The embodiments of the present invention relate to the fields of pharmaceutical chemistry and synthetic organic chemistry, and provide processes and an intermediate for the large-scale synthesis of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyri din-2 -yl]-benzamide hemi-succinate salt, a 5-HT1F receptor agonist, and

formulations and product forms made by these processes, and to preparation of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate and uses thereof for parenteral formulations and treatment of migraine.

Lasmiditan is a selective and highly potent 5-HTIF receptor agonist which is now approved in the United States, as 50 mg or 100 mg tablets, for acute on-demand treatment of migraine (See e.g. 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 No. 439239-90-4) can be described chemically as 2,4,6-trifhioro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide. U.S. Patent No. 7,423,050 and U.S. Publication No. 20080300407 describe the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide having the structural formula:

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

As used herein, useful forms of lasmiditan include pharmaceutically acceptable salts thereof, including but not limited to 2,4,6-trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide mono-hydrochloride salt, and 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemi-succinate salt. A synthetic route for the preparation of the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide has been disclosed previously as shown below in Scheme A. 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 9 steps. Improvements in the synthesis of lasmiditan could provide substantial and varied benefits, particularly for production at large-scale.

Scheme A

Stage 1

Stage 2

Stage 5

Stage 4

Ethylene glycol, ammonia

Cu20, 70 °C, 4 barG

(50-75%)

Chlorobenzene, 100 °C

(75-95%)

V

St 6

Synthetic chemistry process routes may be redesigned or revised aiming to achieve various advantages, including for example: improved yields, obtaining crystalline products, decreasing impurity profiles, utilizing commercially available intermediates, minimizing the number of synthetic steps needed, reducing the inputs required and/or the by-products produced, or any useful combination of such improvements, to achieve important real-world outcomes including decreased costs, providing less resource intensive processes, and facilitating efficient production. Improved methods of making lasmi ditan are needed which may achieve one or more of these aims, particularly for large-scale synthesis.

Further, migraine is one of the most common presenting symptoms in emergency rooms. Current methods for headache relief in the emergency room setting, when using lasmiditan for patients who have difficulty administering a tablet due to nausea and/or vomiting, may need to rely on the preparation of a diluted formulation of about 1 mg/ml lasmiditan delivered intravenously over an extended period of time, for example from about 20-60 minutes. Lasmiditan has been delivered intravenously in clinical studies in doses from about 1- 60 mg delivered in 60 ml infusions over 20 minutes ( See US Patent Application Publication No. 2010/0256187). The safe and effective treatment of migraine with lasmiditan for patients unable to administer tablets would be enabled by the availability of a high concentration parenteral dosage form. The present disclosure also addresses this need.

Summary

The embodiments of the present invention provide processes for the preparation of lasmiditan hemi succinate, 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2-pyridyljbenzamide hemisuccinate salt, and/or compositions thereof, and/or particularly useful intermediates for use in these processes. The embodiments of the present invention further provide for the preparation of lasmiditan acetate, 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate salt, and/or compositions thereof, and/or uses of lasmiditan acetate, and formulations thereof, in subcutaneous drug delivery.

In one embodiment, referred to as Route I, the present invention provides a process for preparing a compound of the formula:

comprising the steps of:

i.) Treatment of piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HC1 followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl -Fischer analysis, to obtain solid 1- methylpiperidine-4-carboxylic acid hydrochloride;

ii.) Treatment of l-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene obtain 1- methylpiperidine-4-carboxylic acid chloride;

iii.) Treatment of l-methylpiperidine-4-carboxylic acid chloride with N,N- diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HC1 in isopropanol to obtain solid N,N-diethyl-l-methyl-piperidine-4-carboxamide hydrate hydrochloride;

iv.) Treatment of N,N-diethyl-l-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 with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight % by Karl Fischer analysis to obtain N,N- di ethyl- 1 -methyl-piperidine-4-carboxamide;

v.) Subsequent treatment of N,N-di ethyl- l-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether with subsequent extraction of the resulting mixture with water and a suitable organic solvent such as «-butanol, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone;

vi.) Treatment of (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone with aqueous HBr and subsequent extraction with «-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo-2- pyridyl)-(l-methyl-4-piperidyl)methanone hydrobromide;

vii.) Treatment of (6-bromo-2-pyridyl-l-methyl-4-piperidyl)methanone

hydrobromide with a solution of NFb in ethylene glycol in the presence of CU2O catalyst at about 80 °C for about 2 hr, with subsequent washes with water, saturated aqueous NaCl, and 20% aqueous NaOH and subsequent extraction with a non-polar aprotic solvent such as methyl-tert-butyl ether, phase separation, and treatment of the organic phase with 5 weight % carbon;

viii.) Filtration of the above mixture, dilution with a suitable polar alcoholic solvent such as isopropanol, and repeated distillation of the organic solvent until the water content is not more than 0.2% by Karl-Fischer analysis, with subsequent treatment of the resulting residue with isopropanol, water, and 20 weight % HC1, wherein the water concentration of the resulting slurry is at least 2%, filtration of the resulting slurry, and drying under vacuum at 40 °C for 16-24 hr to obtain solid (6-amino-2-pyridyl)-(l- methyl-4-piperidyl)methanone dihydrate dihydrochloride;

