EA045247B1 - METHODS AND INTERMEDIATE COMPOUND FOR LARGE-SCALE PRODUCTION OF 2,4,6-TRIFLUORO-N-[6-(1-METHYLPIPERIDIN-4-CARBONYL)PYRIDIN-2-YL]BENZAMIDE HEMISUCCINATE, AS WELL AS PRODUCTION OF 2,4,6-TRIFLUORO-ACETATE N-[6-(1-METHYLPIPERIDINE-4-CARBONYL)PYRIDIN-2-YL]BENZAMIDE - Google Patents

Description

Embodiments of the present invention relate to the fields of pharmaceutical chemistry and synthetic organic chemistry and provide methods and an intermediate for the large-scale synthesis of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin2-yl] hemisuccinate salt benzamide, a 5-HT1F receptor agonist, and compositions and finished preparations obtained by these methods, as well as to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin-2yl]benzamide acetate and its use for parenteral formulations and the treatment of migraine.

Lasmiditan is a selective and highly potent 5-HT _1F receptor agonist currently approved in the United States in the form of 50 or 100 mg tablets for the acute treatment of migraine when needed (see, for example, Rubio-Beltran et al., Pharmacol. Ther., 2018, 186:88-97; and Lasmiditanfor 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 registration number 439239-90-4) can be chemically described as 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl] benzamide. US Patent No. 7,423,050 and US Publication No. 20080300407 disclose a hemisuccinate salt of 2,4,6-trifluoro-N[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide having the structural formula

Methods for preparing lasmiditan and salts, as well as some of their polymorphs, compositions 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.

In this context, useful forms of lasmiditan include its pharmaceutically acceptable salts, including but not limited to the following: 2,4,6-trifluoro-N-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide monohydrochloride salt and hemisuccinate 2,4,6-trifluoro-N-[6-(1methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide salt. The synthetic method for preparing the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide was described previously and is presented below in Scheme A. The total yield of lasmiditan from the commercially available piperidine-4carboxylic acid, when prepared by the method described below in scheme A, is approximately 10-46% for all 9 stages. Improvements in the synthesis of lasmiditan may provide significant and varied benefits, particularly for large-scale production.

Stage 1

BUT.

Stage 2

CH ₂ O, HCO ₂ H

Pd/C, water atmospheric pressure (80-90%)

Q _a Me

HCI

1) SOCI ₂ , THF

2) Εί ₂ ΝΗ/ΤΓΦ/Εί ₃ Ν (75-95%)

Stage 3

N

Me

2) HBr/NOAc (50-80%) η ι-PrMgCI/LiCI, THF

Br^N^^Br 25 °C

Vg

Me

IV

Stage 4

ABOUT

Ethylene glycol, ammonia Cu ₂ O, 70 °C, 4 barg.

(50-75%)

Me

V

Stage 5

Chlorobenzene, 100 °C (75-95%)

Ethanol (80-100%)

Stage 6F

NaHCO ₃ G

VII

Stage 6a Succinic acid

Ethanol (70-95%)

CO ₂ H

Scheme A

- 1 045247

Methods for carrying out the chemical synthesis process can be modified or revised to achieve various advantages, including, for example, improving yield, obtaining crystalline products, reducing the impurity profile, using commercially available intermediates, minimizing the number of synthetic steps required, reducing the amount of consumables required, and /or by-products generated, or any suitable combination of such improvements to achieve important real-world production benefits, including reducing costs, enabling less resource-intensive processes, and ensuring efficient production. Improved methods for producing lasmiditan are needed that can achieve one or more of these objectives, particularly for large-scale synthesis.

Additionally, migraines are one of the most common symptoms in emergency rooms. Current emergency room headache relief with lasmiditan for patients who have difficulty taking the pill due to nausea and/or vomiting may be based on receiving a diluted formulation of approximately 1 mg/mL lasmiditan administered intravenously over an extended period. time, for example, approximately 20-60 minutes. In clinical studies, lasmiditan was administered in doses of approximately 1-60 mg, which were delivered in 60 ml infusions over 20 minutes (see US Patent Application Publication No. 2010/0256187). Safe and effective treatment of migraine with lasmiditan for patients unable to take tablets can be achieved through the availability of a highly concentrated parenteral dosage form. The present description also aims to satisfy this need.

The essence of the invention

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

In one embodiment, referred to as Method I, the present invention provides a method for preparing a compound of formula

including stages

i) treating piperidine-4-carboxylic acid under reductive amination conditions, including formaldehyde and formic acid in water, followed by treatment with an aqueous solution of HCl, followed by distillation of water and addition of acetonitrile, repeating dilution/distillation until the water content is not more than 0.2 % when determined by Karl Fischer analysis to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride;

ii) treating the 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to produce 1-methylpiperidine-4-carboxylic acid chloride;

iii) treating 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by washing with base and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1methylpiperidine-4 hydrate hydrochloride -carboxamide;

iv) treating N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride hydrate with an inorganic base such as aqueous NaOH in a non-polar solvent such as methyl tert-butyl ether, followed by washing with water, separating the phases and distilling off the organic solvent to water content not more than 0.1 wt.% when measured by Karl Fischer analysis to obtain N,N-diethyl-1-methylpiperidine-4-carboxamide;

v) subsequent treatment of N,N-diethyl-1-methylpiperidine-4-carboxamide (6-bromo-2-pyridyl) with lithium in a non-polar 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 repeat distillation of the organic solvent to a water content of not more than 0.2 wt.% as determined by Karl Fischer analysis to obtain (6-bromo-2-pyridyl)-(1-methyl-4-

- 2 045247 piperidyl)methanone;

vi) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with an aqueous solution of HBr and subsequent extraction with n-butanol, followed by repeated distillation of the organic solvent to a water content of not more than 0.3% as measured by analysis Karl Fischer to produce solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide;

vii) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide with a solution of NH3 in ethylene glycol in the presence of a Cu ₂ O catalyst at about 80° C. for about 2 hours, followed by washing with water, a saturated aqueous solution NaCl and 20% aqueous NaOH followed by extraction with a non-polar aprotic solvent such as methyl tert-butyl ether, phase separation and treatment of the organic phase with 5 wt% carbon;

viii) filtering the mixture obtained above, diluting with a suitable polar alcohol solvent such as isopropanol, and repeating the distillation of the organic solvent to a water content of not more than 0.2% water as determined by Karl Fischer analysis, followed by treating the resulting residue with isopropanol, water and 20 wt.% HCl , and the concentration of water in the resulting suspension is at least 2%, filtering the resulting suspension and drying under vacuum at 40°C for 16-24 hours to obtain solid dihydrochloride dihydrate (6-amino-2-pyridyl)-(1-methyl4 -piperidyl)methanone;

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

x) subsequent treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100° C. for about 4 hours, followed by cooling, loading acetonitrile and heating the resulting suspension to 80°C for about 1 hour and then collecting the resulting solid by filtration to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2 hydrochloride -pyridyl]benzamide;

xi) treating 2,4,6-Ίriforo-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide hydrochloride with a saturated aqueous solution of Na ₂ CO ₃ in methyl tert-butyl ether;

xii) treating the mixture obtained above in step xi), SiO ₂ followed by filtration, carbon treatment, filtration and evaporation, dilution with ethanol and distillation to a water content of not more than 1% as determined by Karl Fischer analysis to obtain 2,4,6-trifluoro -N-[6-(1-methylpiperidine4-carbonyl)-2-pyridyl]benzamide;

xiii) treating 2,4,6-trifluoro-N-[6-(1-methylniperidin-4-carbonyl)-2-pyridyl]benzamide in ethanol with a solution of 0.5 equivalents of succinic acid in ethanol at about 55° C. for less than 3 hours at room temperature and then collecting the solid by filtration to obtain solid 2,4,6-trifluoro-N-[6-(1-methylniperidin-4-carbonyl)-2-pyridyl]benzamide hemisuccinate.

In the method presented above as Method I, the reactions are preferably carried out using a batch processing technique. In one embodiment, batches produced by Method I are produced in process volume. In one embodiment, batches produced by Method I are produced in quantities of at least 1 kg. In one embodiment, batches produced by Method I are produced in quantities of at least 10 kg. In one embodiment, batches produced by Method I are produced in quantities of at least 100 kg.

In the process presented above as Method I, the use of chlorobenzene provides the ability to prevent decomposition that occurs in alternative processes, for example, using THF, which reacts with the acid chloride when produced on a large scale (for example, 100 kg), resulting in essentially no release of acid chloride.

In another embodiment, referred to as Method II, the present invention provides a method for preparing a compound of formula comprising the steps

i) treating piperidine-4-carboxylic acid under reductive amination conditions, including formaldehyde and formic acid in water, followed by treatment with an aqueous solution of HCl, followed by distillation of water and addition of acetonitrile, repeating dilution/distillation until the water content is not more than 0.2 % when determined by Karl Fischer analysis to obtain solid hydro-

- 3 045247 1-methylpiperidine-4-carboxylic acid chloride;

ii) treating the 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to produce 1-methylpiperidine-4-carboxylic acid chloride;

iii) treating 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by washing with base and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1methylpiperidine-4 hydrate hydrochloride -carboxamide;

iv) treating N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride hydrate with an inorganic base such as aqueous NaOH in a non-polar solvent such as methyl tert-butyl ether, followed by washing with water, separating the phases and distilling off the organic solvent to water content not more than 0.1 wt.% when measured by Karl Fischer analysis to obtain N,N-diethyl-1-methylpiperidine-4-carboxamide;

v) subsequent treatment of N,N-diethyl-1-methylpiperidine-4-carboxamide (6-bromo-2-pyridyl) with lithium in a non-polar organic solvent such as methyl tert-butyl ether, followed by extraction of the resulting mixture with water and a suitable organic a solvent such as n-butanol, separating the phases and repeating distillation of the organic solvent to a water content of not more than 0.2 wt.% as determined by Karl Fischer analysis to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl) methanone;

vi) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with an aqueous solution of HBr and subsequent extraction with n-butanol, followed by repeated distillation of the organic solvent to a water content of not more than 0.3% as measured by analysis Karl Fischer to produce solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide;

vii) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide in a two-phase mixture of water and toluene with solid KOH for about 3 hours, followed by separating the aqueous layer and evaporating the solvent to obtain (6-bromo- 2-pyridyl-1-methyl-4-piperidyl)methanone;

viii) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing K ₂ CO ₃ , 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 is no more than 0.1% as determined by HPLC, followed by dilution of the reaction mixture with water and EtOAc, followed by treatment silica gel modified with thiourea at 60°C for about 8 hours, followed by filtration to obtain a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide;

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

In the method presented above as method II, the reactions are preferably carried out using a batch processing technique. In one embodiment, batches produced by Method II are produced in process volume. In one embodiment, batches produced by Method II are produced in quantities of at least 1 kg. In one embodiment, batches produced by Method II are produced in quantities of at least 10 kg. In one embodiment, batches produced by Method II are produced in quantities of at least 100 kg.

