Methods and intermediates for large-scale preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate and 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate

Abstract

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

Description

[0001] Embodiments of the present invention relate to the fields of medicinal chemistry and synthetic organic chemistry, and provide methods and intermediates for the large-scale synthesis of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate (5-HT1F receptor agonist), as well as preparations and product forms prepared by these methods, and relate to the preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate and its use in parenteral preparations and in the treatment of migraine.

[0002] Lasmiditan is a selective and highly potent 5-HT 1F Receptor agonist, now approved in the United States as a 50 mg or 100 mg tablet for the emergency on-demand treatment of migraine (see, e.g., Rubio-Beltrán et al., Pharmacol Ther 2018; 186: 88-97, and Lasmiditan for the Treatment of Migraine, Capi, M et al., Expert Opinion Investigational Drugs, (2017), Vol. 26, No. 2, 227-234). Lasmiditan (COL 144, LY 573144, CAS Reg. No. 439239-90-4) can be chemically described as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide. U.S. Patent No. 7,423,050 and U.S. Publication No. 20080300407 describe a hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide having the following structural formula:

[0003]

[0004] Methods for preparing lasmiditan and salts thereof, certain polymorphic forms, formulations and dosage forms are known to those skilled in the art and are described, for example, in WO 2003 / 084949, WO 2011 / 123654 and WO 2018 / 106657.

[0005] As used herein, useful forms of lasmiditan include pharmaceutically acceptable salts thereof, including but not limited to 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide monohydrochloride, and 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. A synthetic route for preparing the hemisuccinate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide has been previously disclosed as shown in Scheme A below. Starting from commercially available piperidine 4-carboxylic acid, the overall yield of lasmiditan in all nine steps is about 10-46% via the route described in Scheme A below. Improving the synthesis of lasmiditan can provide numerous and diverse benefits, particularly for large-scale production.

[0006] Process A

[0007]

[0008] Synthetic chemistry process routes can be redesigned or modified with the goal of achieving a variety of advantages, including, for example: improving yields, obtaining crystalline products, reducing impurity profiles, utilizing commercially available intermediates, minimizing the number of synthetic steps required, reducing the amount of inputs required and / or by-products produced, or any useful combination of these improvements to achieve important practical results, including reducing costs, providing less resource-intensive processes, and facilitating efficient production. There is a need for improved methods of preparing lasmiditan that can achieve one or more of these objectives, particularly for large-scale synthesis.

[0009] In addition, migraine is one of the most common presenting symptoms in the emergency room. When lasmiditan is used for patients who are difficult to administer tablets due to nausea and / or vomiting, the current method for relieving headaches in the emergency room environment may need to rely on the preparation of a diluted formulation of about 1 mg / ml lasmiditan, which is delivered intravenously in an extended period of time, such as about 20-60 minutes. In clinical studies, lasmiditan is delivered intravenously at a dosage of about 1-60 mg, which is delivered by 60 ml infusion within 20 minutes (see U.S. Patent Application Publication No. 2010 / 0256187). For patients who cannot administer tablets, safe and effective treatment of migraine with lasmiditan will become possible through the availability of high-concentration parenteral dosage forms. The present disclosure also addresses this need. SUMMARY OF THE INVENTION

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

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

[0013]

[0014] The following steps are involved:

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

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

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

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

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

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

[0021] vii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidinyl)methanone hydrobromide with a solution of NH in ethylene glycol at about 80° C. for about 2 hours in the presence of a Cu2O catalyst, followed by washing with water, saturated aqueous NaCl and 20% aqueous NaOH, followed by extraction with a nonpolar aprotic solvent such as methyl tert-butyl ether, phase separation, and treating the organic phase with 5 wt% carbon;

[0022] viii.) filtering the mixture, diluting with a suitable polar alcohol solvent such as isopropanol, repeatedly distilling the organic solvent until the water content does not exceed 0.2% by Karl-Fischer analysis, then treating the resulting residue with isopropanol, water and 20 wt % HCl, wherein the resulting slurry has a water concentration of at least 2%, filtering the resulting slurry, and drying under vacuum at 40° C. for 16-24 hours to obtain a solid (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrate dihydrochloride;

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

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

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

[0026] xii.) treating the mixture of step xi above with SiO2, followed by filtering, treating with carbon, filtering, and evaporating, diluting with ethanol, and distilling until the water content does not exceed 1% by Karl-Fischer analysis to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

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

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

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

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

[0031]

[0032] The following steps are involved:

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

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

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

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

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

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

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

[0040] viii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing K2CO3, water, Pd(OAc)2 and Xantphos at about 70°C for about 12 hours until the content of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone does not exceed 0.1% by HPLC, followed by dilution of the reaction mixture with water and EtOAc and subsequent treatment with thiourea-modified silica gel at 60°C for about 8 hours followed by filtration to obtain a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide;

[0041] ix.) A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide in EtOAc is treated with about 0.5 equivalents of succinic acid dissolved in EtOH at 55° C. for about 3 hours, then cooled to room temperature over about 10 hours and the resulting solid is collected by filtration to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hemisuccinate.

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

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

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

[0045]

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

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

[0048]

[0049] In another embodiment, the present invention provides a crystalline form of lasmiditan acetate, and further provides the following crystalline form of lasmiditan acetate, characterized in that the X-ray powder diffraction pattern irradiated with CuKα has a strong peak at a diffraction angle of 2θ26.2°, and one or more peaks selected from 20.4°, 14.0° and 17.9° (±0.2°, respectively). In another embodiment, the present invention provides a pharmaceutical composition comprising lasmiditan acetate according to the above embodiment and one or more pharmaceutically acceptable carriers, diluents or excipients. Preferably, the pharmaceutical composition comprises acetic acid. Preferably, the pharmaceutical composition comprises acetic acid and is used for subcutaneous administration.

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

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

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

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

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

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

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

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

[0058] In embodiments, the present disclosure provides a high concentration of lasmiditan acetate aqueous solution. In embodiments, the high concentration of lasmiditan acetate aqueous solution is formulated into 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 of lasmiditan acetate aqueous solution 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 buffer solution is between pH 6.0-7.5 at 37°C.

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

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

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

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

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

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

[0065] As used herein, "migraine" includes, but is not limited to, a migraine attack. As used herein, "migraine attack" refers to the following description. Symptoms may overlap at various stages of a migraine attack, and not all patients experience the same clinical manifestations. In the prodromal stage, most patients have monitoring pre-symptoms, which may be as long as 72 hours before the headache stage. These include changes in mood and activity, irritability, fatigue, eating urges, repeated yawning, neck stiffness, and high-pitched fear. These symptoms may last sufficiently to the aura, headache, and even post-headache stage. Some patients experience an aura stage, of which about one-third experience transient neurological deficits during the attack. ICHD-3 defines aura as 1 or more transient, fully reversible neurological deficits, at least 1 of which must have unilateral localization, which occurs over 5 minutes or longer, and each of which lasts for 5 to 60 minutes. At this time, visual auras are found in more than 90% of cases, which may show positive (flash dark spots), negative (dark spots), or both phenomena, and the most common defects, sensory, motor, speech, brainstem, and retinal aura symptoms will also appear. Transient waves of depolarization of cortical neurons are thought to be the pathophysiological brain mechanism behind the clinical phenomenon of migraine aura. During the headache phase, headache attacks may last from 4 to 72 hours and are accompanied by nausea, photophobia, and fear of loud sounds, or both. The headache is characterized by being unilateral, pulsating, moderate or severe, and aggravated by physical activity; two of these characteristics are sufficient to meet diagnostic criteria. During the post-headache phase, characteristic symptoms mirror those observed in the pre-monitoring phase. Typical post-headache symptoms include tiredness, difficulty concentrating, and neck stiffness. It is unclear whether these symptoms begin in the pre-monitoring phase and continue throughout the headache phase and into the post-headache phase, or whether they may also begin during the headache phase, or even appear after the headache phase ends.