ix.) Treatment of (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6 weight/weight % NaOH in water at about 54 °C for about 30 min, with subsequent phase separation and vacuum distillation of the aqueous solution to obtain (6- amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone;

x.) Subsequent treatment of (6-amino-2-pyridyl)-(l-methyl-4- piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100 °C for about 4 hr, with subsequent cooling, charging with acetonitrile and heating the resulting slurry to 80 °C for about 1 hr, and subsequent collection of the resulting solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide hydrochloride;

xi.) Treatment of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide hydrochloride with saturated aqueous NaiCCb in methyl-tert-butyl ether;

xii.) Treatment of the mixture of step xi above with S1O2 with subsequent filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation until the water content is not more than 1% by Karl-Fischer analysis, to obtain 2,4,6-trifluoro-N-[6-(l-methylpiperidine- 4-carbonyl)-2-pyridyl]benzamide;

xiii.) Treatment of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide in ethanol with a solution of 0.5 equivalents succinic acid in ethanol at about 55 °C for not less than 3 hr at RT, and subsequent collection of the solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(l- methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemi succinate.

In the process of Route I above, preferably the reactions are performed using batch processing methodology. In an embodiment the batches by Route I are produced at process scale. In an embodiment the batches by Route I are produced in at least 1 kilogram. In an embodiment the batches by Route I are produced in at least 10 kilograms. In an embodiment the batches by Route I are produced in at least 100 kilograms.

In the process of Route I above, the use of chlorobenzene avoids degradation which occurs under alternative methods, such as THF, which reacts with the acid chloride under scale (e.g., 100 kg) resulting in essentially no yield of the acid chloride.

In another embodiment, referred to as Route II, the present invention provides a process for preparing a compound of the formula:

comprising the steps of:

i.) Treatment of piperidine-4-carboxylic acid under reductive amination

conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HC1 followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl -Fischer analysis, to obtain solid 1- methylpiperidine-4-carboxylic acid hydrochloride;

ii.) Treatment of l-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to obtain 1- methylpiperidine-4-carboxylic acid chloride;

iii.) Treatment of l-methylpiperidine-4-carboxylic acid chloride with N,N- diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HC1 in isopropanol to obtain solid N,N-diethyl-l-methyl-piperidine-4-carboxamide hydrate hydrochloride;

iv.) Treatment of N,N-diethyl-l-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 with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight % by Karl Fischer analysis to obtain N,N- di ethyl- 1 -methyl-piperidine-4-carboxamide;

v.) Subsequent treatment of N,N-di ethyl- l-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether with subsequent extraction of the resulting mixture with water and a suitable organic solvent such as «-butanol, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone;

vi.) Treatment of (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone with aqueous HBr and subsequent extraction with «-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo-2- pyridyl)-(l-methyl-4-piperidyl)methanone hydrobromide;

vii.) Treatment of (6-bromo-2-pyridyl-l-methyl-4-piperidyl)methanone hydrobromide in a biphasic mixture of water and toluene with solid KOH for about 3 hr with subsequent separation of the organic layer and evaporation of the solvent to obtain of (6-bromo-2-pyridyl-l-methyl-4- piperidyl)methanone;

viii.) Treatment of (6-bromo-2-pyridyl-l-methyl-4-piperidyl)methanone with

2,4,6-trifluorobenzamide in toluene containing K2CO3, water, Pd(OAc)2, and Xantphos at about 70 °C for about 12 hr, until the (6-bromo-2- pyridyl)-(l-methyl-4-piperidyl)methanone content is not more than 0.1% by HPLC, with subsequent dilution of the reaction mixture with water and EtOAc, subsequent treatment with thiourea-modified silica gel at 60 °C for about 8 hr, with subsequent filtration to obtain a solution of 2,4,6-trifluoro- N-[6-(l-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

ix.) Treatment of a solution of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4- carbonyl)-2-pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid dissolved in EtOH at 55 °C for about 3 hr, with subsequent cooling to RT over about 10 hr, and collection of the resulting solids by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(l- methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemi succinate.

In the process of Route II above, preferably the reactions are performed using batch processing methodology. In an embodiment the batches by Route II are produced at process scale. In an embodiment the batches by Route II are produced in at least 1 kilogram. In an embodiment the batches by Route II are produced in at least 10 kilograms. In an embodiment the batches by Route II are produced in at least 100 kilograms.

In the process of Route II above, the use of chlorobenzene avoids degradation which occurs under alternative methods, such as THF, which reacts with the acid chloride under scale (e.g. 100 kg) resulting in essentially no yield of the acid chloride.

In another embodiment the present invention provides:

which can be named as (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate dihydrochloride. Preferably this compound is crystalline. (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate dihydrochloride is particularly useful in the preparation of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide

hemi succinate, and processes which employ (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate dihydrochloride may provide advantageous process characteristics, including but not limited to the purity of intermediate and/or final materials. (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate

dihydrochloride is believed to be a new stable hydrated form of 6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone. The process to isolate (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate dihydrochloride described herein provides improved impurity rejection and an improved controlled crystallization process. Form and chemical stability studies showed (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate dihydrochloride is generally stable, and drying studies show that over-drying to remove water of hydration is difficult, even under forcing conditions. Use of this intermediate provides advantageously high purity product at expected yield.