In the process presented above as Method II, the use of chlorobenzene provides the ability to prevent decomposition that occurs in alternative processes, for example, using THF, which reacts with the acid chloride when produced on a large scale (for example, 100 kg), resulting in essentially no release of acid chloride.

In another embodiment of the present connection, a connection is provided

HCI

H ₂ O whose name can be written as (6-amino-2-pyridyl)-(1methyl-4-piperidyl)methanone dihydrochloride. Preferably, said compound is crystalline. (6-Amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride is particularly suitable for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl) hemisuccinate -2-pyridyl]benzamide, and processes that use (6-amino-2-pyridyl)-(1-methyl-4piperidyl)methanone dihydrochloride may provide advantageous process characteristics, including, but not limited to, the purity of intermediates and /or final materials. Dihydrochloride dihydrate

- 4 045247 (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone is purported to be a new stable hydrated form of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone. The process for isolating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride described herein provides improved impurity rejection and an improved controlled crystallization process. Form and chemical stability studies have shown that (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride is generally stable, and drying studies have shown that overdrying to remove water of hydration is difficult even in forced conditions. The use of said intermediate advantageously provides a product of high purity in the expected yield.

Another embodiment of the present disclosure provides lasmiditan acetate, which may be represented by the formula

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

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

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

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

Another embodiment of the present disclosure provides lasmiditan acetate and pharmaceutical compositions containing a high concentration of lasmiditan acetate, for example, about 10-200 mg/ml free base equivalents, in an aqueous vehicle. In various embodiments, the pharmaceutical composition contains about 10-200 mg/mL equivalents of lasmiditan free base in a buffered aqueous solution. In various embodiments, the buffer aqueous solution has a pH in the range of pH 6.0-7.5 at 37°C. In various embodiments, the buffer aqueous solution contains acetic acid.

In addition to the aqueous carrier, preferably sterile, deionized, distilled water, the pharmaceutical compositions described herein may further contain one or more pharmaceutically acceptable excipients or co-solvents. Term

- 5 045247 pharmaceutically acceptable refers to excipients and co-solvents that are suitable for use in contact with human tissue without causing excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio. Pharmaceutical compositions and methods for their preparation are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., ed., 21st ed., Mack Publishing Co., 2005 )).

The pharmaceutical composition of lasmiditan acetate may be presented in bulk or in unit dosage form. It is particularly advantageous to formulate pharmaceutical compositions of lasmiditan acetate in unit dosage form for ease of administration and uniformity of dosage. The term unit dosage form as used herein refers to physically discrete units suitable as single doses for the subject to be treated; each unit contains a specified amount of the active compound lasmiditan, calculated to provide the desired therapeutic effect, in combination with the required pharmaceutical carrier. The unit dosage form may be, for example, an ampoule, a vial or a syringe.

Various embodiments of this disclosure provide a pharmaceutical composition containing an amount of lasmiditan acetate described herein, the amount being from 10 to 200 mg per dose. In various embodiments, the present disclosure provides a pharmaceutical composition containing an amount of lasmiditan acetate described herein, the amount being 10, 20, 30, 40, 50, 100, or 200 mg per dose. The above doses are for an adult of average weight. For smaller individuals, such as the elderly or children, lower doses may be acceptable. Thus, in various embodiments, the pharmaceutical composition may contain a lower dose, such as 5, 10 or 15 mg.

As described herein, highly concentrated aqueous solutions of lasmiditan acetate provide the ability to administer a single therapeutically effective dose by injection of a highly concentrated aqueous solution of lasmiditan, for example, by an intravenous, subcutaneous or intramuscular route.

Various embodiments of the present disclosure provide highly concentrated aqueous solutions of lasmiditan acetate. In various embodiments, the highly concentrated aqueous solution of lasmiditan acetate is formulated as a parenteral dosage form. In various embodiments, the highly concentrated aqueous solution contains 10-200 mg/mL equivalents of lasmiditan free base. In various embodiments, the highly concentrated aqueous solution of lasmiditan acetate is provided in a parenteral dosage form. In various embodiments, the parenteral dosage form is a buffered aqueous solution at a concentration of 10-200 mg/mL lasmiditan free base equivalents. In various embodiments, the parenteral dosage form is a buffered aqueous solution at a concentration of 10, 20, 30, 40, 50, 100, or 200 mg/mL lasmiditan free base equivalents. In various embodiments, the parenteral dosage form is suitable for subcutaneous or intramuscular injection. Preferably, the parenteral dosage form is for subcutaneous injection. In various embodiments, the pH of the buffer solution is in the range of pH 6.0-7.5 at 37°C.

In various embodiments, the buffer aqueous solution comprises an organic acid-based buffer system. In various embodiments, the organic acid is a di- or tricarboxylic acid. In various embodiments, the di- or tricarboxylic acid is selected from the group consisting of acetic acid and citric acid. In various embodiments, the organic acid is succinic acid. In various embodiments, the buffer is an acetic acid buffer. In various embodiments, the buffer aqueous solution does not contain organic solvents. In various embodiments, the buffer aqueous solution is free of organic solvents and surfactants. In a preferred embodiment, the buffer aqueous solution contains lasmiditan acetate, acetic acid and sodium hydroxide and is adjusted to a pH of 6.0-7.5 at 37°C.

In various embodiments, the parenteral dosage form of lasmiditan acetate is in the form of a pre-filled syringe suitable for subcutaneous administration. In various embodiments, the prefilled syringe contains 10-50 mg/mL equivalents of lasmiditan free base. In various embodiments, the prefilled syringe contains 10, 20, 30, 40, 50, or 100 mg/mL equivalents of lasmiditan free base. In various embodiments, lasmiditan is presented in a buffered aqueous solution having a pH of 6.0-7.5 at 37°C. In various embodiments, the prefilled syringe is suitable for home use, for example, for migraine sufferers who may experience extreme and rapid onset of headache pain. In various embodiments, the prefilled syringe is contained in a package with instructions for parenteral administration, preferably by subcutaneous injection. In various embodiments, the prefilled syringe is provided in the form of an auto-injector with instructions for administering the injections subcutaneously.

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

Also provided herein are methods of acute treatment of migraine headaches comprising administration of a therapeutically effective dose of lasmiditan acetate as described herein. In various embodiments, the parenteral solution is administered by subcutaneous injection. In various embodiments, the parenteral solution contains 10-50 mg/ml equivalents of lasmiditan acetate free base in a buffered aqueous solution with a pH of 6.0-7.5 at 37°C. In various embodiments, the parenteral solution contains 10, 20, 30, 40, 50, or 100 mg/mL equivalents of lasmiditan free base. In various embodiments, the proposed methods comprise administering a single therapeutically effective dose of lasmiditan acetate in a volume of less than or exactly 1 mL, such as about 0.5 to 1 mL, for example, through a single subcutaneous injection. In various embodiments, the injection volume is approximately 1 ml. In various embodiments, the injection volume is approximately 0.5 ml.

The present invention provides a method of treating migraine in a patient in need thereof, 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 of treating migraine in a patient in need thereof, 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 of treating migraine in a patient in need thereof, 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 of treating migraine in a patient in need thereof, 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 of 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, 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, comprising administering to the patient 200 mg of lasmiditan acetate per subcutaneous dose and a pharmaceutically acceptable diluent or carrier.

In some embodiments, the patient is a person who has been diagnosed as having a condition or disorder that is to be prevented by a pharmaceutical composition described herein. In some embodiments, the patient is a person identified as having a risk of developing a condition or disorder for which administration of a pharmaceutical composition described herein is prescribed. In those cases in which disorders that can be treated by the methods according to the present invention are known by established and recognized classifications, such as migraine, episodic headache, chronic headache, chronic cluster headaches and/or episodic cluster headaches, their classifications can be found in various sources. For example, the current fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IVTM) (1994, American Psychiatric Association, Washington, DC) provides a diagnostic tool for many of the disorders described herein. In addition, many of the disorders described in this document are classified in the International Classification of Diseases, Tenth Revision (ICD-10). Those skilled in the art will appreciate that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-IV and ICD-10, and that terminology and classification systems evolve with medical science. progress. Patients with migraine may additionally be diagnosed with migraine with or without aura (1.1 and 1.2), according to the International Headache Study (IHS) International Classification of Headache Disorders, 3rd edition (ICHD-3), beta -version (The International Classification of Headache Disorders, 3rd edition (beta version), Cephalalgia, 2013, 33:629-808). In some embodiments, the human patient is diagnosed with episodic migraine prior to taking lasmiditan chronically, preferably at night, to prevent migraine. In some embodiments, the human patient is diagnosed with chronic migraine prior to administration of the antibody. In some embodiments, the human patient experiences various auras with migraine headaches. In some embodiments, the human patient does not experience an aura during migraine headaches.