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

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

[0069] Figure 1 :Lasmiditan acetate containing maleic acid (internal standard) 1 Graphic representation of H NMR spectrum (400 MHz, DMSO-d6). DETAILED DESCRIPTION OF THE INVENTION

[0071] The reactions described herein can be carried out by standard techniques known to those skilled in the art using conventional glassware, or can be carried out on a pilot and / or process scale in equipment designed for such transformations. In addition, each of the reactions described can be performed by a batch process or, where applicable, by a flow reaction process. The term "batch process" as used herein refers to a process in which the raw materials are combined in a reactor or container and the product is removed at the end of the reaction.

[0072] In addition, some intermediates described in the following preparations may contain one or more nitrogen protecting groups. Variable protecting groups may be the same or different at each occurrence, depending on specific reaction conditions and specific conversion to be performed. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis", 4th edition, Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0073] When used in this document, the following abbreviations are defined as follows: "ACN" means acetonitrile. "AcOH" means acetic acid. "Bn" means benzyl; "nBuLi" means n-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. "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 isopropanol. "IPC" means in-process quality control. 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 means methyl. "MeOH" means methanol. "min" means minute. "MS" means mass spectrometry or mass spectrum. "MTBE" means methyl tert-butyl ether. "NMR" means nuclear magnetic resonance. "NMT" means not more than. "OAc" means acetate. "psig" means pounds per square inch gauge. "PyBOP" means (benzotriazol-1-yl-oxytripyrrolidin-1-ylphosphonium hexafluorophosphate). "RT" means room temperature / ambient temperature. "sec" as a time unit means seconds. "TBS-Cl" means tert-butyldimethylchlorosilane. "TEA" means triethylamine. "THF" means tetrahydrofuran. "tR" means retention time. "w / w" means weight to weight ratio.

[0074] Improved routes for preparing lasmiditan are provided below, as routes I and / or II, and other additional methods are provided below.

[0075] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to relatively non-toxic, inorganic and organic salts or salts of the compounds of the present invention. Those skilled in the art will appreciate that the compounds of the present invention are capable of forming salts. Some of the compounds of the present invention contain basic heterocycles and therefore react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable acid addition salts and conventional methods for preparing them are well known in the art. See, for example, P. Stahl et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2008); SM Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0076] "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-pyridinyl]benzamide hemisuccinate. Preferably, the "process scale" synthesis is carried out under good manufacturing process (GMP) or similar conditions required for commercial production of pharmaceutical products for human consumption. Preferably, "process scale" in the above-mentioned route I and / or II method refers to batches produced in at least 1 kg, and / or batches produced in at least 10 kg, and / or batches produced in at least 100 kg.

[0077] general chemistry

[0078] Process 1

[0079]

[0080] Scheme 1 describes a process-scale synthesis of lasmiditan hemisuccinate compound I. N-methylation of commercially available piperidine 4-carboxylic acid 1 can be accomplished under a variety of reducing conditions identifiable to one skilled in the art, specifically, treatment of the secondary amine with about 1.3 equivalents of formaldehyde in excess formic acid affords N-methylpiperidine 2. Formation of diethylamide 3 can be accomplished using conventional amide coupling reagents such as benzotriazole, HBTU, or PyBOP, or by converting the carboxylic acid to an acid chloride using reagents known in the art such as oxalyl chloride or thionyl chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 can be converted to an acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50°C for 1 hour, at which point the reaction mixture can be cooled to about 0°C, 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine added. The free base is stirred with HCl to afford the diethylamide hydrochloride hydrate 3. One skilled in the art will recognize that pyridyl ketone 4 can be obtained by treating diethylamide 3 with lithiated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium can be formed by treating 2,6-dibromopyridine with n-BuLi at about -58°C. Separately, piperidine-4-diacetamide hydrochloride hydrate 3 can be treated with about 2 equivalents of NaOH and the resulting free base is added to the lithiate at about -58°C. The resulting mixture can be treated with HBr to form pyridyl bromide hydrobromide 4. Amination of pyridyl bromide hydrobromide 4 can be achieved using transition metal catalysis well known to those skilled in the art. More specifically, about 0.075 equivalents of Cu2O, about 28 equivalents of NH3 in ethylene glycol are added to pyridinium bromide 4 and stirred to about 80°C, the reaction is cooled to room temperature, quenched with H2O, washed with 20% aqueous NaOH, and slurried with 20% HCl in IPA and a small amount of H2O to give aminopyridine dihydrate dihydrochloride 5 as a crystalline solid. Pyridylbenzamide hydrochloride 6 can be prepared by treating the free base of aminopyridine 5 with the acid chloride 5a. More specifically, aminopyridine dihydrate dihydrochloride 5 can be treated with 6% aqueous NaOH to obtain the free base. Alternatively, 2,4,6-trifluorobenzoic acid can be treated with thionyl chloride and the above free base 5 at about 100°C to give pyridylbenzamide hydrochloride 6. Hemisuccinate I can be prepared by treating the hydrochloride 6 with about 2 equivalents of NaHCO3 and then with about 0.55 equivalents of succinic acid to give lasmiditan hemisuccinate compound I.

[0081] Process 2

[0082]

[0083] Scheme 2 describes the synthesis of (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrate hydrochloride 5. Amination of pyridyl bromide hydrobromide 4 can be achieved as described in Scheme 1 using transition metal catalysis well known to those skilled in the art. More specifically, about 0.075 equivalents of Cu2O, about 28 equivalents of NH3 in ethylene glycol are added to pyridyl bromide 4 and stirred at about 80°C, the reaction is cooled to room temperature, quenched with H2O, washed with 20% aqueous NaOH, and slurried with 20% HCl in IPA and a small amount of H2O to give aminopyridine dihydrate hydrochloride 5.

[0084] Process 3

[0085]