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

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

In another embodiment the 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 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 with one or more pharmaceutically acceptable carriers, diluents, or excipients. In another embodiment the 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 with one or more

pharmaceutically acceptable carriers, diluents, or excipients wherein the composition comprises acetic acid.

In another embodiment the invention provides lasmiditan acetate for use in therapy. In another embodiment the invention provides a pharmaceutical composition of lasmiditan acetate with one or more pharmaceutically acceptable carriers, diluents, or excipients for use in therapy. In another embodiment the invention provides a

pharmaceutical composition of lasmiditan acetate with one or more pharmaceutically

acceptable carriers, diluents, or excipients, wherein the composition comprises acetic acid for use in therapy.

In another embodiment the invention provides lasmiditan acetate for use in the treatment of migraine. In another embodiment the invention provides a pharmaceutical composition of lasmiditan acetate with one or more pharmaceutically acceptable carriers, diluents, or excipients for use in the treatment of migraine. In another embodiment the invention provides a pharmaceutical composition of lasmiditan acetate with one or more pharmaceutically acceptable carriers, diluents, or excipients, wherein the composition comprises acetic acid for use in the treatment of migraine.

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

In addition to an aqueous carrier, preferably sterile, deionized, distilled water, the pharmaceutical compositions described herein may further comprise one or more pharmaceutically acceptable excipients or cosolvents. The term“pharmaceutically acceptable” refers to excipients and cosolvents which are suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Pharmaceutical compositions and processes for preparing the same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et ah, eds., 21st ed., Mack Publishing Co., 2005)).

A pharmaceutical composition of lasmiditan acetate can be provided in bulk or in dosage unit form. It is especially advantageous to formulate pharmaceutical compositions 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 physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a

predetermined quantity of active compound lasmi ditan calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. A dosage unit form can be, e.g., an ampoule, a vial, or a syringe.

In embodiments, the disclosure provides a pharmaceutical composition

comprising an amount of lasmiditan acetate as described herein wherein the amount is from 10 mg to 200 mg per dose. In embodiments, the disclosure provides a

pharmaceutical composition comprising an amount of lasmiditan acetate as described herein wherein the amount is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, or 200 mg per dose. The forgoing doses are based on an adult human of average weight. Smaller doses would be acceptable for individuals of lighter weight, for example the elderly or children. Therefore, in embodiments, the pharmaceutical composition may comprise a smaller dose, such as 5, 10, or 15 mg.

As described herein, the highly concentrated aqueous solutions of lasmiditan acetate enables the administration of a single therapeutically effective dose by injection of a high concentration aqueous solution of lasmiditan, for example, by an intravenous, subcutaneous, or intramuscular route.

In embodiments, the disclosure provides high concentration aqueous solutions of lasmiditan acetate. In embodiments, the high concentration aqueous solution of lasmiditan acetate is formulated as a parenteral dosage form. In embodiments, the high concentration aqueous solution contains 10-200 mg/ml free base equivalent of lasmiditan. In

embodiments, the high concentration aqueous solution of lasmiditan acetate is in the form of a parenteral dosage form. In embodiments, the parenteral dosage form is a buffered aqueous solution of 10-200 mg/ml free base equivalent of lasmiditan. In embodiments, the parenteral dosage form is a buffered aqueous solution of 10, 20, 30, 40, 50, 100 or 200 mg/ml free base equivalent of lasmiditan. In embodiments, the parenteral dosage form is suitable for subcutaneous or intramuscular injection. Preferably the parenteral dosage form is for subcutaneous injection. In embodiments, the pH of the buffered solution is between pH 6.0-7.5 at 37°C.

In embodiments, the buffered aqueous solution comprises a buffering system based on an organic acid. In embodiments, the organic acid is a di- or tri-carboxylic acid.

In embodiments, the di- or tri-carboxylic acid is selected from the group consisting of acetic acid and citric acid. In embodiments, the organic acid is succinic acid. In embodiments, the buffer is an acetic acid buffer. In embodiments, the buffered aqueous solution is free of organic solvents. In embodiments, the buffered aqueous solution is free of organic solvents and surfactants. In a preferred embodiment the buffered aqueous solution comprises lasmiditan acetate, and acetic acid, and sodium hydroxide, adjusted to pH between 6.0-7.5 at 37°C.

In embodiments, the parenteral dosage form of lasmiditan acetate is provided in the form of a pre-filled syringe suitable for administration by a subcutaneous route. In embodiments, the pre-filled syringe comprises 10-50 mg/ml free base equivalent of lasmiditan. In embodiments, the pre-filled syringe comprises 10, 20, 30, 40, 50 or 100 mg/ml free base equivalent of lasmiditan. In embodiments, the lasmiditan is provided in a buffered aqueous solution having a pH 6.0-7.5 at 37 °C. In embodiments, the pre-filled syringe is suitable for at-home use, for example, for those migraine sufferers who might face an extreme and rapid onset of headache. In embodiments, the pre-filled syringe is contained in a package with instructions for parenteral administration, preferably by subcutaneous injection. In embodiments, the pre-filled syringe is in the form of an autoinjector with instructions for subcutaneous injection.