In this context, migraine includes, but is not limited to: migraine attacks. In this context, a migraine attack refers to the following description. Symptoms may overlap within different phases of a migraine attack, and not all patients experience the same clinical manifestations. In the prodromal phase, most patients have warning symptoms that may precede the headache phase by up to 72 hours. These include changes in mood and activity, irritability, fatigue, hunger, occasional yawning, neck stiffness, and phonophobia. These symptoms may persist in the aura phase, headache phase and even in the postdromal phase. Some patients experience an aura phase, with approximately a third of patients experiencing temporary neurological deficits during attacks. ICHD-3 defines an aura as 1 or more transient, fully reversible neurological deficits, of which at least 1 must be unilateral, occurring over 5 minutes or more, and each of these deficits lasting 5 to 60 minutes. In this case, visual aura, which can include positive (spectrum of visual hallucinations), negative (scotoma) or positive and negative manifestations, occurs in more than 90% of cases, and the most common symptoms of sensory, motor, speech impairment, aura symptoms from the brain stem and retina. A transient wave of neuronal depolarization of the cerebral cortex is hypothesized to be the pathophysiological brain mechanism underlying the clinical phenomenon of migraine aura. During the headache phase, headache attacks, which can last from 4 to 72 hours, are accompanied by nausea, photophobia and phonophobia, or both. The headache is characterized as unilateral, throbbing, of moderate to severe intensity, and worsens with physical activity; two of these characteristics are sufficient to meet the diagnostic criteria. In the postdromal phase, the characteristic symptoms reflect those observed in the prodromal phase. Typical postdromal symptoms include fatigue, difficulty concentrating, and a stiff neck. It remains unclear whether these symptoms arise in the prodromal phase and progress through the headache phase to the postdromal phase, since they can also occur in the cephalic phase or even after the end of the headache phase.

Migraine headache in this context refers to headache with or without aura lasting >30 minutes with both the required features (A and B) listed below.

A) At least 2 of the following headache characteristics:

1) one-sided localization,

2) pulsating character,

3) moderate to severe pain intensity, and

4) aggravation during normal physical activity or reason for refusal to do so; And

B) during a headache, one or more of the following:

a) nausea and/or vomiting; and/or

b) photophobia and phonophobia.

Possible migraine headache in this context refers to headache lasting more than 30 minutes, with or without aura, but without one of the features of migraine specified in the International Headache Association ICHD-3 definition.

The term "effective amount" or "therapeutically effective amount" means an amount or dose of lasmiditan acetate in a pharmaceutical composition, e.g., the total amount administered, which, when administered in a single or multiple doses to a patient, provides the desired pharmacological effect in the patient, e.g., an amount capable of activating 5-β receptors. HT _1f . In a preferred embodiment, an effective amount means that amount of lasmiditan acetate that, when administered acutely, provides relief from a migraine attack in a patient after administration. Dose refers to a predetermined amount of lasmiditan acetate calculated to provide the desired therapeutic effect in a patient. In this context, mg refers to milligram. In this context, doses described in mg refer to the weight of the active pharmaceutical ingredient lasmiditan in free base equivalents, for example, a 100 mg dose refers to 100 mg of the active pharmaceutical ingredient lasmiditan in free base equivalents. In the context of the present description, this dose can be interpreted as describing doses around the specified amount, in the sense that doses that are higher or lower than the specified dose by a value within 10% are also provided to provide suitable therapeutic regimens, in the same way, as indicated dose.

Brief description of graphic materials

The drawing shows a graphical representation of the 1H NMR spectrum (400 MHz, DMSO-d ₆ ) of lasmiditan acetate containing maleic acid (internal standard).

- 8 045247

Detailed Description of the Invention

The reactions described herein can be carried out using standard techniques known to those skilled in the art using ordinary glassware, or can be carried out on a pilot and/or industrial scale in equipment designed for such transformations. In addition, each of the described reactions can be carried out by a batch method or, if appropriate, by a flow reaction method. The term batch process in this context refers to a process in which raw materials are combined in a reactor or vessel and the product is discharged when the reaction is complete.

In addition, some of the intermediates described in the following preparation methods may contain one or more nitrogen protecting groups. The variable protecting group may be the same or different in each case, depending on the specific reaction conditions and the specific transformations being carried out. Conditions for introducing and removing protecting groups are known to those skilled in the art and 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).

The abbreviations listed below have the following meanings in this context.

A stands for angstrom or angstroms.

ACN stands for acetonitrile.

AcOH means acetic acid.

Bn means benzyl.

nBuLi stands for n-butyllithium.

CAS No. means the number according to the abstract journal Chemical Abstracts.

DCM stands for dichloromethane.

DMF stands for N,N-dimethylformamide.

DIPEA stands for diisopropylethylamine.

DMSO means dimethyl sulfoxide (perdeuterated [d ₆ ] when used for NMR).

EtOAc means ethyl acetate.

EtOH means ethanol or ethyl alcohol.

HBTU means 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.

HPLC stands for High Performance Liquid Chromatography.

HTRF stands for Homogeneous Time Resolved Fluorescence.

H means hour or hours.

IPA stands for isopropyl alcohol.

IPC stands for In-Process Control.

LAH stands for lithium aluminum hydride.

LC-MS stands for liquid chromatography-mass spectrometry.

LDA stands for lithium diisopropylamide.

Me as a substituent in the structural picture of the compound represents a methyl group.

MeOH means methanol or methyl alcohol.

Min means min.

MS stands for mass spectrometry or mass spectrum.

MTBE stands for methyl tert-butyl ether.

NMR stands for Nuclear Magnetic Resonance.

NB means nothing more.

OAc means acetate.

Pound/sq. inch g. means pounds per square inch of gauge pressure.

RuBOP stands for (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate).

Rt means room temperature/ambient temperature.

C stands for second or seconds as a unit of time.

TBS-C1 means tert-butyldimethylsilyl chloride.

TEA stands for triethylamine.

THF stands for tetrahydrofuran.

tR means retention time.

Mac./mas. means the ratio of mass to mass.

The following are improved methods for producing lasmiditan, indicated as Method I and/or II, as well as other additional methods proposed below.

Pharmaceutically acceptable salts or pharmaceutically acceptable salt refers to the relatively non-toxic inorganic and organic salt or salts of the compounds of the present invention. Those skilled in the art will appreciate that the compounds of the present invention may form salts. Certain compounds of the present invention contain basic heterocycles and accordingly react with any of a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and general procedures for their preparation are known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL

SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008); S.M. Berge et al., Pharmaceutical

Salts, Journal of Pharmaceutical Sciences, vol. 66, no. 1, January 1977.

Process volume synthesis refers to the preparation of 500 to 1000 kg or more of 2,4,6-trifluoro-K-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. Preferably, the on-scale synthesis is carried out in accordance with good manufacturing practices (GMP) or similar conditions required for the industrial production of pharmaceutical products for human consumption. Preferably, the processing volume in the methods described above as method I and/or II refers to batches obtained in quantities of at least 1 kg and/or to batches obtained in quantities of at least 10 kg and/or to batches obtained in an amount of at least 100 kg.

General chemical transformations.

ABOUT HE

Stage A

F

O ^J 0.5

Scheme 1

Scheme 1 depicts the on-chip synthesis of compound I, lasmiditan hemisuccinate. N-Methylation of commercially available piperidine-4-carboxylic acid 1 can be accomplished under various reducing conditions known to those skilled in the art, particularly by treating a secondary amine with about 1.3 equivalents of formaldehyde in excess formic acid to give N -methylpiperidine 2. Formation of diethylamide 3 can be accomplished using standard amide coupling reagents such as benzotriazole, HBTU or PyBOP, or by converting a 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 the acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50°C for 1 hour, after which the reaction mixture can be cooled to about 0°C and add 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine. The free base is stirred with HCl to produce diethylamide hydrate hydrochloride 3. Those skilled in the art will appreciate that pyridyl ketone 4 can be prepared by treating diethylamide 3 with literated bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium can be prepared by treating 2,6-dibromopyridine using n-BuLi at about -58°C. Separately, piperidine-4-diethylamide hydrochloride hydrate 3 can be treated with about 2 equivalents of NaOH and the resulting free base added to the literate compound at about -58°C. The resulting mixture can be treated with HBr to produce pyridyl bromide hydrobromide 4. Amination of pyridyl bromide hydrobromide 4 can be accomplished using transition metal catalysis known to those skilled in the art. More specifically, about 0.075 equivalents of Cu ₂ O, about 28 equivalents of NH3 in ethylene glycol can be added to pyridyl bromide 4 and stirred at about 80°C. The reaction mixture can be cooled to room temperature, quenched with H2O, washed with 20% aqueous NaOH, suspended with 20% HCl in IPA and a small amount of _H2O to give aminopyridine dihydrate dihydrochloride 5 as a crystalline solid

- 10 045247 substances. Pyridylbenzamide hydrochloride 6 can be prepared by treating aminopyridine free base 5 with acid chloride 5a. More specifically, aminopyridine dihydrate dihydrochloride 5 can be treated with 6% aqueous NaOH to give the free base. Separately, 2,4,6-trifluorobenzoic acid can be treated with thionyl chloride at about 100°C and the above free base 5 to give pyridylbenzamide hydrochloride 6. Hemisuccinate I can be prepared by treating hydrochloride 6 with about 2 equivalents of NaHCO3, then using about 0.55 equivalent of succinic acid to obtain lasmiditan hemisuccinate, compound I.

synthesis shown

Scheme 2 hydrochloride

In the scheme of (6-amino-2-pyridyl)-(1-methyl-4 piperidyl)methanone dihydrate 5. Amination of pyridyl bromide hydrobromide 4 can be carried out as shown in scheme 1, using transition metal catalysis, known to those skilled in the art field of technology. More specifically, about 0.075 equivalents of Cu ₂ O, about 28 equivalents of NH3 in ethylene glycol can be added to pyridyl bromide 4 and stirred at about 80°C. The reaction mixture can be cooled to room temperature, quenched with H2O, washed with 20% aqueous NaOH, suspended with 20% HCl in IPA and a small amount of H2O to give aminopyridine dihydrate hydrochloride 5.