[0086] Scheme 3 illustrates an improved method for the synthesis of lasmiditan hemisuccinate I. N-methylation of commercially available piperidine 4-carboxylic acid 1 can be accomplished under a variety of reducing conditions identifiable to one skilled in the art, specifically, treatment of the secondary amine with about 1.3 equivalents of formaldehyde in excess formic acid affords N-methylpiperidine 2. Formation of diethylamide 3 can be accomplished using conventional amide coupling reagents such as benzotriazole, HBTU, or PyBOP, or by converting the carboxylic acid to the acid chloride using reagents known in the art such as oxalyl chloride or thionyl chloride. More specifically, N-methylpiperidine-4-carboxylic acid 2 can be converted to the acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50°C for 1 hour, at which point the reaction mixture can be cooled to about 0°C, 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine added. The free base is stirred with HCl to afford the diethylamide hydrochloride hydrate 3. One skilled in the art will recognize that pyridyl ketone 4 can be obtained by treating diethylamide 3 with lithiated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium can be formed by treating 2,6-dibromopyridine with n-BuLi at about -58°C. Separately, piperidine-4-diacetamide hydrochloride hydrate 3 can be treated with about 2 equivalents of NaOH, and the resulting free base is added to the lithiate at about -58°C. The resulting mixture can be treated with HBr to form pyridyl bromide hydrobromide 4. Amination of pyridyl bromide hydrobromide 4 to afford amide 6 can be accomplished using transition metal catalysis well known to those skilled in the art. Specifically, pyridyl ketone 4 can be converted to its corresponding free base form with a suitable inorganic base and subjected to Buchwald-type coupling conditions, 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 about 1-5% by weight of water, about 1.1 equivalents of commercially available 2,4,6-trifluorobenzamide (CAS#82019-50-9), about 1.5 equivalents of potassium carbonate, about 0.005 to about 0.015 equivalents of a suitable palladium catalyst, such as palladium (II) acetate, and about 0.01 to 0.02 equivalents of a suitable phosphine ligand compound such as Xaphos, XPhos or DPEpHos. The resulting mixture can be heated at about 70°C for about 12-24 hours. The reaction mixture can be diluted with a suitable mixture of water and an organic solvent such as DCM or EtOAc, and the organic layer can be treated with a suitable palladium scavenger such as thiourea-modified silica gel at about room temperature to about 65°C for about 8-24 hours. The resulting mixture can be cooled, filtered, treated with activated carbon, filtered and concentrated under reduced pressure. The resulting residue can be dissolved in a suitable alcohol solvent, such as ethanol, and slowly treated with a solution of about 0.5 equivalents of succinic acid dissolved in ethanol at about 55° C. The resulting mixture can be cooled to room temperature over about 10 hours, and the resulting slurry can be slurry milled by treating under a series of thermal cycles of heating to 60° C. and cooling back to room temperature over 4 hours.The resulting solid can be collected by filtration, dried at about 40°C for about 4 hours, and optionally jet milled to obtain lasmiditan hemisuccinate I.

[0087] Experimental Procedure

[0088] The preparation of the following method intermediates further illustrates the present invention and represents a typical synthesis of various compounds. Reagents and starting materials are easily available or can be easily synthesized by those of ordinary skill in the art. It should be understood that the preparations and embodiments are illustrated by way of example, and those of ordinary skill in the art may make various modifications.

[0089] LC-ES / MS HP1100 liquid chromatography system. Electrospray mass spectrometry (acquired in positive and / or negative mode) was performed on a mass selective detector quadrupole mass spectrometer connected to a HP1100 HPLC. LC-MS conditions (low pH): Column: NX C18 2.1mm×50mm, 3.0μ; Gradient: 5-100% B in 3 minutes, then 100% B in 0.75 minutes, column temperature: 50℃±10℃; Flow rate: 1.2mL / min; Solvent A: deionized water containing 0.1% HCOOH; Solvent B: ACN containing 0.1% formic acid; Wavelength 214nm. Alternative LC-MS conditions (high pH): Column: MS C18 columns 2.1×50 mm, 3.5 μm; gradient: 5% solvent A for 0.25 min, 5%-100% solvent B gradient in 3 min, 100% solvent B for 0.5 min, or 10%-100% solvent B in 3 min and 100% solvent B for 0.75 min; column temperature: 50℃±10℃; flow rate: 1.2 mL / min; solvent A: 10 mM NH4HCO3 pH 9; solvent B: ACN; wavelength: 214 nm.

[0090] NMR spectra were performed on a Bruker AVIII HD 400 or 500 MHz NMR spectrometer, obtained as solutions in CDCl3 or (CD3)2SO, and reported in ppm using residual solvent [CDCl3, 7.26 ppm; (CD3)2SO, 2.05 ppm] as reference standards. When reporting peak multiplicities, the following abbreviations may be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br-s (broad singlet), dd (doublet), dt (doublet or triplet). Coupling constants (J), when reported, are reported in Hertz (Hz).

[0091] Chloride Analysis at ESA Plus instrument, which is equipped with (Electrified aerosol detector) -HPLC, AcclaimTrinity P1 (100 x 3.0 mm, 3 um), mobile phase: 50 mM ammonium acetate, pH ~5 in ACN.

[0092] The compounds described herein can be prepared by general methods known to those skilled in the art or by methods described herein. Suitable reaction conditions for the steps of these processes are well known in the art, and appropriate substitutions of solvents and co-reagents are known to those skilled in the art. Similarly, it will be appreciated by those skilled in the art that synthetic intermediates can be separated and / or purified by various known techniques as needed or desired, and generally, various intermediates can be used directly in subsequent synthetic steps with little or no purification. In addition, it will be appreciated by the skilled artisan that, in some cases, the order in which the structural moieties are introduced is not critical.

[0093] Preparation 1

[0094] 1-Methylpiperidine-4-carboxylic acid hydrochloride

[0095]

[0096] Scheme 1, step A: To a jacketed reactor was added piperidine-4-carboxylic acid (10.0 g, 77.5 mmol) and deionized water (40 mL). The mixture was heated to reflux (95-100 °C). Formic acid (13.9 g, 302 mmol) was added over 30 minutes. 37% aqueous formaldehyde solution (8.1 g, 101 mmol) was added dropwise to the mixture over at least 30 minutes. Water (0.3 mL) was used as a line flush into the reactor. The mixture was stirred at reflux (95-100 °C) for 4 hours and sampled by HPLC for IPC analysis (NMT 0.5% piperidine-4-carboxylic acid). If the amount of piperidine-4-carboxylic acid was higher than 0.5%, the mixture was stirred for an additional 2 hours. If within specifications, the solution was concentrated under vacuum until a residual volume of ~20 mL remained, and the residue was cooled to 45-50°C. 33% aqueous HCl (12.8 g, 116 mmol) was added to the cooled solution over not less than 30 minutes. Water (0.3 mL) was used as a line flush into the reactor. Water was removed by vacuum distillation until a residual volume of ~20 mL remained. ACN (42.4 mL) was added to the concentrate at 45–50°C, and the mixture was concentrated at atmospheric pressure to a residual volume of ~40 mL. ACN (20.4 mL) was added to the concentrate at 45–50°C, and the mixture was concentrated at atmospheric pressure to a residual volume of ~40 mL. The dilution / concentration operation was repeated until the process control of the moisture content by Karl-Fischer analysis was NMT 0.2%; a slurry formed during these operations. ACN (10.2 mL) was added to the slurry at 45-50°C, the slurry was cooled to 20°C over 1 hour and stirred for another 2 hours, the resulting solid was separated by filtration, and the filter cake was rinsed with ACN (10.2 mL). The wet filter cake was dried at 40°C under nitrogen and atmospheric pressure to give the title compound (12.1 g, 87% yield). MS (m / z): 144 (M+H).

