Processes and intermediate 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

Abstract

To provide a process for the preparation of lasmiditan that enables large-scale production and, furthermore, allows the use of a high concentration parenteral dosage form for patients who cannot be administered tablets.SOLUTION: The embodiments of present invention provide processes and an intermediate for the large-scale preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and formulations and product forms made by these processes. The embodiments of the present invention further provide for the preparation of lasmiditan acetate, 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate salt, and / or pharmaceutical compositions thereof, and / or uses of lasmiditan acetate and formulations thereof in subcutaneous drug delivery.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to the fields of pharmaceutical chemistry and synthetic organic chemistry and provides processes and intermediates for the large scale synthesis of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, a 5-HT1F receptor agonist, as well as formulations and product forms made by these processes, the preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate and its use for parenteral formulations and treatment of migraine headaches. [Background technology]

[0002] Lasmiditan is a selective and highly potent 5-HT agonist currently approved in the United States as 50 mg or 100 mg tablets for the acute on-demand treatment of migraine. 1F It is a receptor agonist (see, for example, Rubio-Beltran 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 Registry Number 439239-90-4) can be chemically described as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide. No. 7,423,050 and U.S. Patent Publication No. 2008 / 0300407 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: [ka]

[0003] Methods for preparing lasmiditan and salts and certain polymorphic forms, formulations, and dosage forms thereof are known to those skilled in the art and are described, for example, in WO2003 / 084949, WO2011 / 123654, and WO2018 / 106657.

[0004] As used herein, useful forms of lasmiditan include 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-ylcarbonyl)-pyridin-2-yl]-benzamide monohydrochloride, and pharma- ceutically acceptable salts thereof, including but not limited to 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. A synthetic route for the preparation of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide has been previously disclosed as shown in Scheme A below. The overall yield of lasmiditan starting with commercially available piperidine 4-carboxylic acid via the route described in Scheme A below is about 10-46% over all nine steps. Improvements in the synthesis of lasmiditan could offer substantial and diverse benefits, especially for large-scale production. [ka]

[0005] The synthetic chemical process pathways may be redesigned or revised with the goal of achieving various advantages, including, for example, improved yields, obtaining crystalline products, lowering impurity profiles, utilizing commercially available intermediates, minimizing the number of synthetic steps required, reducing inputs required and / or by-products produced, or any useful combination of such improvements, providing reduced cost, less resource-intensive processes, and facilitating efficient production. Improved methods of making lasmiditan that can achieve one or more of these goals are needed, especially for large-scale synthesis.

[0006] Moreover, migraine headaches are one of the most common presenting symptoms in emergency rooms. Current methods for headache relief in emergency room settings, when using lasmiditan in patients who have difficulty administering tablets due to nausea and / or vomiting, may need to rely on the preparation of a dilute formulation of lasmiditan at about 1 mg / ml delivered intravenously over an extended period of time, e.g., about 20-60 minutes. Lasmiditan has been delivered intravenously in clinical studies at doses of about 1-60 mg delivered in a 60 ml infusion over 20 minutes (see U.S. Patent Application Publication No. 2010 / 0256187). Safe and effective treatment of migraine headaches with lasmiditan for patients unable to administer tablets would be made possible by the availability of a highly concentrated parenteral dosage form. The present disclosure also addresses this need. Summary of the Invention

[0007] Embodiments of the present invention provide processes for the preparation of 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 use in these processes.Embodiments of the present invention further provide the use of lasmiditan acetate, and formulations thereof, in 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 in subcutaneous drug delivery.

[0008] In one embodiment, referred to as Route I, the present invention provides a process for preparing a compound of the formula: [ka] i.) treatment of piperidine-4-carboxylic acid under reductive amination conditions with formaldehyde and formic acid in water to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride, followed by treatment with aqueous HCl, followed by water distillation and acetonitrile addition, repeated dilution / distillation steps until the water content is 0.2% or less by Karl Fischer analysis; ii.) treatment of 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent, such as thionyl chloride in chlorobenzene, to give 1-methylpiperidine-4-carboxylic acid chloride; iii.) treatment of 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by a base wash, and then treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; iv.) treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with a mineral base such as aqueous NaOH in a non-polar solvent such as methyl-tert-butyl ether to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide, followed by water washing, phase separation and distillation of the organic solvent until the water content is 0.1 wt.% or less by Karl Fischer analysis; v.) the subsequent treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone, followed by extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and distillation of the organic solvent repeated until the water content is 0.2 wt.% or less by Karl Fischer analysis; vi.) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide, followed by extraction with n-butanol, followed by repeated distillation of the organic solvent until the water content is 0.3% or less by Karl Fischer analysis; vii.) treatment of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide with a solution of NH in ethylene glycol in the presence of 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 non-polar aprotic solvent such as methyl-tert-butyl ether, phase separation, and treatment of the organic phase with 5% by weight carbon; viii.) filtration of the above mixture, dilution with a suitable polar alcoholic solvent such as isopropanol, distillation of the organic solvent repeated until the water content is less than 0.2% by Karl-Fisher analysis, the water concentration of the resulting slurry is at least 2%, followed by treatment of the resulting residue with isopropanol, water, and 20 wt. % HCl, filtration of the resulting slurry, and drying under vacuum at 40° C. for 16-24 hours to obtain solid (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride; ix.) treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6% w / w NaOH in water at about 54° C. for about 30 minutes, followed by phase separation and vacuum distillation of the aqueous solution to obtain (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone; x.) subsequent treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100° C. for about 4 hours, charging with acetonitrile and heating the resulting slurry to 80° C. for about 1 hour, and then collecting the resulting solid by filtration to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride; xi.) treatment of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride with saturated aqueous Na2CO3 in methyl-tert-butyl ether; xii.) treating the mixture of step xi above with SiO2 followed by filtration, treatment with carbon, filtration and evaporation, dilution with ethanol and distillation to a water content of 1% or less by Karl Fischer analysis to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide; xiii.) treating 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in ethanol with a solution of 0.5 equivalents of succinic acid in ethanol at about 55° C. for at least 3 hours at room temperature to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and then collecting the solid by filtration.

[0009] In the above Route I process, preferably the reaction is carried out using batch processing methodology. In one embodiment, the Route I batch is produced at process scale. In one embodiment, the Route I batch is produced at least 1 kilogram. In one embodiment, the Route I batch is produced at least 10 kilogram. In one embodiment, the Route I batch is produced at least 100 kilogram.

[0010] In the Route I process above, the use of chlorobenzene avoids the decomposition that occurs under alternative methods, such as THF, which reacts with acid chlorides under scale (e.g., 100 kg) to essentially yield no acid chloride.

[0011] In another embodiment, referred to as Route II, the present invention provides a process for preparing a compound of the formula: [ka] i.) treatment of piperidine-4-carboxylic acid under reductive amination conditions with formaldehyde and formic acid in water to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride, followed by treatment with aqueous HCl, followed by water distillation and acetonitrile addition, repeated dilution / distillation steps until the water content is 0.2% or less by Karl Fischer analysis; ii.) treatment of 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent, such as thionyl chloride in chlorobenzene, to give 1-methylpiperidine-4-carboxylic acid chloride; iii.) treatment of 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by a base wash, and then treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; iv.) treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with a mineral base such as aqueous NaOH in a non-polar solvent such as methyl-tert-butyl ether to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide, followed by water washing, phase separation and distillation of the organic solvent until the water content is 0.1 wt.% or less by Karl Fischer analysis; v.) the subsequent treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone, followed by extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and distillation of the organic solvent repeated until the water content is 0.2 wt.% or less by Karl Fischer analysis; vi.) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide, followed by extraction with n-butanol, followed by repeated distillation of the organic solvent until the water content is 0.3% or less by Karl Fischer analysis; vii.) treatment of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide in a biphasic mixture of water and toluene with solid KOH for about 3 hours to obtain (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone, followed by separation of the organic layer and evaporation of the solvent; viii.) treatment of (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 less than 0.1% by HPLC to obtain a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide, followed by dilution of the reaction mixture with water and EtOAc, followed by treatment with thiourea modified silica gel at 60° C. for about 8 hours, followed by filtration; ix.) treating a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid in EtOH at 55° C. for about 3 hours to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, followed by cooling to room temperature for about 10 hours and collecting the resulting solid by filtration.