In embodiments, the parenteral dosage form of lasmiditan acetate is provided in the form of a vial containing 10-50 mg/ml free base equivalent of lasmiditan. In embodiments, 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 free base equivalent of lasmiditan. In embodiments, the lasmiditan is provided in a buffered aqueous solution having a pH 6.0-7.5 at 37 °C.

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

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

In some embodiments, a patient is a human who has been diagnosed as having a condition or disorder in need of prevention with a pharmaceutical composition described herein. In some embodiments, a patient is a human that is characterized as being at risk of a condition or disorder for which administration with a pharmaceutical composition described herein is indicated. In those instances where the disorders which can be treated by the methods of the present invention are known by established and accepted classifications, such as migraine, episodic headache, chronic headache, chronic cluster headaches, and/or episodic cluster headaches, their classifications can be found in various sources. For example, at present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IVTM) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool for identifying many of the disorders described herein. Also, the International Classification of Diseases, Tenth Revision (ICD-10), provides classifications for many of the disorders described herein. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for disorders described herein, including those as described in the DSM-IV and ICD-10, and that terminology and classification systems evolve with medical scientific progress. Migraine patients can further be diagnosed with migraine, with or without aura (1.1 and 1.2), as defined by International Headache Society (IHS) International Classification of Headache Disorders, 3rd edition, (ICHD-3) beta version (The International Classification of Headache Disorders, 3rd edition (beta version), Cephalalgia 2013; 33: 629-808). In some embodiments, the human patient has been diagnosed with episodic migraine prior to receiving chronic administration of lasmiditan, preferably nightly, 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 auras with their migraine headaches. In some embodiments, the human patient does not experience auras with their migraine headaches.

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 within various phases of a migraine attack and not all patients experience the same clinical manifestations. In the prodrome phase, the majority of patients have premonitory symptoms that may precede the headache phase by up to 72 hours. These include changes in mood and activity, irritability, fatigue, food cravings, repetitive yawning, stiff neck, and phonophobia. These symptoms may endure well into the aura, headache, and even postdrome phases. Some patients experience an aura phase, wherein about one-third

of patients experience transient neurological deficits during attacks. The ICHD-3 defines aura as 1 or more transient, fully reversible neurological deficits, of which at least 1 has to have a unilateral localization, that develops over 5 minutes or more, and of which each deficit lasts between 5 and 60 minutes. While a visual aura, which may show positive (fortification spectra), negative (scotoma), or both phenomena, is found in over 90% of the cases, and the most common deficit, sensory, motor, speech, brain stem, and retinal aura symptoms may also occur. A transient wave of neuronal depolarization of the cortex is believed to be the pathophysiological brain mechanism underlying the clinical phenomenon of migraine aura. In the headache phase, headache attacks which may last 4 to 72 hours are accompanied by nausea, photophobia and phonophobia, or both. The headache is characterized as unilateral, pulsating, of moderate or severe intensity, and aggravated by physical activity; two of these characteristics suffice to fulfill the diagnostic criteria. In the postdrome phase, characteristic symptoms reflect those observed during the premonitory phase. Typical postdrome symptoms include tiredness, difficulties in concentrating, and neck stiffness. It remains unclear whether these symptoms initiate in the premonitory phase and persist throughout the headache phase into the postdrome phase, if they may also initiate during the headache phase, or even appear after the headache phase has ended.

A“migraine headache” as used herein refers to headache, with or without aura, of > 30 minutes duration, with both of the following required features (A and B): A) at least 2 of the following headache characteristics: 1) unilateral location, 2) pulsating quality, 3) moderate or severe pain intensity, and 4) aggravation by or causing avoidance of routine physical activity; AND B) during headache at least one of the following: a) nausea and/or vomiting, and/or b) photophobia and phonophobia. A“probable migraine headache” as used herein refers to a headache of greater than 30 minutes duration, with or without aura, but missing one of the migraine features in the International Headache Society ICHD-3 definition.

The term“effective amount” or“therapeutically effective amount” means an amount or dose of lasmiditan acetate in a pharmaceutical composition, such as a total amount administered in an administration, which upon single or multiple dose

administration to the patient, provides the desired pharmacological effect in the patient, for example an amount capable of activating 5-HTIF receptors. In a preferred

embodiment,“effective amount” means an amount of lasmiditan acetate that upon acute administration is capable of rendering a patient migraine attack free following

administration. A“dose” refers to a predetermined quantity of lasmiditan acetate calculated to produce the desired therapeutic effect in a patient. As used herein“mg” refers to milligram. As used herein, doses described in mg, refer to the active

pharmaceutical ingredient lasmiditan, as free-base equivalent by mass, for instance a“100 mg” dose, refers to 100 mg of the active pharmaceutical ingredient lasmiditan as free-base equivalent. As used herein, a given dose may be interpreted to describe doses of about the indicated amount, in that doses which are up to 10 percent higher or lower than the indicated dose are likewise contemplated to provide useful regimens in a manner similar to the indicated dose.