[0097] Preparation 2

[0098] N,N-Diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride

[0099]

[0100] Scheme 1, step B: 1-methylpiperidine-4-carboxylic acid hydrochloride (30.0 g, 167 mmol), chlorobenzene (240 mL) and DMF (0.61 g, 8.35 mmol) were added to a jacketed reactor and the resulting mixture was heated to 50°C. Thionyl chloride (24.2 g, 200.4 mmol) was added to the hot suspension over a period of 1 hour. Chlorobenzene (13.5 mL) was used as a line flush into the reactor. The mixture was stirred for 5 hours after the addition of thionyl chloride was complete. The solution was then cooled to 0 to 10°C. A solution prepared from diethylamine (17.7 g, 12.5 mmol) and TEA (50.7 g, 25 mmol) was added to the cold reaction mixture over a period of 3 hours. Chlorobenzene (13.5 mL) was used as a line flush into the reactor. After the amine mixture was completely added, the mixture was stirred for 2 hours. The reactant was treated with 20 wt% NaOH aqueous solution (180.3g, 902mmol) and stirred at room temperature for 2 hours. Water (3mL) was used as the pipeline flushing liquid entering the reactor. The mixture was allowed to settle for 2 hours and the aqueous phase was removed. The remaining organic phase was placed under vacuum. The mixture was heated to evaporate the residual amine and most of the chlorobenzene. After collecting about ten volumes of distillate, the reactor was evacuated to atmospheric pressure using nitrogen. The remaining solution was cooled to between 10°C and 30°C, and THF (120mL) and water (4.54g, 252mmol) were added to the reactor. At room temperature, the reaction mixture was precipitated with the desired product by adding 20 wt% HCl in isopropanol solution (30.4g, 167mmol). THF (5.4mL) was used as the pipeline flushing liquid entering the reactor. After HCl was fully added, the suspension was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and washed with THF (75.0mL). The collected solid was dried under vacuum at 40°C for 16 hours to give the title compound (35.5 g, 84% yield). MS (m / z): 199 (M+H).

[0101] Preparation 3

[0102] (6-Bromo-2-pyridinyl)-(1-methyl-4-piperidinyl)methanone hydrobromide

[0103]

[0104] Scheme 1, Step C: A suspension of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride (21.5 g, 85.1 mmol) in MTBE (109 mL) was treated with 20 wt% aqueous NaOH (34.0 g, 170 mmol). Rinse with water (1.94 mL) to complete the addition. The mixture was stirred at room temperature for 30 minutes, the phases were allowed to settle, and the phases were separated. The aqueous phase was extracted with MTBE (43.7 mL) and the organic phases were combined. The organic phase was dried by distillation at atmospheric pressure until the process control of water content was less than 0.10 wt% by Karl-Fischer analysis. If the target analysis was not met, MTBE (43.7 mL) was added to the reaction and the distillation was repeated. Three distillations were usually required to achieve the target analysis for water. In a separate reactor, a mixture of 2,6-dibromopyridine (30.2 g, 128 mmol) and MTBE (105 mL) was added and cooled to below -58 °C. To the cooled suspension was added a 2.5 M solution of n-BuLi in hexane (51.3 mL, 128 mmol) over 2 hours. The transfer was completed with a rinse of MTBE (4.5 mL). After the n-BuLi addition was complete, the mixture was aged while the temperature was maintained below -58 °C for another 2 hours. After aging, a solution of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride in MTBE was added to the cold reaction over a period of 45 minutes. The transfer was completed with a rinse of MTBE (13.5 mL). After the complete addition of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride in MTBE, the mixture was aged for at least 30 minutes. After aging, the reaction was warmed to 0 °C over 1 hour. The cold reaction mixture was added to a 2.5 M aqueous HCl solution (146 mL, 366 mmol) at a rate to maintain the quenching temperature at NMT 30 °C. The transfer was completed with a rinse of MTBE (13.5 mL). After the transfer was completed, the mixture was stirred for at least 30 min and the phases were allowed to settle. The phases were separated and the aqueous phase was retained. n-BuOH (54.8 mL) was added to the aqueous phase and the mixture was treated with a 20 wt % aqueous solution of NaOH (59.5 g, 298 mmol). The transfer was completed with water (2.80 mL). The mixture was stirred for at least 30 minutes and the phases were allowed to settle. The phases were separated and the organic phase was retained. The aqueous phase was extracted with n-BuOH (54.8 mL). The combined organic phases were dried by vacuum distillation to obtain a process control of water content of <0.20 wt % by Karl-Fischer analysis. If the target analysis was not met, n-BuOH (41.1 mL) was added and the distillation was repeated. Typically, two distillations were required to achieve the process control target analysis. The concentrated solution was clarified by filtration, rinsed with n-BuOH (89.6 mL) to complete the transfer, and the filter was rinsed.The clear solution was treated with 48 wt % HBr aqueous solution (9.91 mL, 87.7 mmol) for 90 minutes. Rinse with n-butanol (13.8 mL) to complete the transfer. pH detection showed that the pH of the reaction mixture was ~1. The mixture was dried by distillation at atmospheric pressure to obtain a process control of water content of <0.30 wt % by Karl-Fischer analysis. The mixture was concentrated to 172 mL. If the target analysis was not met, n-BuOH (54.8 mL) was added and the distillation was repeated. The mixture was cooled to 20 ° C and stirred for 12 hours. The resulting solid was collected by filtration and washed twice with n-BuOH (10.75 mL). The solid was dried in vacuo at 60 ° C to obtain the title compound (24.8 g, 80% yield). MS (m / z): 283, 285 (. 79 Br, 81 Br, M+H).

[0105] Preparation 4

[0106] (6-Amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrate dihydrochloride

[0107]

[0108] Scheme 1, Step D: A pressure reactor was charged with (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide (30 g, 82.9 mmol) and Cu2O (880 mg, 6.2 mmol). The headspace was exchanged three times with nitrogen / vacuum purge cycles. NH3 / ethylene glycol solution (273.5 g total, 39.1 g NH3, 2.33 mol; 210 mL ethylene glycol) was added to the solids and the resulting mixture was stirred at room temperature for 2 hours. The mixture was heated to 80°C, stirred for 10 hours, cooled to room temperature, and an in-process control sample of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide NMT 2% was taken. If the target analysis was not met, the reaction was stirred at 80°C for another 4 hours and sampled again. H2O (90 mL) was added to the completed reaction and the mixture was filtered. The filtrate was added to an aqueous NaCl solution (253.9 g NaCl, 2.73 mol, 13.7 L / kg H2O), and the resulting mixture was stirred at room temperature for 10 minutes. A 20% aqueous NaOH solution (4.44 equiv., 368 mmol) was added to the mixture, and the two-phase mixture was stirred at room temperature for 5 minutes. The mixture was extracted with MTBE (90 mL) 4-5 times at room temperature. The combined MTBE layers were treated with 5 wt% carbon for 30 minutes, and the carbon was removed by filtration. The organic filtrate was concentrated to ~150 mL under vacuum. IPA (200 mL) was added to the concentrated filtrate, and the solution was concentrated to ~150 mL under vacuum twice. The IPA distillation was repeated as needed to meet the target analysis for process control of water. The water content was determined to be no more than 0.2% by Karl-Fischer analysis. At room temperature, a 20 wt% solution of HCl in IPA (30 g, 166 mmol) and water (10.5 mL) were added to another reactor at room temperature. The concentrated product mixture was added to the HCl solution over 90 minutes. The resulting slurry was stirred at room temperature for no less than 8 hours. The slurry was filtered, washed twice with a mixture of 95:5 IPA / H2O (36 mL) at room temperature, and dried under vacuum at 40°C for 16–24 hours to give the title compound (18.4 g 68% yield). MS (m / z): 220 (M+H). 1H NMR(400MHz,D2O / DMSO-d6)δppm 1.74-1.88(m,2H),2.05(br d,J=14.9Hz,2H),2.73(s,3H),3.01(td,J=13.1,2.6Hz,2H),3.41-3.50(m,2H),3.55(tt,J=12 .0,3.5Hz,1H),7.14(dd,J=9.0,0.7Hz,1H),7.59(d,J=7.2Hz,1H),7.90(dd,J=9.0,7.2Hz,1H). 13 C NMR (101 MHz, D2O / / DMSO-d6) δ ppm 27.4, 40.7, 44.6, 54.6, 117.2, 121.1, 137.9, 145.2, 156.2, 196.3. Chloride analysis: 20.23% (n=2).