[0012] In the above Route II process, preferably the reaction is carried out using batch processing methodology. In one embodiment, the Route II batch is produced at process scale. In one embodiment, the Route II batch is produced at least 1 kilogram. In one embodiment, the Route II batch is produced at least 10 kilogram. In one embodiment, the Route II batch is produced at least 100 kilogram.

[0013] In the Route II process above, the use of chlorobenzene avoids the decomposition that occurs under alternative methods, such as THF, which reacts with acid chlorides under scale (e.g., 100 kg) to essentially yield no acid chloride.

[0014] In another embodiment, the present invention provides: [ka] This may be referred to as (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride.Preferably, this compound is crystalline.(6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride is particularly useful in the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and the process using (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride may provide advantageous process features, including but not limited to the purity of intermediates and / or final materials. (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 process for isolating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride described herein provides improved impurity rejection and an improved controlled crystallization process. Morphological and chemical stability studies indicate that (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride is generally stable, and drying studies indicate that over-drying to remove water of hydration is difficult, even under forcing conditions. Use of this intermediate advantageously provides a high purity product in expected yields.

[0015] In another embodiment, the present disclosure provides lasmiditan acetate, which can be represented by the following formula: [ka]

[0016] In another embodiment, the present invention provides a crystalline form of lasmiditan acetate, further characterized by an X-ray powder diffraction pattern using CuKα radiation having an intense peak at a diffraction angle 2-theta of 26.2° combined with one or more of the peaks selected from the group consisting of 20.4°, 14.0°, and 17.9° (each ±0.2°). In another embodiment, the present invention provides a pharmaceutical composition comprising lasmiditan acetate according to the above embodiment together with one or more pharma- ceutically acceptable carriers, diluents, or excipients. Preferably, the pharmaceutical composition comprises acetic acid. Preferably, the pharmaceutical composition comprises acetic acid and is for subcutaneous administration.

[0017] In another embodiment, the present invention provides a method of treating 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 migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of lasmiditan acetate together with one or more pharma- ceutically acceptable carriers, diluents, or excipients. In another embodiment, the present invention provides a method of treating migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of lasmiditan acetate together with one or more pharma- ceutically acceptable carriers, diluents, or excipients, wherein the composition comprises acetic acid.

[0018] 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 with one or more pharma- ceutically acceptable carriers, diluents, or excipients for use in therapy. In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate with one or more pharma- ceutically acceptable carriers, diluents, or excipients, the composition comprising acetic acid for use in therapy.

[0019] In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate having one or more pharma- ceutically acceptable carriers, diluents, or excipients for use in the treatment of migraine. In another embodiment, the present invention provides a pharmaceutical composition of lasmiditan acetate having one or more pharma- ceutically acceptable carriers, diluents, or excipients for use in the treatment of migraine, wherein the composition comprises acetic acid for use in the treatment of migraine.

[0020] In another embodiment, the disclosure provides a pharmaceutical composition comprising lasmiditan acetate and a high concentration of lasmiditan acetate, for example, about 10-200 mg / ml free base equivalent, in an aqueous carrier. In an embodiment, the pharmaceutical composition comprises lasmiditan in a buffered aqueous solution at about 10-200 mg / ml free base equivalent. In an embodiment, the buffered aqueous solution has a pH between pH 6.0-7.5 at 37° C. In an embodiment, the buffered aqueous solution comprises acetic acid.

[0021] In addition to aqueous carrier, preferably sterile, deionized, distilled water, pharmaceutical compositions described herein may further comprise one or more pharma- ceutically acceptable excipients or cosolvents.The term "pharma-ceutically acceptable" refers to excipients and cosolvents that are suitable for use in contact with human tissue without undue toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio.Pharmaceutical compositions and the process for preparing them 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)).

[0022] 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 dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit suitable as a unitary dosage for a subject to be treated, each unit containing a predetermined amount of the active compound lasmiditan calculated to produce the desired therapeutic effect together with the necessary pharmaceutical carrier. The dosage unit form can be, for example, an ampoule, a vial, or a syringe.

[0023] In an embodiment, the present disclosure provides a pharmaceutical composition comprising an amount of lasmiditan acetate as described herein, the amount being 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, the amount being 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, or 200 mg per dose. The above doses are based on an adult of average weight. For individuals with a lower body weight, such as the elderly or children, smaller doses may be tolerated. Thus, in an embodiment, the pharmaceutical composition may comprise a smaller dose, such as 5, 10, or 15 mg.

[0024] As described herein, highly concentrated aqueous solutions of lasmiditan acetate allow for administration of a single therapeutically effective dose by injection of the highly concentrated aqueous solution of lasmiditan, for example, by intravenous, subcutaneous, or intramuscular routes.

[0025] In an embodiment, the disclosure provides a high concentration aqueous solution of lasmiditan acetate. In an embodiment, the high concentration aqueous solution of lasmiditan acetate is formulated as a parenteral dosage form. In an embodiment, the high concentration aqueous solution contains lasmiditan at a free base equivalent of 10-200 mg / ml. In an embodiment, the high concentration aqueous solution of lasmiditan acetate is in the form of a parenteral dosage form. In an embodiment, the parenteral dosage form is a buffered aqueous solution of lasmiditan at a free base equivalent of 10-200 mg / ml. In an embodiment, the parenteral dosage form is a buffered aqueous solution of lasmiditan at a free base equivalent of 10, 20, 30, 40, 50, 100, or 200 mg / ml. In an embodiment, the parenteral dosage form is suitable for subcutaneous or intramuscular injection. Preferably, the parenteral dosage form is for subcutaneous injection. In an embodiment, the pH of the buffered solution is between pH 6.0 and 7.5 at 37°C.

[0026] In an embodiment, the buffered aqueous solution comprises an organic acid based buffer system. In an embodiment, the organic acid is a dicarboxylic acid or tricarboxylic acid. In an embodiment, the dicarboxylic acid or tricarboxylic acid is selected from the group consisting of acetic acid and citric acid. In an embodiment, the organic acid is succinic acid. In an embodiment, the buffer is an acetate buffer. In an embodiment, the buffered aqueous solution does not contain an organic solvent. In an embodiment, the buffered aqueous solution does not contain an organic solvent and a surfactant. In a preferred embodiment, the buffered aqueous solution comprises lasmiditan acetate, acetic acid, and sodium hydroxide, and is adjusted to a pH between 6.0 and 7.5 at 37°C.

[0027] In an embodiment, the parenteral dosage form of lasmiditan acetate is provided in the form of a pre-filled syringe suitable for administration by subcutaneous route. In an embodiment, the pre-filled syringe contains lasmiditan in a free base equivalent of 10-50 mg / ml. In an embodiment, the pre-filled syringe contains lasmiditan in a free base equivalent of 10, 20, 30, 40, 50, or 100 mg / ml. 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 pre-filled syringe is suitable for home use, for example for migraine sufferers who may face extreme and sudden onset of headache. In an embodiment, the pre-filled syringe is contained in a package with instructions for parenteral administration, preferably by subcutaneous injection. In an embodiment, the pre-filled syringe is in the form of an autoinjector with instructions for subcutaneous injection.

[0028] In an embodiment, the parenteral dosage form of lasmiditan acetate is provided in the form of a vial containing 10-50 mg / ml of free base equivalent of lasmiditan. In an embodiment, the parenteral dosage form of lasmiditan acetate is provided in the form of a vial containing 10, 20, 30, 40, 50, or 100 mg / ml of free base equivalent of lasmiditan. In an embodiment, lasmiditan is provided in a buffered aqueous solution having a pH of 6.0-7.5 at 37°C.

[0029] The present disclosure also provides a method for acute treatment of a migraine attack, the method comprising administering a therapeutically effective amount of lasmiditan acetate as described herein. In an embodiment, the parenteral solution is administered by subcutaneous injection. In an embodiment, the parenteral solution comprises lasmiditan acetate at a free base equivalent of 10-50 mg / ml in a buffered aqueous solution at pH 6.0-7.5 at 37° C. In an embodiment, the parenteral solution comprises lasmiditan at a free base equivalent of 10, 20, 30, 40, 50, or 100 mg / ml. In an embodiment, the method comprises administering a single therapeutically effective dose of lasmiditan acetate in a volume of 1 ml or less, such as about 0.5-1 ml, for example, by a single subcutaneous injection. In an embodiment, the injection volume is about 1 ml. In an embodiment, the injection volume is about 0.5 ml.