Brief Description of the Figures

Figure 1 : Graphical representation of an 'H NMR spectrum (400 MHz, DMSO-d6) of lasmiditan acetate containing maleic acid (internal standard).

Detailed Description

The reactions described herein may be performed via standard techniques known to the skilled artisan by employing routine glassware or may be performed on pilot and/or production scale in equipment designed for such transformations. Further, each of these reactions described may be executed via either a batch process, or where applicable, a flow reaction methodology. The term“batch process” as used herein refers to a process in which raw materials are combined in a reactor or vessel and product is removed at the end of the reaction.

Additionally, certain intermediates described in the following preparations may contain one or more nitrogen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example“ Greene’s Protective Groups in Organic Synthesis”, Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

The abbreviations listed below when used herein are defined as follows:“A” means angstrom or angstroms.“ACN” means acetonitrile.“AcOH” means acetic acid. “Bn” means benzyl;“nBuLi” means w-butyllithium.“CAS No.” means Chemical Abstracts Registry number.“DCM” means dichloromethane.“DMF” means N,N-dimethylformamide.“DIPEA” means diisopropylethylamine.“DMSO” means dimethyl sulfoxide (perdeuterated [d6] if used for NMR).“EtOAc” means ethyl acetate.“EtOH” means ethanol or ethyl alcohol.“HBTU” means (2-(lH-bezotriazole-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate.“HPLC” means high performance liquid chromatography.“HTRF” means homogeneous time-resolved fluorescence“hr” or“h” means hour or hours.“IP A” 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 a 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 methy tert-butyl ether.“NMR” means nuclear magnetic resonance.“NMT” means not more than.“OAc” means acetate“psig” means pounds per square inch gauge.“PyBOP” means (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate).“RT” means room temperature/ambient temperature“sec” means second or seconds as a unit of time.“TBS-C1” means /er/-butyldimethylsilyl chloride. “TEA” means triethylamine.“THF” means tetrahydrofuran.“tR” means retention time “w/w” means weight to weight in a ratio.

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

"Pharmaceutically acceptable salts" or“a pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic salt or salts of the compounds of the present invention. It will be understood by the skilled artisan that compounds of the present invention are capable of forming salts. Some compounds of the present invention contain basic heterocycles, and accordingly 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 common methodology for preparing them are well known in the art. See, e.g., P. Stahl, el 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.

“Process scale” synthesis refers to preparations of 500 mg to 1000 kg, or more of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide

hemisuccinate. Preferably“process scale” syntheses are performed under Good

Manufacturing Process (GMP) or similar conditions required for commercial production of pharmaceutical products for human consumption. Preferably,“process scale” in the processes of Route I and/or II above, refers to batches produced in at least 1 kilogram, and/or batches produced in at least 10 kilograms, and/or batches produced in at least 100 kilograms.

General Chemistry

Scheme 1

Scheme 1 depicts a process scale synthesis of lasmiditan hemisuccinate compound I. N-Methylation of commercially available piperidine 4-carboxylic acid 1 may be accomplished under various reductive conditions recognizable to the skilled artisan, specifically treatment of the secondary amine with about 1.3 equivalents of formadehyde in an excess of formic acid, to obtain the N-methylpiperidine 2. Formation of

diethylamide 3 may be achieved using conventional amide coupling reagents such as benzotri azole, HBTU or PyBOP or by converting the carboxylic acid to the acid chloride, using reagents well known in the art such as oxalyl chloride or thionyl chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 may be converted to the acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50 °C for 1 hr, at which time the reaction mixture may be cooled to about 0 °C and 1.5 equivalents diethylamine and 3 equivalents trimethylamine added. The free base is stirred with HC1 to obtain diethylamide hydrate hydrochloride 3. One skilled in the art will recognize that pyridyl ketone 4 may be obtained by treatment of diethylamide 3 with the lithiated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium may be formed by treating 2,6 dibromopyridine with //-BuLi at about -58 °C. Separately, piperidine-4-diethylamide hydrochloride hydrate 3 may be treated with about 2 equivalents NaOH and the resulting free base added to the lithiated species at about -58 °C. The resulting mixture may be treated with HBr to form pyridylbromide hydrobromide 4. Amination of pyridylbromide hydrobromide 4 may be achieved using transition metal catalysis well known to one skilled in the art. More specifically, to pyridylbromide 4 may be added about 0.075 equivalents of CU2O, about 28 equivalents NH3 in ethylene glycol and stirred to about 80 °C. The reaction may be cooled to RT, quenched with H2O, washed with 20% aqueous NaOH, slurried with 20% HC1 in IP A and a small amount of H2O, to obtain a aminopyridine dihydrate dihydrochloride 5 as a crystalline solid. Pyridylbenzamide hydrochloride 6 may be prepared by treating the free base of aminopyriyl 5 with the acid chloride 5a. More specifically, aminopyridine dehydrate dihydrochloride 5 may be treated with 6% aqueous NaOH to furnish the free base. Separately, 2,4,6-trifluorobenzoic acid may be treated with thionyl chloride at about 100 °C and the aforementioned freebase of 5, to provide pyridylbenzamide hydrochloride 6. Hemisuccinate I may be created by treating hydrochloride 6 with about 2 equivalents of NaHC03 followed by about 0.55 equivalents succinic acid to obtain lasmiditan hemisuccinate compound I.