[0109] Crystalline forms by X-ray powder diffraction (XRPD)

[0110] The XRPD pattern of the crystalline solid was obtained on a Bruker D4 Dearter X-ray powder diffractometer, which was equipped with a CuKα source and a Vantec detector, operating at 35kV and 50mA. The sample was scanned between 4 and 40 2θ°, with a step size of 4 and 40 2θ°, a scan rate of 0.5 seconds / step, a divergence of 1.0mm, a fixed anti-scattering of 6.6mm, and a detector slit of 11.3mm. The dried powder was mounted on a quartz sample holder and a glass slide was used to obtain a smooth surface. Crystalline diffraction patterns were collected at ambient temperature and relative humidity. In MDI-Jade, the crystal peak position was determined after the complete pattern was moved according to the internal NIST 675 standard, with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystal form, the relative intensity of the diffraction peaks may vary due to preferred orientation caused by factors such as crystal morphology and habit. When there is the influence of preferred orientation, the peak intensity changes, but the characteristic peak position of the polymorph remains unchanged. See, for example, United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. In addition, it is also well known in the field of crystallography that for any given crystal form, the angular peak position can vary slightly. For example, the peak position may shift due to temperature changes of the analyzed sample, sample displacement, or the presence or absence of an internal standard. In the present case, the peak position variation of ± 0.2 2θ ° is considered to take into account these potential changes without hindering the clear identification of the indicated crystal form. The crystal form can be confirmed based on any unique combination of distinguishing peaks.

[0111] The sample of Preparation 4, (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride, is characterized in that the XRD pattern irradiated with CuKα has the diffraction peaks (2θ values) described in Table 1 below, especially having a peak at 8.3° and one or more peaks selected from 16.6°, 23.5° and 33.7°, and the allowable error of the diffraction angle is 0.2°.

[0112] Table 1: X-ray powder diffraction peaks of the crystalline compound of Preparation 4; (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride

[0113]

[0114]

[0115] Preparation 5

[0116] 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hydrochloride

[0117]

[0118] Scheme 1, Step E: To a suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrochloride dihydrate (10 g, 30.6 mmol) in chlorobenzene (65 mL) was added 6 w / w% aqueous NaOH solution (3 g, 75 mmol). The two-phase mixture was heated to 54°C for 30 minutes with stirring, the mixture was allowed to separate within 30 minutes, and the layers were separated at 54°C. The aqueous layer was stripped with chlorobenzene (45 mL) at room temperature. The organic layers were combined and distilled to ~62 mL under vacuum to give a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. 2,4,6-Trifluorobenzoic acid (5.9 g, 1.1 eq, 33.7 mmol), DMF (62 mg, 0.85 mmol) and chlorobenzene (32 mL) were added to a separate reactor and the mixture was heated to 80°C. Thionyl chloride (4.37 g, 37 mmol) was added to the heated mixture at 80°C over 4 hours, the mixture was stirred at 80°C for at least 6 hours, and heated to 100°C for at least 6 hours to remove residual HCl gas. The acid chloride solution was cooled to room temperature and transferred to a separate reactor. The acid chloride solution was heated to 100°C, and (6-aminopyridine-2-yl) (1-methylpiperidin-4-yl) ketone was added over 4 hours. The resulting slurry was stirred for another 3 hours at 100°C and cooled to room temperature. ACN (100 mL) was added to the cooled slurry. The resulting slurry was heated to 80°C for 1 hour and cooled to room temperature within 2 hours. The resulting slurry was stirred for another 1 hour at room temperature and filtered. The filter cake was washed with ACN (10 mL) at room temperature. The collected solid was dried at 100°C under vacuum for 16 hours to obtain the title compound (10.7 g, 85% yield). MS m / z 378 (M+H).

[0119] Alternative method for preparing 5

[0120] To a suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidinyl)methanone dihydrochloride dihydrate (10 g, 30.6 mmol) in chlorobenzene (65 mL) was added 6 w / w% aqueous NaOH solution (2.97 g, 74.4 mmol). The two-phase mixture was heated to 54°C for 30 minutes with stirring and the layers were separated within 30 minutes. The layers were separated at 54°C and the aqueous layer was back extracted with chlorobenzene (45 mL) at room temperature. The organic layers were combined and distilled to ~62 mL under vacuum to give a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. In another reactor, 2,4,6-trifluorobenzoic acid (5.9 g, 33.7 mmol), DMF (62 mg, 0.85 mmol) and chlorobenzene (32 mL) were added and the mixture was heated to 80°C. Thionyl chloride (4.4 g, 37 mmol) was added to the heated mixture at 80 ° C over 4 hours. The mixture was stirred at 80 ° C for at least 6 hours and heated to 100 ° C for at least 6 hours to remove residual HCl gas. The acid chloride solution was cooled to room temperature and transferred to a separate reactor. The acid chloride solution was heated to 100 ° C and (6-aminopyridine-2-yl) (1-methylpiperidin-4-yl) ketone was added to the solution over 4 hours. The resulting slurry was stirred at 100 ° C for another 3 hours and cooled to room temperature. ACN (100 mL) was added to the cooled slurry. The resulting slurry was heated to 80 ° C for 1 hour and cooled to room temperature within 2 hours. The resulting slurry was stirred at room temperature for another 1 hour and the resulting solid was collected by filtration. The filter cake was washed with ACN (10 mL) at room temperature. The solid was dried at 100 ° C under vacuum for 16 hours to obtain the title compound (10.7 g, 85% yield). MS m / z 378 (M+H).

[0121] Preparation 6

[0122] 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate

[0123]

[0124] Scheme 1, Step F: 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hydrochloride (20 g, 48.4 mmol) and MTBE (202 mL) were added to the reactor. To the stirred slurry was added aqueous NaHCO3 (8.13 g, 96.8 mmol NaHCO3 in 200 mL water) over 1 hour at room temperature. The two phase mixture was separated and the aqueous layer was back extracted with MTBE (202 mL). The combined organic layers were distilled under vacuum to a final volume of ~200 mL. SiO2 (2 g) was added to the distilled solution, the resulting mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was rinsed with MTBE (10.8 mL). Carbon (340 mg; alternatively, the solution can be filtered through a carbon column) was added to the filtrate, the resulting mixture was stirred at room temperature for 30 minutes, filtered through a 1-5 μm filter, and then rinsed with MTBE (21.6 mL). The filtrate was distilled under vacuum to ~80 mL. Ethanol (114 mL) was added to the concentrate and the resulting solution was distilled under vacuum to ~84 mL. The EtOH was added back and distilled until the water content did not exceed 1% by Karl-Fischer analysis to obtain a dry solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide. Succinic acid (3.03 g, 25.7 mmol) and EtOH (60 mL) were added to a separate reactor. The mixture was stirred and heated at 33 °C until the succinic acid was completely dissolved.