[0030] The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 20-200 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier. The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 20 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier. The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 50 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier. The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 75 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier. The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 100 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier.The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 150 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier.The present invention provides a method for the treatment of migraine in a patient in need of such treatment, comprising administering to the patient 200 mg of lasmiditan acetate per subcutaneous dose and a pharma- ceutically acceptable diluent or carrier.

[0031] In some embodiments, the patient is a human who has been diagnosed with a condition or disorder that requires prevention with the pharmaceutical composition described herein. In some embodiments, the patient is a human who is characterized by a risk of a condition or disease that indicates the need for administration with the pharmaceutical composition described herein. If the disorder that can be treated by the method of the present invention is known by an established and accepted classification, such as migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache, the classification can be found in various sources. For example, currently, the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IVTM) (1994, American Psychiatric Association, Washington, DC) provides diagnostic tools for identifying many of the disorders described herein. Also, the International Classification of Diseases, 10th edition (ICD-10) provides classification for many of the disorders described herein. Those skilled in the art 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 with advances in medical science. Migraine patients may further be diagnosed with migraine with or without aura (1.1 and 1.2) as defined by the International Classification of Headache Disorders, 3rd Edition (Beta), Cephalalgia 2013;33:629-808 of the International Headache Society (IHS). In some embodiments, the human patient has been diagnosed with episodic migraine prior to receiving chronic administration of lasmiditan, preferably at night, to prevent migraine. In some embodiments, the human patient has been diagnosed with chronic migraine prior to receiving the antibody. In some embodiments, the human patient experiences aura due to migraine.In some embodiments, the human patient does not experience migraine aura.

[0032] As used herein, "migraine" includes, but is not limited to, migraine attacks. As used herein, "migraine attack" refers to the following description: Symptoms may overlap in the various phases of a migraine attack, and not all patients experience the same clinical signs. In the prodromal phase, the majority of patients have prodromal symptoms that may precede the headache phase by up to 72 hours. These include changes in mood and activity, irritability, fatigue, food cravings, recurrent yawning, stiff neck, and phonophobia. These symptoms may persist into the aura phase, headache phase, and even post-symptomatic phase. Some patients experience a prodromal phase, in which approximately one-third of patients experience a transient neurological deficit during the attack. ICHD-3 defines an aura as one or more transient, fully reversible neurological deficits that develop over 5 minutes or more, of which each deficit lasts 5 to 60 minutes, at least one of which must have a unilateral localization. Visual aura, which may show positive (scintillating scotoma), negative (scotoma), or both phenomena, is found in over 90% of cases, but the most common deficits, sensory, motor, language, brainstem, and retinal aura symptoms, may also occur. A transient wave of cortical neuronal depolarization is thought to be the pathophysiological brain mechanism underlying the clinical phenomenon of migraine aura. During the headache phase, headache attacks, which may last from 4 to 72 hours, are accompanied by nausea, photophobia, and phonophobia, or both. The headache is characterized by being unilateral, pulsatile, of moderate or severe intensity, and aggravated by physical activity; two of these features are sufficient to meet the diagnostic criteria. During the post-symptomatic phase, characteristic symptoms reflect those observed in the prodromal phase. Typical post-symptomatic symptoms include fatigue, impaired concentration, and stiff neck. It remains unclear whether these symptoms begin during the prodromal phase and persist through the headache and post-symptom phases, whether they also begin during the headache phase, or whether they appear after the headache phase has ended.

[0033] "Migraine" as used herein refers to a headache, with or without aura, of ≥ 30 minutes duration, having both of the following required features (A and B): A) at least two of the following headache features: 1) unilateral location, 2) pulsatile quality, 3) moderate or severe pain intensity, and 4) causing exacerbation by or avoidance of usual physical activity, and B) at least one of the following during the headache: a) nausea and / or vomiting, and / or b) photophobia and phonophobia. As used herein, "moderate migraine" refers to a headache with or without aura, of > 30 minutes duration, but lacking one of the features of migraine in the International Headache Society's ICHD-3 definition.

[0034] The term "effective amount" or "therapeutically effective amount" refers to the total amount administered in a single dose that, upon administration in single or multiple doses to a patient, provides the desired pharmacological effect in the patient, e.g., the total amount of 5-HT 1F "Effective amount" refers to the amount or dose of lasmiditan acetate in a pharmaceutical composition, such as the amount capable of activating a receptor. In a preferred embodiment, "effective amount" refers to an amount of lasmiditan acetate that, upon acute administration, can render a patient free of migraine attacks after administration. "Dose" refers to a predetermined amount of lasmiditan acetate calculated to produce a desired therapeutic effect in a patient. As used herein, "mg" refers to milligrams. As used herein, doses described in mg refer to the active pharmaceutical ingredient lasmiditan as the free base equivalent by mass, e.g., a "100 mg" dose refers to 100 mg of the active pharmaceutical ingredient lasmiditan as the free base equivalent. As used herein, a given dose may be interpreted as describing the dose of approximately the indicated amount, in that it is also envisioned that doses up to 10 percent higher or lower than the indicated dose will provide a useful dosing regimen in a similar manner as the indicated dose. [Brief description of the drawings]

[0035] [Figure 1]1 is a graphical representation of the 1H NMR spectrum (400 MHz, DMSO-d6) of lasmiditan acetate containing maleic acid (internal standard). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The reactions described herein may be carried out by standard techniques known to those skilled in the art by using conventional glassware, or may be carried out on a pilot and / or production scale in equipment designed for such conversions. Additionally, each of these reactions described may be carried out by either a batch process, or, where applicable, a flow reaction methodology. As used herein, the term "batch process" refers to a process in which raw materials are combined in a reactor or vessel and the product is removed at the end of the reaction.

[0037] In addition, certain intermediates described in the following preparations may contain one or more nitrogen protecting groups. Variable protecting groups may be the same or different from one occurrence to the next, depending on the specific reaction conditions and the specific transformation carried out. 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", Fourth Edition, by Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0038] The abbreviations listed below as used herein are defined as follows: "Å" means angstrom or angstroms; "ACN" means acetonitrile; "AcOH" means acetic acid; "Bn" means benzyl; "nBuLi" means n-butyl lithium; "CAS Number" means Chemical Abstracts Registry Number; "DCM" means dichloromethane; "DMF" means N,N-dimethylformamide; "DIPEA" means diisopropylethylamine; "DMSO" means dimethylsulfoxide (perdeuterated [d6] when used for NMR); "EtOAc" means ethyl acetate; "EtOH" means ethanol or ethyl alcohol. "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. "LAH" means lithium aluminum hydride. "LCMS" means liquid chromatography mass spectrometry. "LDA" means lithium diisopropylamide. "Me" as a substituent in the structural representation of a compound represents a methyl group. "MeOH" means methanol. or methyl alcohol. "min" means minutes. "MS" means mass spectrometry or mass spectrum. "MTBE" means methyl tert-butyl ether. "NMR" means nuclear magnetic resonance. "NMT" means: "OAc" means acetate. "psig" means pounds per square inch gauge. "PyBOP" means (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate). "RT" means room / ambient temperature. "sec" means second(s) as a unit of time. "TBS-Cl" means tert-butyldimethylsilyl chloride."TEA" means triethylamine. "THF" means tetrahydrofuran. "tR" means retention time. "w / w" means weight to weight ratio.

[0039] Improved routes for the preparation of lasmiditan are provided below as Routes I and / or II, and other additional methods are provided below.

[0040] "Pharmaceutically acceptable salt(s)" refers to the relatively non-toxic inorganic and organic salt(s) of the compound of the present invention. It will be understood by those skilled in the art that the compound of the present invention can form salts. Some 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 the general methodology for their preparation are well known in the art. For example, see 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.

[0041] "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 Practice (GMP) or similar conditions required for commercial production of pharmaceutical products for human consumption. Preferably, "process scale" in the above Route I and / or II processes refers to batches produced at least in 1 kilogram quantities, and / or batches produced at least in 10 kilogram quantities, and / or batches produced at least in 100 kilogram quantities.