Scheme 2

Scheme 2 depicts the synthesis of (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone dihydrate hydrochloride 5. Amination of pyridylbromide hydrobromide 4 may be achieved as outlined in scheme 1 using transition metal catalysis well known to one skilled in the art. More specifically, to pyridylbromide 4 may be added about 0.075 equivalents of CU2O, about 28 equivalents NH3 in ethylene glycol and stirred at about 80 °C. The reaction may be cooled to RT, quenched with H2O, washed with 20% aqueous NaOH, slurried with 20% HC1 in IP A and a small amount of H2O, to obtain aminopyridine dihydrate hydrochloride 5.

Scheme 3

Scheme 3 illustrates a modified process synthesis to lasmiditan hemisuccinate I.

N-Methylation of commercially available piperidine 4-carboxylic acid 1 may be accomplished under various reductive conditions recognizable to the skilled artisan, specifically treatment of the secondary amine with about 1.3 equivalents of formadehyde in an excess of formic acid, to obtain the N-methylpiperidine 2. Formation of

diethylamide 3 may be achieved using conventional amide coupling reagents such as benzotri azole, HBTU or PyBOP or by converting the carboxylic acid to the acid chloride, using reagents well known in the art such as oxalyl chloride or thionyl chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 may be converted to the acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50 °C for 1 hr, at which time the reaction mixture may be cooled to about 0 °C and 1.5 equivalents diethylamine and 3 equivalents trimethylamine added. The free base is stirred with HC1 to obtain diethylamide hydrate hydrochloride 3. One skilled in the art will recognize that pyridyl ketone 4 may be obtained by treatment of diethylamide 3 with the lithiated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium may be formed by treating 2,6 dibromopyridine with «-BuLi at about -58 °C. Separately, piperidine-4-diethylamide hydrochloride hydrate 3 may be treated with about 2 equivalents NaOH and the resulting free base added to the lithiated species at about -58 °C. The resulting mixture may be treated with HBr to form pyridylbromide hydrobromide 4. Amination of pyridylbromide hydrobromide 4 to obtain amide 6 may be achieved using transition metal catalysis well known to one skilled in the art. Specifically, the pyridyl ketone 4 may be sprung to its corresponding free base form with a suitable mineral base and subjected to Buchwald-type coupling conditions, as is well known in the literature. More specifically, the free base of compound 4 may be stirred in a suitable aprotic solvent, such as toluene or xylene, containing a mixture of about 1-5 weight % water, about 1.1 equivalents commercially available 2,4,6-trifluorbenzamide (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 may be heated at about 70 °C for about 12-24 hr. The reaction mixture may be diluted with a suitable mixture of water and organic solvent, such as DCM or EtOAc, and the organic layer may be treated with an appropriate palladium scavenger, such as thiourea-modified silica gel, for about 8-24 hr at about RT to about 65 °C. The resulting mixture may be cooled, filtered, treated with activated charcoal, filtered, and concentrated under reduced pressure. The resulting residue may be dissolved in an appropriate alcoholic solvent, such as ethanol, and treated slowly with a solution of about 0.5 equivalents of succinic acid dissolved in ethanol at about 55 °C. The resulting mixture may be cooled to RT over about 10 hr, and the resulting slurry may be slurry-milled by

treatment under a series of thermal cycles of heating to 60 °C and cooling back to RT over 4 hr. The resulting solid may be collected by filtration, dried at about 40 °C for about 4 hr, and optionally jet milled, to obtain lasmiditan hemisuccinate I.

Experimental Procedures

The following preparations of process intermediates further illustrate the invention and represent typical syntheses of various compounds. The reagents and starting materials are readily available or may be readily synthesized by one of ordinary skill in the art. It should be understood that the Preparations and Examples are set forth by way of illustration, and that various modifications may be made by one of ordinary skill in the art.

LC-ES/MS is performed on an AGILENT® HP 1100 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 Cl 8 2.1 mm x 50 mm, 3.0 m; gradient: 5-100% B in 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. Alternate LC-MS conditions (high pH): column:

XTERRA® MS C18 columns 2.1 x50 mm, 3.5 pm; gradient: 5% of solvent A for 0.25 min, gradient from 5% to 100% of solvent B in 3 min and 100% of solvent B for 0.5 min or 10% to 100% of solvent B in 3 min and at 100% of solvent B for 0.75 min; column temperature: 50 °C +/-10 °C; flow rate: 1.2 mL/min; Solvent A: 10 mM NHdTCCh pH 9; Solvent B: ACN ; wavelength: 214 nm.