[0125] A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide was heated to 55°C, and a portion of a solution of succinic acid in EtOH (about 1.0 L / kg) was added to the heated solution. The resulting solution was then inoculated by adding 1% by weight of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hemisuccinate (200 mg). The resulting slurry was stirred for 30 minutes, and the remaining succinic acid in EtOH was added at a constant rate over 2 hours. The reactor contents were stirred for 30 minutes and linearly cooled to room temperature over 2.5 hours. The resulting slurry was stirred at room temperature for not less than 3 hours. The slurry was filtered and the collected solids were washed with EtOH (60 mL). The solid was dried under vacuum at 45°C for 16 hours to give the title compound (20.4 g, 85% yield). MS m / z 378 (M+H). 1H NMR(500MHz,DMSO-d6)δppm 1.59(d,J=12.1Hz,2H),1.84(d,J=12.8Hz,2H),2.08(t,J=11.4Hz,1H),2.38(s,2H),2.24(s,3H),2.89(d,J=13.1Hz,2H),3 .70(s,1H),7.40(dd,J=9.4,7.8Hz,2H),7.75(d,J=7.6Hz,1H),8.08(t,J=7.9Hz,1H),8.39(d,J=8.2Hz,1H),11.47(s,1H).

[0126] Alternative method for preparing 6

[0127] Scheme 3, Steps D, E and F: To a jacketed reactor was added (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone (50 g, 137 mmol) and toluene (400 mL). Water (250 mL) was added followed by KOH pellets (13.6 g, 206 mmol) and the mixture was stirred at room temperature for 3 hours. The contents of the reactor were filtered and returned to the reactor. The aqueous layer was drained and the organic layer was treated with activated carbon to remove color if necessary. The mixture was concentrated under reduced pressure at 50°C to ~150 mL. Toluene (225 mL) was added back to the reactor under nitrogen, K2CO3 (28.5 g, 206 mmol), 2,4,6-trifluorobenzamide (26.5 g, 151 mmol) and water (2.5 mL) were added and the contents were stirred at room temperature. Under nitrogen, toluene (20 mL), Pd(OAc)2 (154 mg, 0.68 mmol) and Xantphos (795 mg, 1.37 mmol) were added to another flask and the contents were stirred at room temperature for 30 minutes. The resulting solution was transferred to a reactor and the reactor was heated to 70°C with stirring. After 5 hours, the mixture was sampled for IPC HPLC analysis of NMT 0.1% (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone. If the amount of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone was not reached, the mixture was stirred for another 5 hours and sampled again. If the IPC was met, the mixture was stirred at 70°C for another 12 hours, then the contents of the reactor were cooled to 45°C, water (250 mL) and EtOAc (250 mL) were added, and the mixture was stirred for 1 hour. Stirring was stopped and the layers were separated. The aqueous layer was removed and discarded. Water (250 mL) was added and the resulting mixture was stirred for 1 hour. Stirring was stopped and the layers were separated. The aqueous layer was removed and discarded. Thiourea-modified silica gel (5 g) was added and the reactor was heated to 60° C. for 8 hours with stirring. The contents of the reactor were cooled to room temperature. The solution was filtered and returned to the reactor. The thiourea-modified silica gel filter cake was rinsed with EtOAc (150 mL) and the rinse was returned to the reactor. If necessary, activated carbon treatment can be performed to remove color. The solution was passed through a polish filter to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide.

[0128] 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide solution was concentrated to ~150mL under reduced pressure at 50°C. EtOH (250mL, denatured with toluene) was added and the contents were concentrated to ~150mL under reduced pressure at 50°C. This process was repeated for a total of 3 cycles to achieve sufficient toluene removal before the last toluene feed reached a total of 250mL. The resulting toluene mixture was heated to 55°C, and succinic acid (8.6g, 73mmol) and EtOH (200mL, denatured with toluene) were added to another container. The contents of the stirring container were stirred until the succinic acid was completely dissolved. Approximately 30 mL of the succinic acid solution was transferred to the 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide solution, and the resulting solution was stirred at 55°C, and 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hemisuccinate was added as a seed crystal either as a solid or as a slurry in toluene-denatured EtOH. The remaining succinic acid in the toluene-denatured EtOH solution was transferred to the reactor over 1.5 hours. The contents of the reactor were cooled to room temperature over 10 hours. The resulting slurry can be ground to control the particle size. If the slurry is ground, the contents of the reactor can be subjected to a series of thermal cycles, which are performed by heating to 60°C with stirring and cooling back to room temperature over 4 hours to further control the particle size distribution. The slurry was filtered, rinsed with EtOH (100 mL, denatured with toluene), and dried under reduced pressure at 40 °C for 12 h to afford the title compound (43.9 g, 73% yield). The dried solid can then be jet milled to further control particle size.

[0129] Description of the method of preparation of the drug product

[0130] In one embodiment, lasmiditan prepared by the method provided herein can be further prepared into certain useful drug product forms. In one embodiment, the drug product form can be an oval 50 and 100 mg concave, aqueous film-coated immediate release dosage form. The 50 mg tablet is a light gray oval tablet with a concave pattern of "4312" on one side and a concave pattern of "L-50" on the other side. The 100 mg tablet is a light purple, oval tablet with a concave pattern of "4491" on one side and a concave pattern of "L-100" on the other side.

[0131] The following unit formulation can be used to produce lasmiditan tablets. The ingredient naming convention is based on USP.

[0132] Table 2. Unit formulations for lasmiditan 50 mg and 100 mg tablets

[0133]

[0134] Notes to Table 2:

[0135] a. Calculate the amount of lasmiditan hemisuccinate using a salt conversion factor of 0.86469. The amount of microcrystalline cellulose may be adjusted accordingly to maintain the target tablet weight.

[0136] b. Use purified water in the granulation operation. Most of the water is subsequently removed during the drying operation.

[0137] c. A small amount of residual water remains after the drying process, which may be in the form of free water or water of hydration associated with the drug substance.

[0138] d. Purified water is used for the coating unit operation. The coating suspension consists of 20% w / w solids. Sufficient coating is sprayed to achieve a 3% weight gain. This water is removed during the coating unit operation.

[0139] Tablet Preparation:

[0140] Lasmiditan tablets were prepared using a high shear wet granulation process as described below. High shear wet granulation: Sodium lauryl sulfate was passed through a safety screen and added to purified water to form a granulation liquid. The lasmiditan drug substance and the excipients to be wet granulated (microcrystalline cellulose, pregelatinized starch, cross-linked sodium carboxymethyl cellulose) were passed through a safety screen and mixed in a granulator. The materials were mixed with the main impeller of the granulator before adding the granulation liquid. While the powders were mixing, the powder blend was granulated in a granulator by adding the granulation liquid. When the liquid addition was completed, the particles were wet agglomerated to facilitate liquid distribution. The particles were coarsely graded by a conical grinder before drying.

[0141] Fluid Bed Drying: Dry the granules in a fluid bed dryer until reaching a moisture value of (50 mg and 100 mg: NMT 7%) as measured by loss on drying or using a scientifically sound equivalent method. The dried granules are passed through a cone mill and added to a tumble bin.

[0142] Final Blend - Extragranular Powder Blend and Final Blend Lubrication: Pass extragranular croscarmellose sodium through a safety screen and add it to the dry milled granules in a tumble hopper. Tumble mix the material. Pass extragranular magnesium stearate through a safety screen and add it to a tumble hopper. Tumble mix the material.

[0143] Tablet Compression: The blended granules were compressed into tablets using a rotary tablet press. Compression parameters were selected at the start of a batch to achieve target mean (n=10) tablet weight (50 mg: 111.4 mg–123.2 mg, 100 mg: 222.8–246.2 mg) and mean (n=10) tablet crushing force (50 mg: 4.1–13.7 kgf, 100 mg: 6.0–17.9 kgf). Mean (n=10) core weight, tablet crushing force, and tablet thickness were evaluated during startup and throughout the compression unit operation. Tablet friability and tablet disintegration time were evaluated at the start of compression.