[0042] General Chemistry

change

[0043] [ka] Scheme 2 shows the synthesis of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate hydrochloride 5. Amination of pyridyl bromide hydrobromide 4 can be accomplished as outlined in Scheme 1 using transition metal catalysis well known to those skilled in the art. More specifically, pyridyl bromide 4 can be added with about 0.075 equivalents of Cu2O, about 28 equivalents of NH3 in ethylene glycol and stirred at about 80°C. The reaction can be cooled to room temperature, quenched with HO, washed with 20% aqueous NaOH, and slurried with 20% HCl in IPA and a small amount of HO to obtain aminopyridine dihydrate hydrochloride 5.

[0044] [ka] Scheme 3 shows the modified process synthesis to rasmiditane hemisuccinate I. N-Methylation of commercially available piperidine 4-carboxylic acid 1 can be achieved under various reduction conditions recognizable to those skilled in the art, specifically, treatment of secondary amine with about 1.3 equivalents of formaldehyde in excess formic acid to obtain N-methylpiperidine 2. Formation of diethylamide 3 can be achieved by using conventional amide coupling reagents such as benzotriazole, HBTU, or PyBOP, or by using reagents well known in the art such as oxalyl chloride or thionyl chloride to convert the carboxylic acid to an acid chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 can be converted to an acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50° C. for 1 hour, at which time the reaction mixture can be cooled to about 0° C. and 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine can be added. The free base can be stirred with HCl to obtain diethylamide hydrate hydrochloride 3. Those skilled in the art will recognize that pyridyl ketone 4 can be obtained by treatment of 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 can be added to the lithiated species 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 obtain amide 6 can be achieved using transition metal catalysis well known to those skilled in the art. Specifically, pyridyl ketone 4 can be subjected to Buchwald-type coupling conditions to give its corresponding free base form with an appropriate mineral base, as is well known in the literature.More specifically, the free base of compound 4 can be stirred in a suitable aprotic solvent, such as toluene or xylene, containing a mixture of about 1-5% by weight 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 Xantphos, XPhos, or DPEPhos. The resulting mixture can be heated at about 70° C. for about 12 to 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, for about 8 to 24 hours at about room temperature to about 65° C. 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 treatment under a series of thermal cycles of heating to 60° C. for 4 hours and recooling to room temperature. The resulting solid can be collected by filtration, dried at about 40° C. for about 4 hours, and optionally jet-milled to obtain lasmiditane hemisuccinate I.

[0045] Experimental procedure The following preparations of process intermediates further illustrate the invention and represent exemplary syntheses of various compounds. The reagents and starting materials are readily available or can be readily synthesized by one skilled in the art. It should be understood that the preparations and examples are given by way of illustration and that various modifications can be made by those skilled in the art.

[0046] LC-ES / MS is performed on an AGILENT® HP1100 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and / or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to the HP1100 HPLC. LC-MS conditions (low pH): Column: PHENOMENEX® GEMINI® NX C18 2.1 mm x 50 mm, 3.0μ, Gradient: 5 to 100% B for 3 min, then 100% B for 0.75 min, Column temperature: 50°C + / - 10°C, Flow rate: 1.2 mL / min, Solvent A: deionized water with 0.1% HCOOH, Solvent B: ACN with 0.1% formic acid, Wavelength 214 nm. Alternative LC-MS conditions (high pH): Column: XTERRA® MS C18 column 2.1 x 50 mm, 3.5 μm, gradient: 5% solvent A for 0.25 min, gradient of 5% to 100% solvent B for 3 min and 100% solvent B for 0.5 min or 10% to 100% solvent B for 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.

[0047] NMR spectra were performed on a Bruker AVIII HD 400 or 500 MHz NMR Spectrometer and obtained as CDCl3 or (CD3)2SO solutions reported in ppm using residual solvent [CDCl3, 7.26 ppm, (CD3)2SO, 2.05 ppm] as the reference standard. When reporting peak multiplicities, the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broadband singlet), dd (doublet of doublets), dt (doublet of triplets). When reporting coupling constants (J), they are reported in Hertz (Hz).

[0048] Chloride analysis is performed on an ESA CORONA® Plus instrument equipped with a CORONA® CAD® (charged aerosol detector)-HPLC, Acclaim Trinity P1 (100×3.0 mm, 3 um), mobile phase: 50 mM ammonium acetate in ACN, pH approx. 5.

[0049] The compounds described herein can be prepared by general methods known to those skilled in the art or by the processes described herein. Suitable reaction conditions for the steps of these schemes are well known in the art, and appropriate substitution of solvents and co-reagents is within the skill of the art. Similarly, those skilled in the art will understand that synthetic intermediates can be isolated and / or purified by various well-known techniques as necessary or desired, and often various intermediates can be used directly in subsequent synthetic steps with little or no purification. Furthermore, those skilled in the art will recognize that in some situations the order in which multiple moieties are introduced is not important.

[0050] Preparation 1 1-Methylpiperidine-4-carboxylic acid hydrochloride [ka] Scheme 1, Step A: A jacketed reactor is charged with piperidine-4-carboxylic acid (10.0 g, 77.5 mmol) and deionized water (40 mL). The mixture is heated to reflux (95-100 °C). Formic acid (13.9 g, 302 mmol) is added over 30 min. A 37% aqueous solution of formaldehyde (8.1 g, 101 mmol) is added dropwise to the mixture over at least 30 min. Water (0.3 mL) is used as a line rinse to the reactor. The mixture is stirred at reflux (95-100 °C) for 4 h and sampled by HPLC for IPC analysis (piperidine-4-carboxylic acid with NMT 0.5%). If the amount of piperidine-4-carboxylic acid is greater than 0.5%, the mixture is stirred for an additional 2 h. If specifications are met, the solution is concentrated under vacuum until a residual volume of approximately 20 mL remains, and the residue is cooled to 45-50 °C. Charge the cooled solution with 33% aqueous HCl (12.8 g, 116 mmol) over 30 min. Use water (0.3 mL) as a line rinse to the reactor. Distill water under vacuum until a residual volume of about 20 mL remains. Charge ACN (42.4 mL) to the concentrated solution at 45-50 °C and concentrate the mixture at atmospheric pressure until a residual volume of about 40 mL remains. Charge ACN (20.4 mL) to the concentrated solution at 45-50 °C and concentrate the mixture at atmospheric pressure until a residual volume of about 40 mL remains. Repeat the dilution / concentration operations until the in-process control of water content by Karl Fischer analysis is NMT 0.2%, during which a slurry is formed. Charge ACN (10.2 mL) to the slurry at 45-50 °C. Cool the slurry to 20 °C over 1 h and stir for an additional 2 h. Isolate the resulting solid by filtration and rinse the cake with ACN (10.2 mL). The wet cake is dried at 40° C. under nitrogen at atmospheric pressure to give the title compound (12.1 g, 87% yield). MS (m / z): 144 (M+H).

[0051] Preparation 2 N,N-Diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride [ka] Scheme 1, Step B: A jacketed reactor is charged with 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 is heated to 50 °C. Thionyl chloride (24.2 g, 200.4 mmol) is charged to the hot suspension over 1 h. Chlorobenzene (13.5 mL) is used as a line rinse to the reactor. After the thionyl chloride addition is complete, the mixture is stirred for 5 h. The solution is then cooled to 0-10 °C. A solution prepared from diethylamine (17.7 g, 12.5 mmol) and TEA (50.7 g, 25 mmol) is charged to the cold reaction mixture over 3 h. Chlorobenzene (13.5 mL) is used as a line rinse to the reactor. After the complete addition of the amine mixture, the mixture is stirred for 2 h. Treat the reaction with 20 wt% aqueous NaOH (180.3 g, 902 mmol) and stir at room temperature for 2 h. Use water (3 mL) as a line rinse to the reactor. Allow the mixture to stand for 2 h and remove the aqueous phase. Place the remaining organic phase under vacuum. Heat the mixture to distill off the residual amine and most of the chlorobenzene. After approximately 10 volumes of distillate have been collected, vent the reactor to atmospheric pressure using nitrogen. Cool the remaining solution to between 10 °C and 30 °C. Charge THF (120 mL) and water (4.54 g, 252 mmol) to the reactor. With the reaction mixture at room temperature, precipitate the desired product by the addition of 20 wt% aqueous HCl in isopropanol (30.4 g, 167 mmol). Use THF (5.4 mL) as a line rinse to the reactor. After complete addition of the HCl, stir the suspension at room temperature for 2 h. Collect the resulting solid by filtration and wash with THF (75.0 mL). The collected solid is dried under vacuum for 16 hours at 40° C. to give the title compound (35.5 g, 84% yield). MS (m / z): 199 (M+H).