NMR spectra are performed on a Bruker AVIII HD 400 or 500 MHz NMR Spectrometer, obtained as CDCl·, or (CD3)2SO solutions reported in ppm, using residual solvent [CDCh, 7.26 ppm; (CD3)2SO, 2.05 ppm] as reference standard. When peak multiplicities are reported, the following abbreviations may be used: s (singlet), d

(doublet), t (triplet), q (quartet), m (multiplet), br-s (broad singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants (J), when reported, are reported in hertz (Hz).

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

The compounds described herein can be prepared by general methods known to the skilled artisan or by processes described herein. Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and/or purified by various well-known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical.

Preparation 1

l-methylpiperidine-4-carboxylic acid hydrochloride

Scheme 1, step A: To a jacketed reactor is charged 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 to the mixture dropwise over at least 30 min. Water (0.3 mL) is used as a line rinse into the reactor. The mixture is stirred for 4 hr at reflux (95-100 °C) and sampled by HPLC for IPC analysis (NMT 0.5% of piperidine-4-carboxylic acid). If the amount of piperidine-4-carboxylic acid is above 0.5%, the mixture is stirred 2 additional hr. If the specification is met, the solution is concentrated under vacuum until ~ 20 mL of residual volume remains and the residue is cooled to 45-50 °C. To the cooled solution is charged 33% aqueous HCI (12.8 g, 116 mmol) over not less than 30 min. Water (0.3 mL) is used as a line rinse into the reactor. Water is distilled off under vacuum until ~ 20 mL of residual volume remains. To the concentrated solution at 45-50 °C is charged ACN (42.4 mL) and the mixture is concentrated under atmospheric pressure until ~ 40 mL of residual volume remains. To the concentrated solution at 45-50 °C is charged ACN (20.4 mL) and the mixture is concentrated under atmospheric pressure until ~ 40 mL of residual volume remains. The dilution/concentration operations are repeated until the in process control for water content by Karl-Fischer analysis is NMT 0.2%; during these operations a slurry forms. To the slurry is charged ACN (10.2 mL) at 45-50 °C. The slurry is cooled to 20 °C over 1 h and stirred for an additional 2 h. The resulting solid is isolated by filtration and the cake is rinsed 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).

Preparation 2

N,N-diethyl-l-methyl-piperidine-4-carboxamide hydrate hydrochloride

Scheme 1, step B: To a jacketed reactor is charged l-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. To the hot suspension is charged thionyl chloride (24.2 g, 200.4 mmol) over a 1 hr period. Chlorobenzene (13.5 mL) is used as a line rinse into the reactor. The mixture is stirred for 5 hr after the completion of the thionyl chloride addition. The solution is then cooled to 0 to 10 °C. A solution prepared from diethylamine (17.7 g, 12.5 mmol) and TEA (50.7 g, 25 mmol) is charged to the cold reaction mixture over a 3 hr period. Chlorobenzene (13.5 mL) is used as a line rinse into the reactor. The mixture is stirred for 2 hr after the complete addition of the amine mixture. The reaction is treated with 20 weight % aqueous NaOH (180.3 g, 902 mmol) and stirred at RT for 2 hr. Water (3 mL) is used as a line rinse into the reactor.

WE CLAIM:

A process for preparing a compound of the formula:

0.5

comprising the steps of:

i.) Treatment of piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HC1 followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl -Fischer analysis, to obtain solid 1- methylpiperidine-4-carboxylic acid hydrochloride;

ii.) Treatment of l-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to obtain 1- methylpiperidine-4-carboxylic acid chloride;

iii.) Treatment of l-methylpiperidine-4-carboxylic acid chloride with N,N- diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HC1 in isopropanol to obtain solid N,N-diethyl-l-methyl-piperidine-4-carboxamide hydrate hydrochloride;

iv.) Treatment of N,N-diethyl-l-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 with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight t% by Karl Fischer analysis to obtain N,N- di ethyl- 1 -methyl-piperidine-4-carboxamide;

v.) Subsequent treatment of N,N-di ethyl- l-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether with subsequent extraction of the resulting mixture with water and a suitable organic solvent such as «-butanol, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone;

vi.) Treatment of (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone with aqueous HBr and subsequent extraction with «-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo-2- pyridyl)-(l-methyl-4-piperidyl)methanone hydrobromide;

vii.) Treatment of (6-bromo-2-pyridyl-l-methyl-4-piperidyl)methanone

hydrobromide with a solution of NFb in ethylene glycol in the presence of CU2O catalyst at about 80 °C for about 2 hr, with subsequent washes with water, saturated aqueous NaCl, and 20% aqueous NaOH and subsequent extraction with a non-polar aprotic solvent such as methyl-tert-butyl ether, phase separation, and treatment of the organic phase with 5 weight % carbon;

viii.) Filtration of the above mixture, dilution with a suitable polar alcoholic solvent such as isopropanol, and repeated distillation of the organic solvent until the water content is not more than 0.2% by Karl-Fischer analysis,

with subsequent treatment of the resulting residue with isopropanol, water, and 20 weight % HC1, wherein the water concentration of the resulting slurry is at least 2%, filtration of the resulting slurry, and drying under vacuum at 40 °C for 16-24 hr to obtain solid (6-amino-2-pyridyl)-(l- methyl-4-piperidyl)methanone dihydrate dihydrochloride;