[0144] Film Coating of Tablet Cores: The color mixture (grey for 50 mg and purple for 100 mg) is passed through a safety screen and mixed with purified water to form a coating suspension. The tablets are film coated with the suspension using a spray gun in a perforated coating pan. The pan is rotated while the coating suspension is applied using pneumatic atomization at a controlled rate and dry air is passed through the tablet bed to produce an acceptable exhaust temperature. Sufficient coating is sprayed to achieve the desired coating percentage applied (50 mg and 100 mg: 2.0%-5.5%). After the coating step is completed, the visual quality of the film-coated tablets is inspected. The film-coated tablets are discharged into bulk storage containers and can be sorted (optional).

[0145] Container Closure System - Unit Dose Blister:

[0146] The lasmiditan tablets are provided in individual blister cavities formed from a polychlorotrifluoroethylene (PCTFE) / polyvinyl chloride (PVC) laminate film and sealed with an aluminum foil laminate lidding material comprising a PVC-based heat seal coating.

[0147] Preparation and Description of 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate

[0148]

[0149] 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide acetate (also known as lasmiditan acetate) was prepared by placing 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide (541 mg, 1.6 mmol) in isopropyl acetate (5 mL) while stirring at 1000 rpm at room temperature. Acetic acid (100 μL) was added. After stirring for about two minutes, a white solid precipitated from the solution. After 10 minutes, stirring was stopped and the white solid was collected by vacuum filtration on Whatman filter paper and dried in situ under air flow for 10 minutes to give the title compound (650 mg, 92% yield).

[0150] Counterion stoichiometry was measured by nuclear magnetic resonance using an Agilent 400-MHz spectrometer. The sample solution was 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 the other measurement standard in DMSO-d6 (about 0.75 mL). The following parameters were used to obtain 0-12 ppm of the sample. 13 C-decoupled 1 H spectrum: 90 degree excitation pulse, 64 scans, 25 second relaxation delay, and 4.5 second acquisition time. The resonance of acetate at approximately 1.9 ppm (3H) and the resonance of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide at approximately 7.8 ppm (1H) were integrated to give areas of 29094 and 9508, respectively. The molar ratio of acetate to 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide was calculated by taking the ratio of these areas, accounting for the difference in the resonance proton counts, giving an observed molar ratio of 29094 / (3 x 9508) = 1.02 acetate:2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide. See, e.g. Figure 1 , which shows the concentration of lasmiditan acetate containing maleic acid (internal standard) 1 H NMR spectrum (400 MHz, DMSO-d6). The results provide experimental evidence that the preparation example of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide acetate is a monoacetate.

[0151] X-Ray Powder Diffraction (XRPD) of 2,4,6-Trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide acetate

[0152] The XRPD pattern of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate crystalline solid was obtained on a Bruker D4 Dearter X-ray powder diffractometer equipped with a CuKα source and a Vantec detector, operating at 35 kV and 50 mA. The sample was scanned between 4 and 40 2θ° with a step size of 4 and 40 2θ° and a scan rate of 0.5 sec / step, using a divergence of 1.0 mm, a fixed anti-scatter of 6.6 mm, and a detector slit of 11.3 mm. The dried powder was mounted on a quartz sample holder and a glass slide was used to obtain a smooth surface. The crystal diffraction pattern was collected at ambient temperature and relative humidity. The crystal peak positions were determined in MDI-Jade based on the internal NIST 675 standard after a complete pattern move, with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystal form, the relative intensity of the diffraction peak may vary due to the preferred orientation caused by factors such as crystal morphology and habit. When there is the influence of preferred orientation, the peak intensity changes, but the characteristic peak position of the polymorph remains unchanged. See, for example, USP #23, National Formulary #18, pages 1843-1844, 1995. In addition, it is also well known in the field of crystallography that for any given crystal form, the angular peak position may vary slightly. For example, the peak position may shift due to temperature changes, sample displacement, or the presence or absence of an internal standard in the analyzed sample. In the present case, the peak position variation of ± 0.2 2θ ° is considered to take into account these potential changes without hindering the clear identification of the indicated crystal form. Crystal form can be confirmed based on any unique combination of distinguishing peaks.

[0153] The sample of the prepared crystalline acetate is characterized by an XRPD pattern using CuKa irradiation, which has diffraction peaks (2θ values) as described in Table 3 below, especially having a peak at 26.2 and one or more peaks selected from 20.4, 14.0 and 17.9; the allowable error of the diffraction angle is 0.2 degrees.

[0154] Table 3. X-ray powder diffraction peaks of crystalline 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide acetate

[0155]

[0156] Solubility of lasmiditan acetate and its use in subcutaneous injection preparations:

[0157] For the preparation of subcutaneous formulations, it was found that lasmiditan acetate was surprisingly superior to many alternative salt forms, which delivered the dose of lasmiditan in a minimum volume close to physiological fluids. It was found that lasmiditan acetate was able to reach the desired dose target of about 50 mg in a minimum volume less than or equal to about 1 mL, while reaching the desired target pH close to neutral, and was also relatively isotonic and physically and chemically stable. Using lasmiditan hemisuccinate, it was experimentally determined that it was difficult to reach a solubility of>50 mg / mL without using a cosolvent when approaching neutral pH. In order to determine the solubility, 10 mmol buffer was prepared with the corresponding acid and salt, and the pH was adjusted by changing the acid / salt ratio. The excess solid was balanced at room temperature overnight, the solution concentration was analyzed by HPLC, and the solid was characterized by XRPD. On the contrary, for lasmiditan acetate, it was found that when approaching neutral pH, the solubility of>50 mg / mL could be reached without adjusting the pH.

[0158] Table 4:

[0159] Solubility of lasmiditan acetate in acetate, citrate or phosphate buffers. 10 mmol of buffer was prepared with the corresponding acid and salt, and the pH was adjusted by varying the acid / salt ratio. All added solutes went into solution forming a viscous solution.

[0160]

[0161]

[0162] It has been found that lasmiditan acetate surprisingly shows a combination of highly favorable drug properties. For the required unit dose, lasmiditan acetate can provide the required solubility to provide a high concentration formulation with a dosage volume less than or equal to about 1 mL, which is critical for clinical applications such as use in available automatic injector devices. In addition, the dissolution of lasmiditan acetate at 50 mg / mL leads to a pH close to neutral (pH about 6.8), which is isotonic and remains stable for at least 2 months. Lasmiditan acetate shows a significantly higher solubility than lasmiditan hemisuccinate with a pH property that meets the requirements, making it possible to deliver the required unit dose with a volume of about 1 mL or less.