[0052] Preparation 3 (6-Bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide [ka] 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) is treated with a 20 wt% aqueous solution of NaOH (34.0 g, 170 mmol). A water rinse (1.94 mL) is used to complete the addition. The mixture is stirred at room temperature for 30 min, the phases are allowed to settle, and the phases are separated. The aqueous phase is extracted with MTBE (43.7 mL) and the organic phases are combined. The organic phase is dried by distillation at atmospheric pressure until the in-process control of water content by Karl-Fischer analysis is <0.10 wt%. If the target analysis is not met, charge the reaction with MTBE (43.7 mL) and repeat the distillation. Typically, three distillations are required to reach the target analysis of water. A separate reactor is charged with a mixture of 2,6-dibromopyridine (30.2 g, 128 mmol) and MTBE (105 mL) and cooled to below −58° C. The cooled suspension is charged with a 2.5 M solution of n-BuLi in hexane (51.3 mL, 128 mmol) over 2 h. A rinse of MTBE (4.5 mL) is used to complete the transformation. After complete n-BuLi addition, the mixture is aged while the temperature is maintained below −58° C. for an additional 2 h. After aging, a solution of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride in MTBE is added to the cold reaction over 45 min. A rinse of MTBE (13.5 mL) is used to complete the transformation. After complete addition of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride in MTBE, the mixture is aged for at least 30 min. After aging, the reaction is warmed to 0° C. over 1 h. The cold reaction mixture is added to a 2.5 M aqueous solution of HCl (146 mL, 366 mmol) at a rate to maintain the quench temperature at NMT 30° C. A rinse of MTBE (13.5 mL) is used to complete the transformation. After the transformation is complete, the mixture is stirred for at least 30 min and the phases are 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 mixture is treated with a 20 wt % aqueous solution of NaOH (59.5 g, 298 mmol). A rinse of water (2.80 mL) is used to complete the transformation. The mixture is stirred for at least 30 min and the phases are 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 phase is dried by distillation under vacuum to obtain an in-process control of water content by Karl-Fischer analysis of <0.20 wt%. If the target analysis is not met, n-BuOH (41.1 mL) is charged and the distillation is repeated. Typically, two distillations are required to reach the in-process control target analysis. The concentrated solution is clarified by filtration and a rinse with n-BuOH (89.6 mL) is used to complete the transfer and rinse the filter. The clarified solution is treated with a 48 wt% aqueous solution of HBr (9.91 mL, 87.7 mmol) over 90 minutes. A rinse of n-butanol (13.8 mL) is used to complete the transfer. A check of the pH indicates that the reaction mixture has a pH of about 1. The mixture is dried by distillation at atmospheric pressure to obtain an in-process control of water content by Karl-Fischer analysis of <0.30 wt%. The mixture is concentrated to 172 mL. If the target analysis is not met, charge n-BuOH (54.8 mL) and repeat the distillation. Cool the mixture to 20° C. and stir for 12 h. Collect the resulting solid by filtration and wash twice with n-BuOH (10.75 mL). Dry the solid under vacuum at 60° C. to give the title compound (24.8 g, 80% yield). MS (m / z): 283, 285 (. 79 Br, 81 Br, M+H).

[0053] Preparation 4 (6-Amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride [ka] Scheme 1, Step D: A pressure reactor is 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 is exchanged with three nitrogen / vacuum purge cycles. The solid is charged with a solution of NH3 / ethylene glycol (total 273.5 g, 39.1 g NH3, 2.33 mol, 210 mL ethylene glycol) and the resulting mixture is stirred at room temperature for 2 hours. The mixture is heated to 80° C., stirred for 10 hours, and cooled to room temperature for in-process control sampling of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide NMT 2%. If the target analysis is not met, the reaction is stirred at 80° C. for an additional 4 hours and sampled again. To the completed reaction, H2O (90 mL) is charged and the mixture is filtered. The filtrate is charged with aqueous NaCl (253.9 g NaCl, 2.73 mol, 13.7 L / kg HO) and the resulting mixture is stirred at room temperature for 10 min. The mixture is charged with a 20% aqueous solution of NaOH (4.44 equiv., 368 mmol) and the biphasic mixture is stirred at room temperature for 5 min. The mixture is extracted with MTBE (90 mL) 4-5 times at room temperature. The combined MTBE layers are treated with 5 wt.% carbon for 30 min and the carbon is removed by filtration. The organic filtrate is concentrated under vacuum to approximately 150 mL. The concentrated filtrate is charged with IPA (200 mL) and the solution is concentrated under vacuum twice to approximately 150 mL. The IPA distillation is repeated as necessary to meet the target analysis for in-process control of water. The water content is confirmed to be 0.2% or less by Karl-Fischer analysis. In a separate reactor, a 20 wt.% solution of HCl in IPA (30 g, 166 mmol) and water (10.5 mL) are charged at room temperature. The concentrated product mixture is placed in the HCl solution over 90 min. The resulting slurry is stirred at room temperature for 8 h or more. The slurry is filtered, rinsed twice with a mixture of 95:5 IPA / H2O (36 mL) at room temperature, and dried under vacuum at 40 °C for 16-24 h to give the title compound (18.4 g 68% yield). MS (m / z): 220 (M+H). 1H NMR (400MHz, D2O / DMSO-d6) δ ppm 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. Analysis of salt: 20.23% (n=2).

[0054] X-ray powder diffraction (XRPD) of crystalline form XRPD patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray powder diffractometer operating at 35 kV and 50 mA, equipped with a CuKα source and Vantec detector. Samples are scanned from 4 to 40 2θ° using a 1.0 mm divergence slit, a 6.6 mm fixed anti-scatter slit, and an 11.3 mm detection slit, with a step size of 0.008 2θ° and a scan rate of 0.5 sec / step. Dry powder is loaded into a quartz sample holder and a glass slide is used to obtain a smooth surface. Diffraction patterns of crystalline forms are collected at ambient temperature and relative humidity. Crystalline peak positions are determined in MDI-Jade after shifting the entire pattern based on an internal NIST675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystalline form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. In the presence of preferred orientation effects, the peak intensities change, but the characteristic peak positions of the polymorphs do not. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is well known in the field of crystallography that for any given crystalline form, the angular peak positions may vary slightly. For example, peak positions may vary due to variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, the variation in peak positions of ±0.2 2θ° is estimated to take into account these potential variations without preventing unambiguous identification of the indicated crystalline form. Confirmation of a crystalline form can be based on any unique combination of prominent peaks.

[0055] The sample of Preparation 4, (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride, is characterized by an XRD pattern using CuKα radiation as having the diffraction peaks (2θ values) set forth in Table 1 below, in particular as having a peak at 8.3° in combination with one or more peaks selected from the group consisting of 16.6°, 23.5°, and 33.7°, with a diffraction angle tolerance of 0.2 degrees. [Table 1]

[0056] Preparation 5 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride [ka] Scheme 1, Step E: To a suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride dihydrate (10 g, 30.6 mmol) in chlorobenzene (65 mL) is charged 6 w / w% aqueous NaOH (3 g, 75 mmol). The biphasic mixture is heated to 54° C. with stirring for 30 min, the mixture is allowed to separate over 30 min, and the layers are separated at 54° C. The aqueous layer is back-extracted with room temperature chlorobenzene (45 mL). The organic layers are combined and distilled under vacuum to approximately 62 mL to obtain a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. In a separate reactor, 2,4,6-trifluorobenzoic acid (5.9 g, 1.1 eq, 33.7 mmol), DMF (62 mg, 0.85 mmol), and chlorobenzene (32 mL) are charged and the mixture is heated to 80° C. Charge the heated mixture with thionyl chloride (4.37 g, 37 mmol) at 80° C. over 4 hours. Stir the mixture at 80° C. for at least 6 hours and heat to 100° C. for at least 6 hours to purge residual HCl gas. Cool the acid chloride solution to room temperature and transfer to a separate reactor. Heat the acid chloride solution to 100° C. and charge with (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone over 4 hours. Stir the resulting slurry at 100° C. for an additional 3 hours and cool to room temperature. Charge the cooled slurry with ACN (100 mL). Heat the resulting slurry to 80° C. for 1 hour and cool to room temperature over 2 hours. Stir the resulting slurry at room temperature for an additional 1 hour and filter. Wash the filter cake with room temperature ACN (10 mL). The collected solid is dried under vacuum at 100° C. for 16 hours to give the title compound (10.7 g, 85% yield). MS m / z 378 (M+H).

