray powder diffraction pattern using CuKα irradiation, wherein the X-ray powder diffraction pattern has a strong peak at a diffraction angle 2-θ of 26.2° and one or more peaks selected from 20.4°, 14.0° and 17.9° (±0.2° respectively).

[0210] 16. A pharmaceutical composition comprising a compound according to any one of embodiments 13 to 15 and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0211] 17. The pharmaceutical composition according to embodiment 16, further comprising acetic acid.

[0212] 18. A method of treating migraine in a patient, said method comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments 13-15.

[0213] 19. A compound according to any one of embodiments 13 to 15 for use in therapy.

[0214] 20. A compound according to any one of embodiments 13 to 15 for use in the treatment of migraine.

Claims

1. A compound of the formula:

2. A crystalline form of the compound according to claim 1.

3. The compound according to claim 2, characterized in that An X-ray powder diffraction pattern using CuKα irradiation, the X-ray powder diffraction pattern having a strong peak at a diffraction angle 2-θ of 26.2°, and one or more peaks selected from 20.4°, 14.0° and 17.9° (±0.2° respectively).

4. The compound according to claim 2, characterized in that An X-ray powder diffraction pattern using CuKα irradiation having peaks at diffraction angles 2-θ of 8.2°, 9.7°, 12.0°, 14.0°, 16.9°, 17.9°, 20.4°, 23.3°, 24.3° and 26.2° (±0.2° respectively).

5. The compound according to claim 2, characterized in that The X-ray powder diffraction pattern using CuKα irradiation has the diffraction peaks (2θ values) described in the following table: 。 6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers, diluents or excipients.

7. The pharmaceutical composition of claim 6, further comprising acetic acid.

8. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating migraine in a patient.

9. A compound according to any one of claims 1 to 5 for use in therapy.

10. A compound according to any one of claims 1 to 5 for use in the treatment of migraine.

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