[0163] These results indicate that lasmiditan acetate enables an aqueous solution of lasmiditan to have surprisingly high concentrations, and has useful pharmaceutical properties for clinical parenteral administration, such as subcutaneous injection. The pharmacological activity of lasmiditan is well established (Curto, M et al., Profiling lasmiditan as a treatment option for migraine, Expert Opinion on Pharmacotherapy (2020), Vol. 21, No. 2, pp. 147-153). Preferably, subcutaneous injection is administered by prefilled syringe or automatic syringe, using a device known to the technician (see, for example, Stauffer VL et al., Comparison between prefilled syringe and autoinjector devices on patient-reported experiences and pharmacokinetics in galcanezumabstudies., Patient Prefer Adherence. (2018) 12: 1785-1795 and van den Bemt BJF et al., A portfolio of biologic self-injection devices in rheumatology: how patient involvement in device design can improve treatment experience., Drug Deliv. (2019), 26 (1): 384-392). These forms provide fixed doses without the need for patient measurement, providing dose accuracy and safety while enabling patients to operate autonomously. The use of lasmiditan acetate in a form such as an auto-injector for the acute treatment of a migraine attack provides an improved tool for institutional patients, such as in a hospital emergency setting, where the patient's use of tablets is disrupted by a migraine attack and associated nausea and vomiting, and the patient and / or provider prefers to use an improved injectable form of lasmiditan. It is expected that a lasmiditan acetate parenteral formulation provides immediate release, enabling a rapid onset of action, and when used as needed at the onset of a migraine attack, may preferably allow for a shorter onset of action relative to an oral dosage form.

[0164] Providing a lasmiditan formulation for injection at neutral and physiological pH (about 6.0-7.5) and isotonic with physiological fluids (e.g., 280-300mosm / kg) is highly desirable clinically and is considered to minimize the possibility of pain and / or tissue irritation during, for example, injection. Achieving an injection volume of about 1 ml or less enables the use of available syringe technology such as an auto-injector, and provides an improved injection and delivery experience for patients, for example, in terms of injection time and / or pain during injection. Being able to use pre-filled syringes, pens, and / or auto-injector technology is clinically important for migraine patients because these devices provide ease of use during migraine attacks, when patients are often in duress when using the product. In addition, being able to use pre-filled syringes, pens, and / or auto-injector technology is clinically important because they provide portable medications at any time, which can be easily obtained during daily life (migraine attacks can occur at any time).

[0165] The following unit formula can be used to produce lasmiditan solution for injection.

[0166] Table 5. Unit formulation for lasmiditan 50 mg solution in autoinjector

[0167]

Claims

1. A method for preparing the compound of the formula: The following steps are involved: i.) treating piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water, followed by treatment with aqueous HCl, followed by distillation of the water and addition of acetonitrile, and repeating the dilution / distillation until the water content does not exceed 0.2% by Karl-Fischer analysis to give solid 1-methylpiperidine-4-carboxylic acid hydrochloride; ii.) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent, thionyl chloride, in chlorobenzene to obtain 1-methylpiperidine-4-carboxylic acid chloride; iii.) treating 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by alkaline washing and subsequent treatment with aqueous HCl in isopropanol to give solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; iv.) treating N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with an aqueous solution of an inorganic base NaOH in a non-polar solvent of methyl tert-butyl ether, followed by water washing, phase separation, and distillation of the organic solvent until the water content measured by Karl Fischer analysis does not exceed 0.1% by weight to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide; v.) subsequently treating N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a nonpolar organic solvent, methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic solvent, n-butanol, phase separation, and repeated distillation of the organic solvent until the water content does not exceed 0.2% by weight by Karl-Fischer analysis to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone; vi.) treating (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr solution, followed by extraction with n-butanol, and then repeatedly distilling the organic solvent until the water content does not exceed 0.3% by Karl-Fischer analysis to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide; vii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidinyl)methanone hydrobromide with a solution of NH3 in ethylene glycol at 80°C for 2 hours in the presence of a Cu2O catalyst, followed by washing with water, saturated aqueous NaCl solution and 20% aqueous NaOH solution, followed by extraction with a non-polar aprotic solvent methyl tert-butyl ether, phase separation and treating the organic phase with 5 wt% carbon; viii.) filtering the mixture, diluting with a suitable polar alcohol solvent, isopropanol, repeatedly distilling the organic solvent until the water content does not exceed 0.2% by Karl-Fischer analysis, then treating the residue obtained with isopropanol, water and 20 wt % HCl, wherein the water concentration of the obtained slurry is at least 2%, filtering the obtained slurry, and drying under vacuum at 40° C. for 16-24 hours to obtain a solid (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride; ix.) treating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6% w / w aqueous NaOH at 54° C. for 30 minutes, followed by phase separation and vacuum distillation of the aqueous solution to give (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone; x.) (6-amino-2-pyridinyl)-(1-methyl-4-piperidinyl)methanone is then treated with 2,4,6-trifluorobenzoyl chloride in chlorobenzene at 100° C. for 4 hours, followed by cooling, addition of acetonitrile and heating the resulting slurry to 80° C. for 1 hour, followed by collection of the resulting solid by filtration to give solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hydrochloride; xi.) treating 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride with saturated aqueous Na2CO3 solution in methyl tert-butyl ether; xii.) treating the mixture of step xi above with SiO2, followed by filtering, treating with carbon, filtering, and evaporating, diluting with ethanol, and distilling until the water content does not exceed 1% by Karl-Fischer analysis to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide; xiii.) 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide in ethanol is treated with 0.5 equivalent of succinic acid in ethanol at 55°C for not less than 3 hours at room temperature, followed by collection of the solid by filtration to give solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hemisuccinate.

2. A method for preparing the compound of the formula: The following steps are involved: i.) treating piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water, followed by treatment with aqueous HCl, followed by distillation of the water and addition of acetonitrile, and repeating the dilution / distillation until the water content does not exceed 0.2% by Karl-Fischer analysis to give solid 1-methylpiperidine-4-carboxylic acid hydrochloride; ii.) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent, thionyl chloride, in chlorobenzene to obtain 1-methylpiperidine-4-carboxylic acid chloride; iii.) treating 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by alkaline washing and subsequent treatment with aqueous HCl in isopropanol to give solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; iv.) treating N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with an aqueous solution of an inorganic base NaOH in a non-polar solvent of methyl tert-butyl ether, followed by water washing, phase separation, and distillation of the organic solvent until the water content measured by Karl Fischer analysis does not exceed 0.1% by weight to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide; v.) subsequently treating N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a nonpolar organic solvent, methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic solvent, n-butanol, phase separation, and repeated distillation of the organic solvent until the water content does not exceed 0.2% by weight by Karl-Fischer analysis to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone; vi.) treating (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr solution, followed by extraction with n-butanol, and then repeatedly distilling the organic solvent until the water content does not exceed 0.3% by Karl-Fischer analysis to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide; vii.) treating (6-bromo-2-pyridinyl-1-methyl-4-piperidinyl)methanone hydrobromide with solid KOH in a two-phase mixture of water and toluene for 3 hours, followed by separation of the organic layer and evaporation of the solvent to give (6-bromo-2-pyridinyl-1-methyl-4-piperidinyl)methanone; viii.) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing K2CO3, water, Pd(OAc)2 and Xantphos at 70°C for 12 hours until the content of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone does not exceed 0.1% by HPLC, followed by dilution of the reaction mixture with water and EtOAc and subsequent treatment with thiourea-modified silica gel at 60°C for 8 hours followed by filtration to give a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide; ix.) A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide in EtOAc was treated with 0.5 equivalent of succinic acid in EtOH at 55°C for 3 hours, then cooled to room temperature over 10 hours and the resulting solid was collected by filtration to give solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridinyl]benzamide hemisuccinate.

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

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

5. The method of claim 4, wherein the batch produced is at least 1 kg.

6. The method of claim 4, wherein the batch produced is at least 10 kg.

7. The method of claim 4, wherein the batch produced is at least 100 kg.

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