[0057] Alternative procedure for preparation 5 A suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride dihydrate (10 g, 30.6 mmol) in chlorobenzene (65 mL) is charged with 6 w / w% aqueous NaOH (2.97 g, 74.4 mmol). The biphasic mixture is heated to 54° C. with stirring for 30 min and the layers are allowed to separate over 30 min. The layers are separated at 54° C. The aqueous layer is back extracted with room temperature chlorobenzene (45 mL). The organic layers are combined and distilled under vacuum to approximately 62 mL to obtain a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. A separate reactor is charged with 2,4,6-trifluorobenzoic acid (5.9 g, 33.7 mmol), DMF (62 mg, 0.85 mmol), and chlorobenzene (32 mL) and the mixture is heated to 80° C. Charge the heated mixture with thionyl chloride (4.4 g, 37 mmol) at 80° C. over 4 hours. Stir the mixture at 80° C. for at least 6 hours and heat to 100° C. for at least 6 hours to purge residual HCl gas. Cool the acid chloride solution to room temperature and transfer to a separate reactor. Heat the acid chloride solution to 100° C. and charge the solution with (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone over 4 hours. Stir the resulting slurry at 100° C. for an additional 3 hours and cool to room temperature. Charge the cooled slurry with ACN (100 mL). Heat the resulting slurry to 80° C. for 1 hour and cool to room temperature over 2 hours. Stir the resulting slurry at room temperature for an additional hour and collect the resulting solid by filtration. Wash the filter cake with room temperature ACN (10 mL). The solid is dried under vacuum at 100° C. for 16 hours to give the title compound (10.7 g, 85% yield). MS m / z 378 (M+H).

[0058] Preparation 6 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate [ka] Scheme 1, Step F: A reactor is charged with 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride (20 g, 48.4 mmol) and MTBE (202 mL). A solution of aqueous NaHCO3 (8.13 g, 96.8 mmol NaHCO3 in 200 mL water) is charged to the stirred slurry at room temperature over 1 h. The biphasic mixture is separated and the aqueous layer is back-extracted with MTBE (202 mL). The combined organic layers are distilled under vacuum to a final volume of about 200 mL. The distilled solution is charged with SiO2 (2 g) and the resulting mixture is stirred at room temperature for 30 min, filtered, and the filter cake is rinsed with MTBE (10.8 mL). Charge the filtrate with carbon (340 mg; alternatively, the solution can be filtered through a carbon cartridge) and the resulting mixture is stirred at room temperature for 30 min, filtered through a 1-5 μm filter, followed by rinsing with MTBE (21.6 mL). Distill the filtrate under vacuum to approximately 80 mL. Charge the concentrated solution with ethanol (114 mL) and distill the resulting solution under vacuum to approximately 84 mL. Add back EtOH and continue distillation until the water content is 1% or less by Karl Fischer analysis to provide a dry solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide. Charge a separate reactor with succinic acid (3.03 g, 25.7 mmol) and EtOH (60 mL). Stir and heat the mixture at 33 °C until the succinic acid is completely dissolved.

[0059] The solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide is heated to 55° C. A portion of the solution of succinic acid in EtOH (approximately 1.0 L / kg) is charged to the heated solution. The resulting solution is then seeded by the addition of 1 wt % 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate (200 mg). The resulting slurry is stirred for 30 minutes and the remainder of the succinic acid in EtOH solution is charged at a constant rate over 2 hours. The reactor contents are stirred for 30 minutes and cooled linearly to room temperature over 2.5 hours. The resulting slurry is stirred at room temperature for 3 hours or more. The slurry is filtered and the collected solid is washed with EtOH (60 mL). The solid is 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). 1 H NMR (500MHz, DMSO-d6) δ ppm 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).

[0060] Alternative procedure for preparation 6 Scheme 3, Steps D, E, and F: A jacketed reactor is charged with (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone (50 g, 137 mmol) and toluene (400 mL). Water (250 mL) is added, followed by KOH pellets (13.6 g, 206 mmol), and the mixture is stirred at room temperature for 3 h. The contents of the reactor are filtered and returned to the reactor. The aqueous layer is drained, and if necessary, the organic layer is treated with activated charcoal to decolorize. The mixture is concentrated at 50 °C and reduced pressure to approximately 150 mL. Toluene (225 mL) is returned to the reactor under a nitrogen atmosphere, K2CO3 (28.5 g, 206 mmol), 2,4,6-trifluorobenzamide (26.5 g, 151 mmol), and water (2.5 mL) are added, and the contents are stirred at room temperature. In a separate flask under nitrogen atmosphere, toluene (20 mL), Pd(OAc)2 (154 mg, 0.68 mmol), and Xantphos (795 mg, 1.37 mmol) are placed and the contents are stirred at room temperature for 30 min. The resulting solution is transferred to a reactor and the reactor is heated to 70° C. with stirring. After 5 h, the mixture is sampled for IPC HPLC analysis of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone at NMT 0.1%. If the amount of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone is not satisfied, the mixture is stirred for an additional 5 h and sampled again. If the IPC is satisfied, the mixture is stirred at 70° C. for an additional 12 h. The contents of the reactor are then cooled to 45° C. Water (250 mL) and EtOAc (250 mL) are added and the mixture is stirred for 1 h. Stirring is stopped and the layers are allowed to separate. The aqueous layer is removed and discarded. Water (250 mL) is charged and the resulting mixture is stirred for 1 hour. Stirring is stopped and the layers are allowed to separate. The aqueous layer is removed and discarded. Thiourea modified silica gel (5 g) is charged and the reactor is heated to 60° C. with stirring for 8 hours. The reactor contents are cooled to room temperature. The solution is filtered and returned to the reactor. The thiourea modified silica gel filter cake is rinsed with EtOAc (150 mL) and returned to the reactor. Activated charcoal treatment can be performed to remove color, if necessary. The solution is passed through a polishing filter to give a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide.

[0061] The solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide is concentrated under reduced pressure at 50° C. to approximately 150 mL. EtOH (250 mL, denatured with toluene) is charged and the contents are concentrated under reduced pressure at 50° C. to approximately 150 mL. This is repeated for a total of three cycles to achieve adequate toluene removal before final toluene charge to a total of 250 mL. The resulting toluene mixture is heated to 55° C. In a separate vessel, succinic acid (8.6 g, 73 mmol) and EtOH (200 mL, denatured with toluene). The contents of the vessel are stirred until complete dissolution of the succinic acid is achieved. Approximately 30 mL of the succinic acid solution is transferred to the solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide and the resulting solution is stirred at 55° C. 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate is added as a seed crystal either as a solid or as a slurry in toluene-modified EtOH. The remainder of the succinic acid in toluene-modified EtOH solution is transferred to the reactor over 1.5 hours. The reactor contents are cooled to room temperature over 10 hours. The resulting slurry can be slurry milled to control particle size. If slurry milled, the reactor contents can be subjected to a series of thermal cycles via heating to 60° C. for 4 hours with stirring and recooling to room temperature to further control particle size distribution. The slurry is filtered, rinsed with EtOH (100 mL, toluene-modified), and dried under vacuum at 40° C. for 12 hours to give the title compound (43.9 g, 73% yield). MS m / z 378 (M+H). The dried solid can then be jet milled for further particle size control.