Scheme 3

Scheme 3 shows a modified bulk synthesis of lasmiditan hemisuccinate I. N-Methylation of commercially available piperidine-4-carboxylic acid 1 can be carried out under various reducing conditions known to those skilled in the art, particularly by treatment of a secondary amine using about 1.3 equivalents of formaldehyde in excess formic acid to give N-methylpiperidine 2. Formation of diethylamide 3 can be accomplished using standard amide coupling reagents such as benzotriazole, HBTU or PyBOP, or by converting a 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 the acid chloride by treatment with about 1.2 equivalents of thionyl chloride at about 50°C for 1 hour, after which the reaction mixture can be cooled to about 0°C and add 1.5 equivalents of diethylamine and 3 equivalents of trimethylamine. The free base is stirred with HCl to produce diethylamide hydrate hydrochloride 3. Those skilled in the art will appreciate that pyridyl ketone 4 can be prepared by treating diethylamide 3 with

- 11 045247 bromopyridine 3a. More specifically, (6-bromo-2-pyridyl)lithium can be prepared by treating 2,6-dibromopyridine using n-BuLi at about -58°C. Separately, piperidine-4-diethylamide hydrochloride hydrate 3 can be treated with about 2 equivalents of NaOH and the resulting free base added to the lithiated compound at about -58°C. The resulting mixture can be treated with HBr to produce pyridyl bromide hydrobromide 4. Amination of pyridyl bromide hydrobromide 4 to produce amide 6 can be accomplished using transition metal catalysis known to those skilled in the art. In particular, pyridyl ketone 4 can be converted to its corresponding free base form using a suitable inorganic base and under Buchwald-type condensation reaction conditions described in the literature. More specifically, the free base of compound 4 can be stirred in a suitable aprotic solvent such as toluene or xylene containing a mixture of about 1-5 wt.% water, about 1.1 equivalents of commercially available 2,4,6-trifluorobenzamide (CAS No. 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 compound. a ligand such as Xantphos, 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. for about 8-24 hours at a temperature of about room temperature to about 65°C. The resulting mixture can be cooled, filtered, treated with activated carbon, filtered and concentrated under reduced pressure. The resulting residue can be dissolved in an appropriate alcohol solvent such as ethanol and treated slowly with a solution of about 0.5 equivalents of succinic acid dissolved in ethanol at about 55°C. The resulting mixture can be cooled to room temperature over about 10 hours, and the resulting suspension can be crushed through a series of thermal cycles of heating to 60° C. and cooling 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 I hemisuccinate.

Experimental methods.

The following preparatory syntheses of process intermediates further illustrate the present invention and represent typical methods for the synthesis of various compounds. The reagents and starting materials are readily available or can be easily synthesized by those skilled in the art. It should be understood that the following preparatory syntheses and examples are presented for purposes of illustration and that various modifications may be made by those skilled in the art.

LC-ES/MS was performed on an AGILENT® HP 1100 liquid chromatography system. Electrospray mass spectrometry measurements (recorded in positive and/or negative mode) were performed on a quadrupole mass spectrometer with mass selective detector connected to an PH 1100 HPLC system .

Conditions for LC-MS (low pH).

Column: PHENOMENEX® GEMINI® NX C18 2.1x50 mm, 3.0 µm;

gradient: 5-100% B for 3 min, then 100% B for 0.75 min;

column temperature: 50±10°C;

flow rate: 1.2 ml/min;

solvent A: deionized water with 0.1% HCOOH, solvent B: ACN with 0.1% formic acid;

wavelength 214 nm.

Alternative conditions for LC-MS (high pH).

Column: XTERRA® MS, C18 columns 2.1x50 mm, 3.5 µm;

gradient: 5% solvent A over 0.25 min, gradient from 5 to 100% solvent B over 3 min and 100% solvent B over 0.5 min, or from 10 to 100% solvent B over 3 min and at 100% solvent B for 0.75 min;

column temperature: 50±10°C;

flow rate: 1.2 ml/min;

solvent A: 10 mM NH ₄ HCO ₃ pH 9;

solvent B: ACN; wavelength: 214 nm.

NMR spectra were recorded on a Bruker AVIII HD NMR spectrometer at 400 or 500 MHz, samples were prepared as solutions in CDCl ₃ or (CD ₃ ) ₂ SO, the results were recorded in ppm using residual solvent [CDCl ₃ , 7.26 m .d.; (CD ₃ ) ₂ SO, 2.05 ppm] as the reference standard. When recording multiplicity of peaks, the following abbreviations can be used: s (singlet), d (doublet), t (triplet), k (quartet), m (multiplet), shs (wide singlet), dd (doublet of doublets), dt (doublet triplets).

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When specified, coupling constants (J) are written in hertz (Hz).

Chloride analysis was performed on an ESA CORONA® Plus instrument equipped with a CORONA® CAD® charged aerosol detector and an HPLC system, Acclaim Trinity P1 (100x3.0 mm, 3 µm), mobile phase: 50 mM ammonium acetate, pH ~5 in ACN.

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 various steps of the described schemes are known in the art, and appropriate substitutions of solvents and co-reagents are also known in the art. Likewise, those skilled in the art will appreciate that synthetic intermediates can be isolated and/or purified by various known techniques as needed or desired, and that the various intermediates can often be used in subsequent synthetic steps directly, with little or no purification. . In addition, those skilled in the art will understand that in some cases the order in which the fragments are introduced is not critical.

Preparatory synthesis 1. 1-Methylpiperidine-4-carboxylic acid hydrochloride.

Scheme 1, Step A. A jacketed reactor was charged with piperidine-4-carboxylic acid (10.0 g, 77.5 mmol) and deionized water (40 ml). The mixture was heated to boiling under reflux (95-100°C). Formic acid (13.9 g, 302 mmol) was added over 30 min. A 37% aqueous solution of formaldehyde (8.1 g, 101 mmol) was added dropwise to the mixture over at least 30 minutes. Water (0.3 ml) was used to flush the line and flush into the reactor. Stir the mixture for 4 hours at reflux (95-100°C) and take a sample using HPLC for IPC analysis (not more than 0.5% piperidine-4-carboxylic acid). If the amount of piperidine-4carboxylic acid was more than 0.5%, then the mixture was stirred for another 2 hours. Upon reaching the specification criterion, the solution was concentrated under vacuum to a residual volume of ~20 ml and the residue was cooled to 45-50°C. A 33% aqueous HCl solution (12.8 g, 116 mmol) was added to the cooled solution over a period of at least 30 minutes. Water (0.3 ml) was used to flush the line and flush into the reactor. The water was distilled off under vacuum to a residual volume of ~20 ml. ACN (42.4 ml) was added to the concentrated solution 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 concentrated solution at 45-50°C and the mixture was concentrated at atmospheric pressure to a residual volume of ~40 ml. The dilution/concentration operations were repeated until a value of no more than 0.2% was achieved during in-process monitoring of water content when determined by Karl Fischer analysis; During these operations, a suspension was formed. ACN (10.2 ml) was added to the resulting suspension at 45-50°C. Cool the suspension to 20° C. over 1 hour and stir for a further 2 hours. The resulting solid is isolated by filtration and the filter cake is washed with ACN (10.2 ml). The wet filter cake was dried at 40°C under nitrogen at atmospheric pressure to obtain the title compound (12.1 g, 87% yield).

MS (m/z): 144 (M+H).

Preparatory synthesis 2. N,N-diethyl-1-methylpiperidine-4-carboxamide hydrate hydrochloride.

Scheme 1, Step B. A jacketed reactor was charged with 1-methylpiperidine-4carboxylic acid hydrochloride (30.0 g, 167 mmol), chlorobenzene (240 ml) and DMF (0.61 g, 8.35 mmol) and heated the resulting mixture to 50°C. Thionyl chloride (24.2 g, 200.4 mmol) was added to the hot suspension over 1 hour. Chlorobenzene (13.5 ml) was used to flush the line and rinse into the reactor. After the addition of thionyl chloride was completed, the mixture was stirred for 5 hours. The solution was then cooled to 0-10°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 3 hours. Chlorobenzene (13, 5 ml). After the addition of the amine mixture was completed, the mixture was stirred for 2 hours. The reaction mixture was treated with 20 wt% NaOH aqueous solution (180.3 g, 902 mmol) and stirred at room temperature for 2 hours. Water was used to flush the line and rinse into the reactor (3 ml).

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The mixture was left to settle for 2 hours and the aqueous phase was removed. The remaining organic phase was placed under vacuum. The mixture was heated to distill off residual amines, as well as most of the chlorobenzene. After collecting approximately ten volumes of distillate, the reactor was depressurized to atmospheric pressure using nitrogen. The remaining solution was cooled to a temperature of 10 to 30°C. THF (120 mL) and water (4.54 g, 252 mmol) were added to the reactor. The desired product was precipitated from the room temperature reaction mixture by adding 20 wt% aqueous HCl in isopropanol (30.4 g, 167 mmol). THF (5.4 mL) was used to flush the line and rinse into the reactor. After the addition of HCl was completed, the suspension was stirred for 2 hours at room temperature. The resulting solid was collected by filtration and washed with THF (75.0 ml).

The collected solid was dried under vacuum for 16 hours at 40°C to obtain the title compound (35.5 g, 84% yield).

MS (m/z): 199 (M+H).

Preparatory synthesis 3. (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide.