ix.) Treatment of (6-amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone

dihydrate dihydrochloride in chlorobenzene with 6 weight/weight % NaOH in water at about 54 °C for about 30 min, with subsequent phase separation and vacuum distillation of the aqueous solution to obtain (6- amino-2-pyridyl)-(l-methyl-4-piperidyl)methanone;

x.) Subsequent treatment of (6-amino-2-pyridyl)-(l-methyl-4- piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100 °C for about 4 hr, with subsequent cooling, charging with acetonitrile and heating the resulting slurry to 80 °C for about 1 hr, and subsequent collection of the resulting solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide hydrochloride;

xi.) Treatment of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide hydrochloride with saturated aqueous NaiCCb in methyl-tert-butyl ether;

xii.) Treatment of the mixture of step xi above with S1O2 with subsequent

filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation until the water content is not more than 1% by Karl-Fischer analysis, to obtain 2,4,6-trifluoro-N-[6-(l-methylpiperidine- 4-carbonyl)-2-pyridyl]benzamide;

xiii.) Treatment of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide in ethanol with a solution of 0.5 equivalents succinic acid in ethanol at about 55 °C for not less than 3 hr at RT, and subsequent collection of the solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(l- methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemi succinate.

2. A process for preparing a compound of the formula:

i.) Treatment of piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HC1 followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl -Fischer analysis, to obtain solid 1- methylpiperidine-4-carboxylic acid hydrochloride;

ii.) Treatment of l-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene obtain 1- methylpiperidine-4-carboxylic acid chloride;

iii.) Treatment of l-methylpiperidine-4-carboxylic acid chloride with N,N- diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HC1 in isopropanol to

obtain solid N,N-diethyl-l-methyl-piperidine-4-carboxamide hydrate hydrochloride;

iv.) Treatment of N,N-di ethyl- l-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 with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight % by Karl Fischer analysis to obtain N,N- di ethyl- 1 -methyl-piperidine-4-carboxamide;

v.) Subsequent treatment of N,N-di ethyl- l-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether with subsequent extraction of the resulting mixture with water and a suitable organic solvent such as «-butanol, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone;

vi.) Treatment of (6-bromo-2-pyridyl)-(l-methyl-4-piperidyl)methanone with aqueous HBr and subsequent extraction with «-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo-2- pyridyl)-(l-methyl-4-piperidyl)methanone hydrobromide;

vii.) Treatment of (6-bromo-2-pyridyl-l-methyl-4-piperidyl)methanone

hydrobromide in a biphasic mixture of water and toluene with solid KOH for about 3 hr with subsequent separation of the organic layer and evaporation of the solvent to obtain of (6-bromo-2-pyridyl-l-methyl-4- piperidyl)methanone;

viii.) Treatment of (6-bromo-2-pyridyl-l-methyl-4-piperidyl)methanone with

2,4,6-trifluorobenzamide in toluene containing K2CO3, water, Pd(OAc)2, and Xantphos at about 70 °C for about 12 hr, until the (6-bromo-2- pyridyl)-(l-methyl-4-piperidyl)methanone content is not more than 0.1% by HPLC, with subsequent dilution of the reaction mixture with water and EtOAc, subsequent treatment with thiourea-modified silica gel at 60 °C for about 8 hr, with subsequent filtration to obtain a solution of 2,4,6-trifluoro- N-[6-(l-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

ix.) Treatment of a solution of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4- carbonyl)-2-pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid dissolved in EtOH at 55 °C for about 3 hr, with subsequent cooling to RT over about 10 hr, and collection of the resulting solids by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(l- methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

3. A process of Claim 1 or 2 wherein the reactions are performed using batch

processing methodology.

4. A process of Claim 3 wherein the batch produced is at process scale.

5. A process of Claim 4 wherein the batch produced is at least 1 kilogram.

6. A process of Claim 4 wherein the batch produced is at least 10 kilograms.

7. A 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 - 7 wherein the tablet comprises 50 mg of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide hemisuccinate.

9. A tablet produced by the process of any one of claims 1 - 7 wherein the tablet comprises 100 mg of 2,4,6-trifluoro-N-[6-(l-methylpiperidine-4-carbonyl)-2- pyridyljbenzamide hemisuccinate.

10. A compound of the formula:

11. The compound of Claim 10 which is crystalline.

12. The compound according to claim 11 characterized by an X-ray powder

diffraction pattern using CuKa radiation having an intense peak at diffraction angle 2-theta of 8.3° in combination with one or more of the peaks selected from the group consisting of 16.6°, 23.5°, and 33.7° (± 0.2° respectively).

13. A compound of the formula:

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

15. The compound according to claim 14 characterized by an X-ray powder

diffraction pattern using CuKa radiation having an intense peak at diffraction angle 2-theta of 26.2° in combination with one or more of the peaks selected from the group consisting of 20.4°, 14.0°, and 17.9° (± 0.2° respectively).

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

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

18. A method of 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.