[0062] Description of drug product manufacturing methods In one embodiment, the lasmiditan prepared by the process provided herein can be further prepared as a specific useful drug product form. In one embodiment, such drug product form is available as an oval 50 and 100 mg debossed, aqueous film coated, immediate release tablet. The 50 mg tablet is a light gray, oval tablet debossed with "4312" on one side and "L-50" on the other. The 100 mg tablet is a light purple, oval tablet debossed with "4491" on one side and "L-100" on the other.

[0063] The following unit formulas can be used to manufacture Lasmiditan tablets. The ingredient naming rules are in accordance with USP: [Table 2]

[0064] Tablet manufacturing: Lasmiditan tablets are manufactured using a high shear wet granulation process described below: High Shear Wet Granulation: Sodium lauryl sulfate is passed through a security screen and added to purified water to form the granulation liquid. Lasmiditan drug substance and excipients to be wet granulated (microcrystalline cellulose, pregelatinized starch, croscarmellose sodium) are passed through a security screen and combined in a granulator. The ingredients are mixed in the main impeller of the granulator prior to the addition of the granulation liquid. The powder blend is granulated in the granulator by adding the granulation liquid while the powders are mixing. Upon completion of the liquid addition, the granulation is wet massed to facilitate liquid distribution. The granulation is coarsely sized by passing through a cone mill before drying.

[0065] Fluid Bed Drying: The granulation is dried in a fluid bed dryer until a moisture value of (50mg and 100mg: NMT7%) is achieved, measured by weight loss on drying or using an equivalent scientifically justified method. The dried granules are passed through a cone mill and added to a tumble bin.

[0066] Final Blend - Extragranular Powder Blend and Final Blend Lubrication: Pass the extragranular croscarmellose sodium through a security screen and add to the dry milled granules in the tumble bin. Tumble blend the ingredients. Pass the extragranular magnesium stearate through a security screen and add to the tumble bin. Tumble blend the ingredients.

[0067] Tablet Compression: The blended granulation is compressed into tablets using a rotary compressor. Compression parameters are selected at the beginning of the batch to achieve target average (n=10) tablet weights of (50 mg: 111.4 mg-123.2 mg, 100 mg: 222.8-246.2 mg) and average (n=10) tablet breaking forces of (50 mg: 4.1-13.7 kponds, 100 mg: 6.0-17.9 kponds). Average (n=10) core tablet weights, tablet breaking forces, and tablet thickness are assessed at the beginning and throughout the compression unit operation. Tablet friability and tablet disintegration times are assessed at the beginning of compression.

[0068] Film Coating of Core Tablets: The color mixture (gray for 50 mg, purple for 100 mg) is passed through a security screen and mixed with purified water to form a coating suspension. The tablets are film coated with the suspension utilizing a spray gun in a perforated coating pan. The pan is rotated, drawing dry air through the tablet bed while the coating suspension is applied at a controlled rate with pneumatic atomization, resulting in an acceptable exhaust temperature. Sufficient coating is sprayed to achieve the desired coating application percentage (50 mg and 100 mg: 2.0% to 5.5%). The film coated tablets are inspected for visual quality after completion of the coating step. The film coated tablets are discharged into a bulk storage container and may be sorted (optional).

[0069] Container Closure System - Unit Dose Blister: Lasmiditan tablets are provided in individual blister cavities formed from a polychlorotrifluoroethylene (PCTFE) / polyvinyl chloride (PVC) laminate film and sealed with an aluminium foil laminated lidding material containing a PVC-based heat seal coating.

[0070] Preparation and description of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate [ka] The preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate (also called lasmiditan acetate) is carried out 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) with stirring at 1000 rpm at room temperature. Acetic acid (100 μL) is added. After approximately 2 minutes of stirring, a white solid precipitates from the solution. After 10 minutes, the stirring is stopped and the white solid is collected by vacuum filtration on Whatman paper and dried in place under air flow for 10 minutes to give the title compound (650 mg, 92% yield).

[0071] Counterion stoichiometry is measured by nuclear magnetic resonance using an Agilent 400 MHz spectrometer. Sample solutions are 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 a standard for other measurements, in DMSO-d6 (approximately 0.75 mL). The concentrations of the samples from 0 to 12 ppm are 13 C-Decoupling 1The H spectrum is acquired using the following parameters: 90 degree excitation pulse, 64 scans, 25 s relaxation delay, and 4.5 s acquisition time. The acetate resonances at approximately 1.9 ppm (3H) and 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide at approximately 7.8 ppm (1H) are 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 number of protons for the resonances, resulting in an observed molar ratio of acetate:2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide of 29094 / (3 x 9508) = 1.02. For example, for lasmiditan acetate containing maleic acid (internal standard), 1 See Figure 1 showing the H NMR spectrum (400 MHz, DMSO-d6). This result provides experimental evidence that the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate is a monoacetate.

[0072] X-ray powder diffraction (XRPD) of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate XRPD patterns of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate crystalline solid are obtained on a Bruker D4 Endeavor X-ray powder diffractometer operating at 35 kV and 50 mA, equipped with a CuKα source and Vantec detector. Samples are scanned from 4 to 40 2θ° using a 1.0 mm divergence slit, a 6.6 mm fixed anti-scatter slit, and an 11.3 mm detection slit, with a step size of 0.008 2θ° and a scan rate of 0.5 s / step. The dry powder is loaded into a quartz sample holder and a glass slide is used to obtain a smooth surface. Diffraction patterns of the crystalline form are collected at ambient temperature and relative humidity. The crystalline peak positions are determined in MDI-Jade after shifting the entire pattern based on an internal NIST675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystalline form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. When the effect of preferred orientation is present, the peak intensities change, but the characteristic peak positions of the polymorph do not. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. It is also well known in the field of crystallography that for any given crystalline form, the angular peak positions may vary slightly. For example, the peak positions may vary due to variations in the temperature at which the sample is analyzed, the displacement of the sample, or the presence or absence of an internal standard. In the case of the present invention, the variation in peak positions of ±0.2 2θ° is estimated to take into account these potential variations without preventing unambiguous identification of the indicated crystalline form. Confirmation of the crystalline form may be based on any unique combination of prominent peaks.

[0073] A prepared sample of the crystalline acetate salt is characterized by an XRPD pattern using CuKα radiation as having the diffraction peaks (2-theta values) set forth in Table 3 below, in particular as having a peak at 26.2 in combination with one or more peaks selected from the group consisting of 20.4, 14.0, and 17.9, with a diffraction angle tolerance of 0.2 degrees. [Table 3]

[0074] Solubility of Lasmiditan Acetate and Use for Formulation for Subcutaneous Injection: Lasmiditan acetate was found to deliver a dose of lasmiditan in a minimal volume in a near-physiological fluid, surprisingly superior to many alternative salt forms for the preparation of subcutaneous formulations. Lasmiditan acetate was found to enable a desired dose target of about 50 mg in a minimal volume of about 1 mL or less while achieving a desired target pH close to neutral, plus being relatively isotonic and physically and chemically stable. It was experimentally determined that achieving a solubility of >50 mg / mL at near-neutral pH using lasmiditan hemisuccinate was difficult without the use of a co-solvent. For solubility determination, 10 mmol buffers were made with each acid and salt, and the pH was adjusted by varying the acid / salt ratio. Excess solids were equilibrated overnight at room temperature, the solution concentrations were analyzed by HPLC, and the solids were characterized by XRPD. In contrast, it was found that for lasmiditan acetate, a solubility of >50 mg / mL could be achieved at near-neutral pH without adjusting the pH. [Table 4]

[0075] It has been surprisingly discovered that lasmiditan acetate exhibits a highly advantageous combination of pharmaceutical properties. Lasmiditan acetate allows for the desired solubility to provide a highly concentrated formulation with a dose volume of about 1 mL or less for the desired unit dose, which is important for clinical applications such as use in available autoinjector devices. In addition, dissolution of lasmiditan acetate at 50 mg / mL results in a near-neutral pH (pH about 6.8), is isotonic, and is stable for at least 2 months. Lasmiditan acetate exhibits significantly higher solubility than lasmiditan hemisuccinate with a desirable pH profile, allowing delivery of the required unit dose in a volume of about 1 mL or less.