Scheme 1, step C. A suspension of N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride hydrate (21.5 g, 85.1 mmol) in MTBE (109 ml) was treated with a 20 wt.% aqueous solution of NaOH (34, 0 g, 170 mmol). Wash water (1.94 ml) was used to complete the addition. The mixture was stirred at room temperature for 30 minutes, the phases were left 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 water content was <0.10 wt.% determined by Karl Fischer analysis. If the target of the analysis was not achieved, then MTBE (43.7) was added to the reaction mixture. ml) and repeated the distillation. Typically three distillations are required to achieve the target water content analysis value. A mixture of 2,6-dibromopyridine (30.2 g, 128 mmol) and MTBE (105 ml) was charged into a separate reactor and cooled to below -58°C. A 2.5 M solution of n-BuLi in hexanes (51.3 mL, 128 mmol) was added to the cooled suspension over 2 hours. MTBE wash (4.5 mL) was used to complete the transfer. The mixture was left to mature while maintaining the temperature below -58°C for an additional 2 hours after completion of the n-BuLi addition. After ripening, a solution of N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride hydrate in MTBE was added to the cold reaction mixture over 45 min. MTBE wash (13.5 mL) was used to complete the transfer. The mixture was allowed to mature for at least 30 minutes after completion of the addition of N,N-diethyl-1methylpiperidine-4-carboxamide hydrochloride hydrate to MTBE. After ripening, the reaction mixture was heated to 0°C for 1 hour. The cold reaction mixture was added to 2.5 M aqueous HCl solution (146 ml, 366 mmol) at a rate to maintain the quench temperature no more than 30°C. MTBE wash (13.5 mL) was used to complete the transfer. Stir the mixture for at least 30 minutes after completion of the transfer and allow the phases 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 resulting mixture was treated with 20 wt% aqueous NaOH (59.5 g, 298 mmol). Wash water (2.80 ml) was used to complete the transfer. Stir the mixture for at least 30 minutes and allow the phases to settle. The phases were separated and the aqueous phase was retained. The aqueous phase was extracted using n-BuOH (54.8 ml). The combined organic phases were dried by vacuum distillation to obtain a Karl Fischer water content of <0.20 wt.% as in-house control. If the target of the analysis was not achieved, then n-BuOH (41.1 ml) was added and the distillation was repeated. Typically, two distillations are required to achieve the target in-process assay value. The concentrated solution was clarified by filtration and n-BuOH wash (89.6 mL) was used to complete the transfer and wash the filter. The clarified solution was treated with 48 wt% aqueous HBr (9.91 mL, 87.7 mmol) for 90 min. Wash n-butanol (13.8 mL) was used to complete the transfer. Checking the pH showed that the reaction mixture had a pH of ~1. The mixture was dried by distillation at atmospheric pressure until the water content, determined by Karl Fischer analysis, was <0.30 wt.% with in-process control. Concentrate the mixture to 172 ml. If the target of the analysis was not achieved, then n-BuOH (54.8 ml) was added and the distillation was repeated. Cool the mixture to 20°C and stir for 12 hours. The resulting solid was collected by filtration and washed twice with n-BuOH (10.75 ml). The solid was dried under vacuum at 60°C to obtain the title compound (24.8 g, 80% yield).

MS (m/z): 283, 285 ( ⁷⁹ Br, ⁸¹ Br, M+H).

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Preparatory synthesis 4. (6-Amino-2-pyridyl)-(1-methyl-4piperidyl)methanone dihydrochloride.

Scheme 1, Step D. The pressure reactor was charged with (6-bromo-2pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide (30 g, 82.9 mmol) and Cu ₂ O (880 mg, 6 .2 mmol). The free volume of the reactor was purged/filled with nitrogen three times. A solution of NH ₃ in ethylene glycol (total 273.5 g, 39.1 NH ₃ , 2.33 mol; 210 ml ethylene glycol) was added to the solid and the resulting mixture was stirred at room temperature for 2 hours. The mixture was heated to 80 ° C, stirred for 10 hours and cooled to room temperature to select a sample for in-process control, in which the content of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide should be no more than 2%. If the target analysis value was not achieved, the reaction mixture was stirred for another 4 h at 80°C and the sample was taken again. After completion of the reaction, H ₂ O (90 ml) was added 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 H ₂ O) 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 resulting mixture, and the two-phase mixture was stirred at room temperature for 5 minutes. The MTBE mixture (90 ml) was extracted 4-5 times at room temperature. The combined MTBE layers were treated with 5 wt.% carbon for 30 min 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 twice. Distillation with IPA was repeated as necessary until the required in-house water content analysis was achieved. The confirmed water content when determined by Karl Fischer analysis should be no more than 0.2%. A separate reactor was charged with a 20 wt.% solution of HCl in IPA (30 g, 166 mmol) and water (10.5 ml) at room temperature. The concentrated product mixture was added to the HCl solution over 90 minutes. The resulting suspension was stirred at room temperature for at least 8 hours. The suspension was filtered, washed twice with 95:5 IPA/H2O (36 ml) at room temperature and dried under vacuum at 40°C for 16-24 hours to obtain the title compound (18.4 g, 68% yield).

MS (m/z): 220 (M+H).

¹ H NMR (400 MHz, D2O/DMSO-d6) δ ppm 1.74-1.88 (m, 2 N), 2.05 (shd, J=14.9 Hz, 2 N), 2.73 (s, 3H), 3.01 (td, J=13, 1, 2.6 Hz, 2 N), 3.41-3.50 (m, 2H), 3.55 (tt, J=12.0, 3.5 Hz, 1 N), 7.14 (dd , J=9.0, 0.7 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.90 (dd, J=9.0, 7.2 Hz, 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 content analysis: 20.23% (n=2).

X-ray powder diffraction (XPD) of crystalline forms.

RPD profiles of crystalline solids were obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source and a Vantec detector operating at 35 kV and 50 mA. The sample was scanned from 4 to 40 2θ° with a step size of 0.008 2θ° and a scanning speed of 0.5 s/step, and using a divergence slit of 1.0 mm, a fixed anti-scattering slit of 6.6 mm, and a detector slit of 11.3 mm. The dry powder was placed on a quartz sample holder and a glass slide was used to ensure a smooth surface. Diffraction profiles of the crystalline form were recorded at ambient temperature and relative humidity. Crystal peak positions were determined using MDI-Jade after a full profile shift relative to the NIST 675 internal 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 intensities of the diffraction peaks can vary due to preferred orientation caused by factors such as crystal morphology and habit. In the presence of a preferred orientation effect, the peak intensities are variable, but the positions of the polymorph's characteristic peaks do not change. See, for example, USP No. 23, National Formulary No. 18, p. 1843-1844, 1995. In addition, it is well known in the field of crystallography that for any given crystal form the angular positions of the peaks can vary slightly. For example, peak positions may shift due to changes in the temperature at which the sample is analyzed, due to sample drift, or the presence or absence of an internal standard. In this case, the peak position variability of ±0.2 2θ° takes into account these possible deviations without interfering with the accurate determination of the specified crystalline form. Confirmation of the crystalline form can be made based on any unique combination of characteristic peaks.

The sample obtained in preparatory synthesis 4, (6-amino-2-pyridyl)(1-methyl-4-piperidyl)methanone dihydrochloride, is characterized by an ROC profile recorded using CuKa radiation, which has diffraction peaks (2θ values) indicated below in the table. 1, and in particular has peaks at 8.3° in combination with one or more peaks selected from the group consisting of 16.6, 23.5 and 33.7° with a tolerance for diffraction angles of 0.2°.

Table 1

X-ray powder diffraction peaks of a crystalline compound from preparatory synthesis 4; (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride

Peak Angle (°Θ) +/- 0.2° Relative intensity (% of the most intense peak) 1 8.3 100.0% 2 16.6 49.8% 3 19.9 8.1% 4 22.5 15.2% 5 23.5 25.7% 6 25.1 17.1% 7 28.8 11.0% 8 29.7 17.0% 9 30.0 13.9% 10 33.7 23.7%

Preparatory synthesis 5. 2,4,6-Trifluoro-N-[6-(1-methylpiperedin-4-carbonyl)-2pyridyl]benzamide hydrochloride.

Scheme 1, Step E. To a suspension of (6-amino-2-pyridyl)-(1-methyl-4piperidyl)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 with stirring for 30 minutes, the mixture was left to separate for 30 minutes, and the layers were separated at 54°C. The aqueous layer was extracted with chlorobenzene (45 ml) at room temperature. Combine the organic layers and distill under vacuum to ~62 mL to obtain a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. A separate reactor was charged with 2,4,6-trifluorobenzoic acid (5.9 g, 1.1 eq., 33.7 mmol), DMF (62 mg, 0.85 mmol) and chlorobenzene (32 ml) and the mixture was heated to 80°C. Thionyl chloride (4.37 g, 37 mmol) was added to the heated mixture over 4 hours at 80°C. Stir the mixture at 80°C for at least 6 hours and heat to 100°C for at least 6 hours to clear residual HCl gas. The acid chloride solution was cooled to room temperature and transferred to a separate reactor. The acid chloride solution was heated to 100°C and (6-aminopyridin-2-yl)(1-methylpiperidin4-yl)methanone was added over 4 hours. The resulting suspension was stirred for another 3 hours at 100°C and cooled to room temperature. ACN (100 ml) was added to the cooled suspension. The resulting suspension was heated to 80°C for 1 hour and cooled to room temperature over 2 hours. The resulting suspension was further stirred at room temperature for another 1 hour and filtered. The filter cake was washed with ACN (10 ml) at room temperature. The collected solid was dried under vacuum at 100°C for 16 hours to obtain the title compound (10.7 g, 85% yield).

MS m/z: 378 (M+H).

Alternative method of preparatory synthesis 5.

To a suspension of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)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 with stirring for 30 min and left to separate the layers for 30 min. The layers were separated at 54°C. The aqueous layer was extracted with chlorobenzene (45 ml) at room temperature

- 16 045247 at natural temperature. The organic layers were combined and distilled under vacuum to ~62 mL to obtain a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. 2,4,6-trifluorobenzoic acid (5.9 g, 33.7 mmol), DMF (62 mg, 0.85 mmol) and chlorobenzene (32 ml) were charged into a separate reactor and the mixture was heated to 80°C. Thionyl chloride (4.4 g, 37 mmol) was added to the heated mixture over 4 hours at 80°C. Stir the mixture at 80°C for at least 6 hours and heat to 100°C for at least 6 hours to clear residual HCl gas. The acid chloride solution was cooled to room temperature and transferred to a separate reactor. The acid chloride solution was heated to 100°C and (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone was added to the resulting solution over 4 hours. The resulting suspension was stirred for another 3 hours at 100°C and cooled to room temperature. ACN (100 ml) was added to the cooled suspension. The resulting suspension was heated to 80°C for 1 hour and cooled to room temperature over 2 hours. The resulting suspension was further 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 under vacuum at 100°C for 16 hours to obtain the title compound (10.7 g, 85% yield).

MS m/z: 378 (M+H).

Preparatory synthesis 6. 2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2pyridyl]benzamide hemisuccinate.

Scheme 1, step F. The reactor was charged with 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide hydrochloride (20 g, 48.4 mmol) and MTBE (202 ml ). An aqueous solution of NaHCO ₃ (8.13 g, 96.8 mmol NaHCO ₃ in 200 ml water) was added to the stirred suspension at room temperature over 1 hour. The two-phase mixture was separated and the aqueous layer was extracted using MTBE (202 ml). The combined organic layers were distilled under vacuum to a final volume of ~200 mL. SiO ₂ (2 g) was added to the distilled solution, the resulting mixture was stirred for 30 minutes at room temperature, filtered and the filter cake was washed using MTBE (10.8 ml). Carbon (340 mg; alternatively, the solution can be filtered through a carbon cartridge) was added to the filtrate, the resulting mixture was stirred at room temperature for 30 minutes and filtered through a 1-5 μm filter, then washed with MTBE (21.6 ml). The filtrate was distilled under vacuum to ~80 ml. Ethanol (114 ml) was added to the concentrated solution and the resulting solution was distilled under vacuum to ~84 ml. Continue adding EtOH and distilling until the water content was no more than 1% by Karl Fischer analysis to obtain a dry solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide . A separate reactor was charged with succinic acid (3.03 g, 25.7 mmol) and EtOH (60 ml). The mixture was stirred and heated at 33°C until the succinic acid was completely dissolved.

A solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamideα was heated to 55°C. A portion of a solution of succinic acid in EtOH (approximately 1.0 L/kg) was added to the heated solution. Then the resulting solution was seeded with 1 wt.% 2,4,6-trifluoro-K-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide hemisuccinate (200 mg). The resulting suspension was stirred for 30 minutes and the remaining solution of succinic acid in EtOH was added at a constant rate over 2 hours. The reactor contents were stirred for 30 minutes and cooled to room temperature, linearly, over 2.5 hours. The resulting suspension was stirred at room temperature temperature for at least 3 hours. Filter the suspension and wash the collected solid using EtOH (60 ml). The solid was dried under vacuum at 45°C for 16 hours to obtain the title compound (20.4 g, 85% yield).

MS m/z: 378 (M+H).

¹ H NMR (500 MHz, DMSO-Y6) δ ppm 1.59 (d, J=12.1 Hz, 2H), 1.84 (d, J=12.8 Hz, 2H), 2.08 (t, J=11.4 Hz, 1H), 2, 38 (s, 2H), 2.24 (s, 3H), 2.89 (d, J=13.1 Hz, 2H), 3.70 (s, 1H), 7.40 (dd, J=9 ,4, 7.8 Hz, 2H), 7.75 (d, J=7.6 Hz, 1H), 8.08 (t, J=7.9 Hz, 1H), 8.39 (d, J =8.2 Hz, 1H), 11.47 (s, 1H).

Alternative method of preparatory synthesis 6.

Scheme 3, steps D, E and F. A jacketed reactor was charged with (6-bromo-2-pyridyl)-(1methyl-4-piperidyl)methanone (50 g, 137 mmol) and toluene (400 ml). Water (250 ml) was added followed by KOH granules (13.6 g, 206 mmol) and the mixture was stirred for 3 hours at room temperature. The reactor contents were filtered and returned to the reactor. The aqueous layer was drained and, if necessary, the organic layer was treated with activated carbon to remove color. The mixture was concentrated at 50°C and

- 17 045247 reduced pressure to ~150 ml. Toluene (225 ml) was added to the reactor under nitrogen atmosphere and K ₂ CO ₃ (28.5 g, 206 mmol), 2,4,6-trifluorobenzamide (26.5 g, 151 mmol) and water (2.5 ml) were added ) and stirred the contents at room temperature. Toluene (20 ml), Pd(OAc)2 (154 mg, 0.68 mmol) and Xantphos (795 mg, 1.37 mmol) were charged into a separate flask under nitrogen atmosphere and the contents were stirred at room temperature for 30 min. The resulting solution was transferred to the reactor and the reactor was heated to 70°C with stirring. After 5 hours, a sample of the mixture was taken for IPC analysis by HPLC, in which the content of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone should be at least 0.1%. If the required amount of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone was not reached, the mixture was stirred for another 5 hours and the sample was taken again. If the target IPC value was achieved, the mixture was stirred for another 12 hours at 70°C. 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. Stop stirring and allow the layers to separate. The aqueous layer was removed and discarded. Water (250 ml) was added and the resulting mixture was stirred for 1 hour. Stirring was stopped and the layers were allowed to separate. 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 washed with EtOAc (150 mL) and the wash solution was returned to the reactor. If necessary, activated carbon treatment can be applied to remove color. The solution was passed through a fine filter to obtain a solution of 2,4,6-trifluoro-b-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide.

A solution of 2,4,6-trifluoro-K-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide was concentrated at 50°C under reduced pressure to ~150 ml. EtOH (250 ml, denatured with toluene) was added and the contents were concentrated at 50°C under reduced pressure to ~150 ml. The procedure described was repeated a total of 3 times until sufficient removal of toluene was achieved before the final addition of toluene to a total volume of 250 ml. The resulting toluene mixture was heated to 55°C. Succinic acid (8.6 g, 73 mmol) and EtOH (200 ml, denatured with toluene) were loaded into a separate container. The contents of the 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-K-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide solution and the resulting solution was stirred at 55°C. 2,4,6-Trifluoro-K-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide hemisuccinate was added as seeds in the form of a solid or suspension in toluene-denatured EtOH. The remainder of the solution of succinic acid in EtOH, denatured with toluene, was transferred to the reactor over 1.5 hours. The contents of the reactor were cooled to room temperature over 10 hours. The resulting suspension can be subjected to grinding of the suspension to control the particle size. In the case of slurry grinding, the reactor contents can be subjected to a series of thermal cycles by heating to 60°C and cooling to room temperature over 4 hours while stirring to further control the particle size distribution. Filter the suspension and wash with EtOH (100 ml, denatured with toluene) and dry at 40°C under reduced pressure for 12 hours to obtain the title compound (43.9 g, 73% yield).

MS m/z: 378 (M+H).

The dried solid can then be jet milled to further control particle size.

Description of methods for producing a medicinal product.

In one embodiment, lasmiditan produced by the methods presented herein can be further prepared in specific drug product forms suitable for use. In one embodiment, such drug product forms are available in the form of embossed oval aqueous film-coated instant release tablets of 50 and 100 mg. The 50 mg tablet is a light gray oval tablet embossed with 4312 on one side and L-50 on the other. The 100 mg tablet is a light pink oval tablet embossed with 4491 on one side and L-100 on the other.

For the production of lasmiditan tablets, the following single form formulation can be used. Ingredient naming guidelines follow US Pharmacopeia.

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table 2

Single form formulation for lasmiditan tablets 50 and 100 mg

Component Amount (mg/tablet) Description 50 mg 100 mg Tablet core - intragranular components Lasmiditan hemisuccinate ^a 57,824 115.65 Active Ingredient Lasmiditan free base 50 100 Microcrystalline cellulose 30.86 61.71 Filler Pregelatinized starch 7,500 15.00 Binder Croscarmellose sodium 5,630 11.26 Baking powder Sodium lauryl sulfate 0.5600 1.120 Wetting agent ^Purified water (4.774) ^s (9.548) ^s Liquid for granulation Tablet core - extragranular components Croscarmellose sodium 7,880 15.76 Baking powder Magnesium stearate 2,250 4,500 Lubricating substance Weight of core tablet: 117.3 234.5 Film coating Gray dye mixture 3,519 - - Coloring agent Purple dye mixture - - 7.035 Coloring agent Purified water ⁰ - - - - Solvent Total tablet weight: 120.8 241.5

Notes.

^a To calculate the amount of lasmiditan hemisuccinate, a salt conversion factor of 0.86469 was used. The amount of microcrystalline cellulose can be adjusted accordingly to maintain the desired tablet weight. ^b Purified water was used in the granulation process. The drying process then removed most of the water.

^c After the drying process, a small amount of residual water remained, which may be in the form of free water or in the form of water of hydration associated with the drug substance.

^d Purified water was used during the coating process. The coating suspension consisted of 20% w/w. solids. Sufficient coating was sprayed to achieve the required 3% weight gain. During the coating process, water is removed.

Production of tablets.

Lasmiditan tablets are manufactured using a high shear wet granulation process, which is described below. High Shear Wet Granulation: Sodium lauryl sulfate is passed through a protective screen and added to purified water to produce a granulating liquid. The drug substance lasmiditan and excipients to be wet granulated (microcrystalline cellulose, pregelatinized starch, croscarmellose sodium) are passed through a protective sieve and combined in a granulator. The materials are mixed using the granulator's main impeller before the granulating liquid is added. The powder mixture is granulated in a granulator by adding granulating liquid while mixing the powder. After liquid addition is complete, the granulated mass is piled up in a wet state to facilitate liquid distribution. The granulate is crushed into coarse particles by passing through a cone mill before drying.