[0076] These results indicate that lasmiditan acetate allows for a surprisingly high concentration of aqueous solution of lasmiditan with pharmaceutical properties useful 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), Volume 21, Issue 2, pages 147-153). Preferably, subcutaneous injections are administered by prefilled syringes or autoinjectors using devices known to those skilled in the art (see, e.g., Stauffer VL, et al., Comparison between prefilled syringe and autoinjector devices on patient-reported experiences and pharmacokinetics in galcanezumab studies., 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 formats provide a fixed dose without patient measurement, allowing patient independence while providing dose accuracy and safety. The use of lasmiditan acetate for the acute treatment of migraine attacks in a format such as an autoinjector provides an improved tool for institutionalized patients, such as those in a hospital acute care setting, where migraine attacks and associated nausea and vomiting compromise the patient's use of tablets and the patient and / or provider would prefer an improved injectable form of lasmiditan.A parenteral formulation of lasmiditan acetate is expected to provide immediate release, allowing for a rapid time to onset of action, and may preferably allow for a shorter time to effectiveness compared to an oral dosage form when used on demand at the onset of a migraine attack.

[0077] Providing a lasmiditan formulation for injection at neutral and physiological pH (about 6.0-7.5) and isotonic with physiological fluids (e.g., 280-300 mosm / kg) would be highly clinically desirable, e.g., minimizing pain on injection and / or potential tissue irritation. Achieving an injection volume of about 1 ml or less would allow the use of available syringe technologies, such as autoinjectors, providing an improved injection and delivery experience for patients, e.g., in terms of injection time and / or pain on injection. Enabling the use of pre-filled syringes, pens, and / or autoinjector technologies is clinically important for migraine sufferers, as these devices provide ease of use during a migraine attack, when patients are often under duress when using the product. Additionally, enabling the use of pre-filled syringes, pens, and / or autoinjector technologies is clinically important, as they provide portable access to the medication at any time, which is easily accessible in the course of daily life, where a migraine attack may occur at any time.

[0078] The following unit formula can be used to prepare an injectable solution of lasmiditan: [Table 5]

Claims

1. A process for preparing a compound of the formula 【Chemistry 1】 i.) treatment of piperidine-4-carboxylic acid under reductive amination conditions involving formaldehyde and formic acid in water to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride, followed by treatment with aqueous HCl, followed by water distillation and acetonitrile addition, repeated dilution / distillation steps until the water content is 0.2% or less by Karl Fischer analysis; ii.) treatment of 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to give 1-methylpiperidine-4-carboxylic acid chloride; iii.) treatment of 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by a base wash, and then treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; iv.) treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with a mineral base such as aqueous NaOH in a non-polar solvent such as methyl-tert-butyl ether to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide, followed by washing with water, phase separation and distillation of the organic solvent until the water content is less than or equal to 0.1 wt % by Karl Fischer analysis; v.) the subsequent treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone, followed by extraction of the resulting mixture with a suitable organic solvent such as water and n-butanol, phase separation, and distillation of said organic solvent repeated until the water content is 0.2 wt.% or less by Karl Fischer analysis; vi.) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide, followed by extraction with n-butanol, followed by repeated distillation of the organic solvent until the water content is 0.3% or less by Karl Fischer analysis; vii.) (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide at about 80° C. for about 2 hours with Cu ２ NH in ethylene glycol in the presence of O catalyst ３ followed by washing with water, saturated aqueous NaCl, and 20% aqueous NaOH, followed by extraction with a non-polar aprotic solvent such as methyl-tert-butyl ether, phase separation, and treatment of the organic phase with 5 wt. % carbon; viii.) filtration of the above mixture, dilution with a suitable polar alcoholic solvent such as isopropanol, and distillation of the organic solvent repeated until the water content is 0.2% or less by Karl-Fisher analysis, the water concentration of the resulting slurry is at least 2%, followed by treatment of the resulting residue with isopropanol, water, and 20% by weight HCl, filtration of the resulting slurry, and drying under vacuum at 40° C. for 16-24 hours to obtain solid (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride; ix.) treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6 wt / wt % NaOH in water at about 54° C. for about 30 minutes to obtain (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone, followed by phase separation and vacuum distillation of the aqueous solution; x.) subsequent treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100° C. for about 4 hours to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride, charging with acetonitrile and heating the resulting slurry to 80° C. for about 1 hour, and then collecting the resulting solid by filtration; xi.) 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride in methyl tert-butyl ether using a saturated aqueous Na ２ CO ３ and the steps of processing in xii.) SiO2 extraction of the mixture from step xi above to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide. ２ followed by filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation to a water content of 1% or less by Karl Fischer analysis; xiii.) treating 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in ethanol with a solution of 0.5 equivalents of succinic acid in ethanol at about 55° C. for not less than 3 hours at room temperature to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and then collecting the solid by filtration.

2. A process for preparing a compound of the formula 【Chemistry 2】 i.) treatment of piperidine-4-carboxylic acid under reductive amination conditions involving formaldehyde and formic acid in water to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride, followed by treatment with aqueous HCl, followed by water distillation and acetonitrile addition, repeated dilution / distillation steps until the water content is 0.2% or less by Karl Fischer analysis; ii.) treatment of 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent, such as thionyl chloride in chlorobenzene, to give 1-methylpiperidine-4-carboxylic acid chloride; iii.) treatment of 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by a base wash, and then treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; iv.) treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with a mineral base such as aqueous NaOH in a non-polar solvent such as methyl-tert-butyl ether to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide, followed by water washing, phase separation and distillation of the organic solvent until the water content is 0.1 wt.% or less by Karl Fischer analysis; v.) the subsequent treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone, followed by extraction of the resulting mixture with a suitable organic solvent such as water and n-butanol, phase separation, and distillation of said organic solvent repeated until the water content is 0.2 wt.% or less by Karl Fischer analysis; vi.) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide, followed by extraction with n-butanol, followed by repeated distillation of the organic solvent until the water content is 0.3% or less by Karl Fischer analysis; vii.) treatment of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide in a biphasic mixture of water and toluene with solid KOH for about 3 hours to obtain (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone, followed by separation of the organic layer and evaporation of the solvent; viii.) Catalyst reaction of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone at about 70° C. for about 12 hours until the (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone content is less than 0.1% by HPLC to obtain a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide. ２ CO ３ , water, Pd(OAc) ２ and 2,4,6-trifluorobenzamide in toluene containing Xantphos, followed by dilution of the reaction mixture with water and EtOAc, followed by treatment with thiourea modified silica gel at 60° C. for about 8 hours, followed by filtration. ix.) A process comprising the steps of treating a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid in EtOH at 55° C. for about 3 hours to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, followed by cooling to room temperature for about 10 hours and collecting the resulting solid by filtration.

3. 3. The process of claim 1 or 2, wherein the reaction is carried out using batch processing methodology.

4. 4. The process of claim 3, wherein the batches produced are process scale.

5. 5. The process of claim 4, wherein the batch produced is at least 1 kilogram.

6. 5. The process of claim 4, wherein the batch produced is at least 10 kilograms.

7. 5. The process of claim 4, wherein the batch produced is at least 100 kilograms.

8. A tablet produced by the process of any one of claims 1 to 7 comprising 50 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

9. A tablet produced by the process of any one of claims 1 to 7 comprising 100 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

10. A compound of the formula: 【Chemistry 3】

11. The compound of claim 10 which is crystalline.

12. 12. The compound of claim 11, characterized by an X-ray powder diffraction pattern using CuKα radiation having a strong peak at a diffraction angle 2-theta of 8.3° combined with one or more of the peaks selected from the group consisting of 16.6°, 23.5°, and 33.7° (each ±0.2°).

13. A compound of the formula: 【Chemistry 4】

14. A crystalline form of the compound of claim 13.

15. 15. The compound of claim 14, characterized by an X-ray powder diffraction pattern using CuKα radiation having a strong peak at a diffraction angle 2-theta of 26.2° combined with one or more of the peaks selected from the group consisting of 20.4°, 14.0°, and 17.9° (each ±0.2°).

16. A pharmaceutical composition comprising a compound according to any one of claims 13 to 15, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

17. 17. The pharmaceutical composition of claim 16, further comprising acetic acid.

18. A method for treating migraine in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 13 to 15.

19. A compound according to any one of claims 13 to 15 for use in therapy.

20. A compound according to any one of claims 13 to 15 for use in the treatment of migraine.

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