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Fluid bed drying. The granulate is dried in a fluid bed dryer until the required moisture content is achieved (50 and 100 mg: not more than 7%) as measured by the gravimetric loss on drying method or a scientifically proven equivalent method. The dried granules are passed through a cone mill and placed in a turning drum.

Finished Blend - Extragranular Powder Blend and Final Coating of Blend: Extragranular croscarmellose sodium is passed through a screen and added to the dry crushed granules in the turntable. The materials are mixed in a rotary drum. Extragranular magnesium stearate is passed through a protective sieve and added to the turntable. The materials are mixed in a rotary drum.

Pressing tablets. The mixed granulate is compressed into tablets using a rotary tablet compression machine. Compression parameters are selected at the beginning of batch production to achieve the required average (n=10) tablet weight (50 mg: 111.4-123.2 mg, 100 mg: 222.8-246.2 mg) and average (n=10) tablet crushing forces (50 mg: 4.1-13.7 kiloponds, 100 mg: 6.0-17.9 kiloponds). The average (n=10) weight of the core tablet, the force of destruction of the tablet and the thickness of the tablet are assessed at startup and during operation of the pressing unit. The fragility of the tablets and the disintegration time of the tablets are assessed when starting the pressing process.

Film coating of tablet cores. The dye mixture (gray for 50 mg and purple for 100 mg) is passed through a protective sieve and mixed with purified water to form a coating suspension. The tablets are film coated from the resulting suspension using spray guns in a perforated coating tank. The tank is rotated while the coating slurry is applied at a controlled rate by pneumatic atomization, and drying air is passed through the tablet bed to obtain an acceptable exhaust gas temperature. Spray enough coating to achieve the required percentage of coating applied (50 and 100 mg: 2.0-5.5%). After completion of the coating stage, the quality of the film-coated tablets is visually checked. Film-coated tablets are unloaded into bulk storage containers and (if necessary) sorted. Packaged packaging system - blisters with single doses:

Lasmiditan tablets are provided in individual blister recesses formed from a polychlorotrifluoroethylene (PCTFE)/polyvinyl chloride (PVC) laminated film and sealed with a laminated aluminum foil closure material that contains a heat-sealable PVC coating.

Preparation and characterization of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2pyridyl]benzamide acetate.

The preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide acetate (also referred to as lasmiditan acetate) was accomplished by the addition of 2,4,6-trifluoro-K- [6-(1methylpiperidine-4-carbonyl)-2-pyridyl]benzamide (541 mg, 1.6 mmol) into isopropyl acetate (5 ml) with stirring at 1000 rpm at room temperature. Acetic acid (100 µl) was added. After approximately 2 minutes of stirring, a white precipitate precipitated from the solution. After 10 min, stop stirring, collect the white solid by vacuum filtration on Whatman paper and dry on the filter under air flow for 10 min to give the title compound (650 mg, 92% yield).

Counterion stoichiometry was measured by nuclear magnetic resonance on an Agilent 400 MHz spectrometer. A sample solution was prepared by dissolving the resulting 2,4,6-trifluoro-N-[6(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide acetate (7.715 mg) and maleic acid (5.949 mg) used as a standard for other measurements, in DMSO-66 (approximately 0.75 ml). ^{The 13C} -unbound 1H spectrum of the sample was recorded in the range 0-12 ppm using the following parameters: 90° excitation pulse, 64 scans, relaxation delay 25 s and recording time 4.5 s. Resonances for acetate at approximately 1.9 ppm. (3H) and for 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide at approximately 7.8 ppm. (1H) were integrated to give areas of 29094 and 9508, respectively. The polar ratio of acetate to 2,4,6-trifluoro-N-[6-(1-methylpiperidin4-carbonyl)-2-pyridyl]benzamide was calculated from the ratio of the indicated areas, taking into account the difference in the number of protons for resonance, obtaining the observed molar ratio of 29094/ (3x9508)=1.02 acetate:2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide. See, for example, the drawing showing the 1H NMR spectrum (400 MHz, DMSO-66) of lasmiditan acetate containing maleic acid (internal standard). The obtained result provides experimental evidence that the resulting sample of 2,4,6-trifluoro-N-[6-(1-methylpiperudin4-carbonyl)-2-pyridyl]benzamide acetate is a monoacetate salt.

X-ray powder diffraction (XPD) of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide acetate.

RPD profiles of the crystalline solid 2,4,6-trifluoro-X-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide acetate were obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source and a Vantec detector operating at 35 kV and 50 mA. The sample was scanned from 4 to 40 2θ° with a step size of 0.008 2θ° and a scanning speed of 0.5 s/step using a divergence slit of 1.0 mm, a fixed anti-scattering slit of 6.6 mm, and a detector slit of 11.3 mm. The dry powder was placed on a quartz sample holder and a glass slide was used to ensure a smooth surface. Diffraction profiles of the crystalline form were recorded at ambient temperature and relative humidity. Crystal peak positions were determined using MDIJade after a full profile shift relative to the NIST 675 internal 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 intensities of the diffraction peaks can vary due to preferred orientation caused by factors such as crystal morphology and habit. In the presence of a preferred orientation effect, the peak intensities are variable, but the positions of the polymorph's characteristic peaks do not change. See, for example, USP No. 23, National Formulary No. 18, p. 1843-1844, 1995. Moreover, it is well known in the field of crystallography that for any given crystal form the angular positions of the peaks may vary slightly. For example, peak positions may shift due to changes in the temperature at which the sample is analyzed, due to sample drift, or the presence or absence of an internal standard. In this case, the peak position variability of ±0.2 2θ° takes into account these possible deviations without interfering with the accurate determination of the specified crystalline form. Confirmation of the crystal form can be made based on any unique combination of characteristic peaks.

The resulting crystalline acetate salt sample, characterized by an RPD profile recorded using CuKa radiation, has diffraction peaks (2-theta values) indicated below in the table. 3, and in particular has peaks at 26.2 in combination with one or more peaks selected from the group consisting of 20.4, 14.0 and 17.9; with a tolerance for diffraction angles of 0.2°.

Table 3

X-ray powder diffraction peaks of crystalline acetate salt of 2,4,6-trifluoro-K-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide

2,4,6-trifluoro-X-[6-(1-methylpiperidin-4carbonyl)-2-pyridyl]benzamide acetate Angle (°2-theta) +/- 0.2° Relative intensity (% of the most intense peak) 8.2 40.4% 9.7 29.6% 12.0 35.8% 14.0 65.0% 16.9 43.8% 17.9 63.2% 20.4 70.5% 23.3 30.6% 24.3 43.9% 26.2 100.0%

Lasmiditan acetate solubility and use for subcutaneous injection dosage forms.

Lasmiditan acetate has been found to be surprisingly superior to many alternative salt forms for the preparation of a subcutaneous dosage form for delivering a dose of lasmiditan in a minimal volume of near-bodily fluid. It has been found that lasmiditan acetate can provide the required dose of about 50 mg in a minimum volume of less than or exactly about 1 ml, while achieving the required near-neutral pH, and is also relatively isotonic and physically and chemically stable. When using lasmiditan hemisuccinate, it was experimentally established that achieving solubility >50 mg/ml at a pH close to neutral was difficult without the use of cosolvents. To determine solubility, a 10 mM buffer with the appropriate acid and salt was prepared and the pH was adjusted by changing the acid/salt ratio. Excess solid was equilibrated at room temperature overnight and the solution concentration was analyzed by HPLC and the solid was characterized by RPD. In contrast, for lasmiditan acetate it has been found that solubility >50 mg/mL can be achieved at near neutral pH without pH adjustment.

Table 4

Solubility of lasmiditan acetate in acetate, citrate or phosphate buffer

Buffer medium Solid form pH (up to) pH (after) Solubility (free base equivalent, mg/ml) Acetate Lasmiditan acetate 3.69 6.25 >441 Acetate Lasmiditan acetate 4.05 6.41 >430 Acetate Lasmiditan acetate 4.4 6.31 >412 Acetate Lasmiditan acetate 5.09 6.50 >430 Acetate Lasmiditan acetate 5.71 6.56 >486 Citrate Lasmiditan acetate 2.5 5.60 >300 Citrate Lasmiditan acetate 3.84 5.72 >300 Citrate Lasmiditan acetate 4.99 6.23 >300 Citrate Lasmiditan acetate 5.96 6.24 >300 Phosphate Lasmiditan acetate 8.24 6.42 >300

A 10 mM buffer was prepared with the appropriate acid and salt and the pH was adjusted by changing the acid/salt ratio. The added solute went completely into solution to form a viscous solution.

Lasmiditan acetate has been found to surprisingly exhibit a very advantageous combination of pharmaceutical properties. Lasmiditan acetate provides the required solubility for the preparation of highly concentrated dosage forms having a dose volume of less than or exactly about 1 ml for the required unit doses, which is important for clinical applications such as use in accessible self-injection devices. In addition, dissolution of lasmiditan acetate at 50 mg/ml results in a nearly neutral pH (pH approximately 6.8), the solution is isotonic and stable for at least 2 months. Lasmiditan acetate exhibits significantly higher solubility than lasmiditan hemisuccinate salt with the desired pH profile and provides the ability to deliver required unit doses of approximately 1 mL or less.

The results obtained indicate that lasmiditan acetate provides the possibility of producing an unexpectedly highly concentrated aqueous solution of lasmiditan with useful pharmaceutical properties for clinical parenteral administration, such as subcutaneous injection. The pharmacological properties of lasmiditan have been well studied (Curto, M. et al., Profiling lasmiditan as a treatment option for migraine, Expert Opinion on Pharmacotherapy (2020), vol. 21, issue 2, pp. 147-153). Preferably, subcutaneous injection is performed using a prefilled syringe or autoinjector, using devices known to those skilled in the art (see, for example, Stauffer V.L. et al., Comparison between prefilled syringe and autoinjector devices on patientreported experiences and pharmacokinetics in galcanezumab studies, Patient Prefer Adherence (2018), 12:1785-1795; and van den Bemt B.J.F et al., A portfolio of biological self-injection devices in rheumatology: how patient involvement in device design can improve treatment experience, Drug Deliv. (2019) , 26(l):384-392). These formats provide a fixed dose that does not require patient measurement, resulting in dose accuracy and safety, as well as patient confidence. The use of lasmiditan acetate salt for the acute treatment of migraine attacks in formats such as auto-injectors provides an improved treatment for inpatients, such as patients in acute care hospitals

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Claims (17)

assistance if the patient's tablet intake is impaired due to a migraine attack and associated nausea and vomiting, and patients and/or staff prefer the improved injectable form of lasmiditan. Parenteral dosage forms of lasmiditan acetate are expected to provide immediate release, resulting in a rapid onset of action, and may advantageously provide a reduced time to effect compared to oral dosage forms when used as needed at the onset of a migraine attack. Providing dosage forms of lasmiditan for injection at a neutral and physiological pH (approximately 6.0 to 7.5) that are isotonic with physiological fluid (eg, 280 to 300 mOsm/kg) is clinically desirable and is expected to minimize the likelihood of injection site pain and/or, for example, tissue irritation. Achieving an injection volume of about 1 ml or less allows for the use of available injection technologies, such as auto-injectors, and provides the opportunity to improve patient perception of injections and delivery in terms of injection time and/or, for example, pain at the injection site. Enabling the use of pre-filled syringe, pen and/or auto-injector technologies is clinically significant for patients suffering from migraine, as such devices provide ease of use during migraine attacks, where patients are often forced to use the product. Additionally, enabling pre-filled syringe, pen and/or auto-injector technologies is clinically significant as it provides mobile access to medication at any time that is easily accessible in everyday life when a migraine attack can occur at any time. To produce lasmiditan injection solution, the following unit form formulation can be used. Table 5 Formulation of a single dose of 50 mg lasmiditan solution in an auto-injector Component Quantity Description (mg/auto-injector) Lasmiditan 50.00 Active Lasmiditan acetate 57.96 ingredient Acetic acid solution (10%) Sufficient amount to achieve the required pH pH regulator Sodium hydroxide solution (10%) Sufficient amount to achieve the required pH pH regulator Water for injections the rest up to 1 ml Solvent CLAIM 1. Method for preparing a compound of the formula including stages i) treating piperidine-4-carboxylic acid under reductive amination conditions, including formaldehyde and formic acid in water, followed by treatment with an aqueous solution of HCl, followed by distillation of water and addition of acetonitrile, repeating dilution/distillation until the water content is not more than 0.2 % when determined by Karl Fischer analysis to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride; ii) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent 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 washing with base and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1methylpiperidine-4 hydrate hydrochloride -carboxamide; iv) treating N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride hydrate with inorganic - 23 045247 with a base in a non-polar solvent, followed by washing with water, phase separation and distillation of the organic solvent to a water content of no more than 0.1 wt.% when measured by analysis Karl Fischer to produce N,N-diethyl-1-methylpiperidine-4-carboxamide; v) subsequent treatment of N,N-diethyl-1-methylpiperidine-4-carboxamide (6-bromo-2-pyridyl) with lithium in a non-polar organic solvent, followed by extraction of the resulting mixture with water and a suitable organic solvent, phase separation and repeated distillation of the organic solvent to water content of not more than 0.2 wt.% when determined by Karl Fischer analysis to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone; vi) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with an aqueous solution of HBr and subsequent extraction with n-butanol, followed by repeated distillation of the organic solvent to a water content of not more than 0.3% as measured by analysis Karl Fischer to produce solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide; vii) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide with a solution of NH3 in ethylene glycol in the presence of a Cu ₂ O catalyst at about 80° C. for about 2 hours, followed by washing with water, a saturated aqueous solution NaCl and a 20% aqueous solution of NaOH, followed by extraction with a non-polar aprotic solvent, phase separation and treatment of the organic phase with 5 wt.% carbon; viii) filtering the mixture obtained above, diluting with a suitable polar alcohol solvent and repeating the distillation of the organic solvent to a water content of not more than 0.2% as determined by Karl Fischer analysis, followed by treating the resulting residue with isopropanol, water and 20 wt.% HCl, with a water concentration of the resulting suspension is at least 2%, filtering the resulting suspension and drying under vacuum at 40°C for 16-24 hours to obtain solid (6-amino-2-pyridyl)-(1-methyl-4-piperidyl) dihydrochloride dihydrate methanone; ix) treating (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrochloride dihydrate in chlorobenzene 6% w/w. a solution of NaOH in water at about 54°C for about 30 minutes, followed by phase separation and vacuum distillation of the aqueous solution to obtain (6-amino-2pyridyl)-(1-methyl-4-piperidyl)methanone; x) subsequent treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100° C. for about 4 hours, followed by cooling, loading acetonitrile and heating the resulting suspension to 80°C for about 1 hour and then collecting the resulting solid by filtration to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2 hydrochloride -pyridyl]benzamide; xi) treating 2,4,6-trifluoro-N-[6-(1-methylniperidin-4-carbonyl)-2-pyridyl]benzamide hydrochloride with a saturated aqueous solution of Na ₂ CO ₃ in methyl tert-butyl ether; xii) treating the mixture obtained above in step xi), SiO ₂ followed by filtration, carbon treatment, filtration and evaporation, dilution with ethanol and distillation to a water content of not more than 1% as determined by Karl Fischer analysis to obtain 2,4,6-trifluoro -N-[6-(1-methylniperidin4-carbonyl)-2-pyridyl]benzamide; xiii) treating 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide in ethanol with a solution of 0.5 equivalents of succinic acid in ethanol at approximately 55° C. for less than 3 hours at room temperature and then collecting the solid by filtration to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpineridin-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. 2. A method for preparing a compound of the formula, comprising the steps i) treating piperidine-4-carboxylic acid under reductive amination conditions, including formaldehyde and formic acid in water, followed by treatment with an aqueous solution of HCl, followed by distillation of water and addition of acetonitrile, repeating dilution/distillation until the water content is not more than 0.2 % when determined by Karl Fischer analysis to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride; ii) treating 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent in chlorobenzene to obtain 1-methylpiperidine-4-carboxylic acid chloride; iii) treating the 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine, followed by washing with base and subsequent treatment - 24 045247 with an aqueous solution of HCl in isopropanol to obtain solid hydrochloride hydrate N,N-diethyl-1-methylpiperidine-4-carboxamide; iv) treating N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride hydrate with an inorganic base in a non-polar solvent, followed by washing with water, phase separation and distillation of the organic solvent to a water content of not more than 0.1 wt.% as measured by Karl Fischer analysis to obtain N,N-diethyl-1-methylpiperidine-4-carboxamide; v) subsequent treatment of N,N-diethyl-1-methylpiperidine-4-carboxamide (6-bromo-2-pyridyl)lithium in a non-polar organic solvent, followed by extraction of the resulting mixture with water and a suitable organic solvent, phase separation and repeated distillation of the organic solvent until water content of not more than 0.2 wt.% when determined by Karl Fischer analysis to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone; vi) treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with an aqueous solution of HBr and subsequent extraction with n-butanol, followed by repeated distillation of the organic solvent to a water content of not more than 0.3% as measured 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-piperidyl)methanone hydrobromide in a two-phase mixture of water and toluene with solid KOH for about 3 hours, followed by separating the aqueous layer and evaporating the solvent to obtain (6-bromo- 2-pyridyl-1-methyl-4-piperidyl)methanone; viii) treating (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing K ₂ CO ₃ , 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 is no more than 0.1% as determined by HPLC, followed by diluting the reaction mixture with water and EtOAc, followed by treatment with thiourea modified silica gel at 60°C for about 8 hours, followed by filtration to obtain a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide ; ix) treating a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)-2-pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid dissolved in EtOH at 55° C for about 3 hours, followed by cooling to room temperature over about 10 hours and collecting the resulting solid by filtration to give solid 2,4,6-trifluoro-N-[6(1-methylpiperidin-4-carbonyl)- hemisuccinate. 2-pyridyl]benzamide. 3. Method according to claim 1 or 2, where the chlorinating agent is thionyl chloride. 4. Method according to claim 1 or 2, where the inorganic base is an aqueous solution of NaOH. 5. Method according to claim 1 or 2, wherein the non-polar solvent in step iv) is methyl tert-butyl ether. 6. Method according to claim 1 or 2, wherein the non-polar organic solvent in step v) is methyl tert-butyl ether. 7. Method according to claim 1 or 2, where the organic solvent in step v) is n-butanol. 8. The method according to claim 1, where the non-polar aprotic solvent is methyl tert-butyl ether. 9. The method according to claim 1, where the polar alcohol solvent is isopropanol. 10. Method according to any one of claims 1 to 9, characterized in that the reactions are carried out using a batch processing technique. 11. The method according to claim 10, characterized in that the resulting batch is obtained on a technological scale. 12. Method according to claim 11, characterized in that the resulting batch is at least 1 kg. 13. Method according to claim 11, characterized in that the resulting batch is at least 10 kg. 14. Method according to claim 11, characterized in that the resulting batch is at least 100 kg. 15. Compound formula 2 HCI _2H2O 16. The compound according to claim 15, which is a crystalline substance. 17. The compound of claim 16, characterized by an X-ray powder diffraction profile obtained using CuKa radiation having an intense peak at a 2-theta diffraction angle of 8.3° in combination with one or more peaks selected from the group consisting of 16.6 , 23.5 and 33.7° (±0.2°, respectively). -