DESC:INTRODUCTION
The present application relates to improved processes for preparation of Lasmiditan and its salts thereof. Further, the present application provides the solid state forms of Lasmiditan hemi-succinate, including amorphous solid dispersions and the processes for the preparations thereof.
2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide of Formula I, is a new selective and highly potent 5-HT1F receptor agonist, with a Ki at human 5-HT1F receptors of 2.21 nM and an affinity which is more than 450-fold higher for 5-HT1F receptors than for other 5-HT1 receptor subtypes.

US Patent No., 7423050, 8697876 describe compound of Formula I and its hydrochloride, hemi-succinate salts and also other selective pyridinoyl piperidine 5-HT1F agonists, which are active in neutrally mediated preclinical models of migraine, without causing vasoconstriction (i.e., neutrally active anti-migraine agents (NAANAs)).
US Patent Nos, 7423050, 8697876 and WO 2018106657 reported crystalline Forms and amorphous form of Lasmiditan hemi-succinate.
There is an ongoing need for improved processes for Lasmiditan and its salts, where the yields are improved and large scale synthesis is possible. This application describes such improved methods of synthesis.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konno T., Chem. Pharm. Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailability pattern may be favoured over another. Amorphous form of Cefuroxime axetil, Venetoclax, Apalutamide are good examples for exhibiting higher bioavailability than the crystalline form.
Solid amorphous dispersions of drugs are known generally to improve the stability and solubility of drug products. However, such dispersions are generally unstable over time. Amorphous dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. The present invention, however, provides stable amorphous dispersions of Lasmiditan hemi-succinate. Moreover, the present invention provides solid dispersions of Lasmiditan hemi-succinate which may be reproduced easily and is amenable for processing into a dosage form.

SUMMARY
In the first embodiment, the present application provides a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers.
In the second embodiment, the present application provides a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by any of the Figures 1-4.
In the third embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of Lasmiditan hemi-succinate and pharmaceutically acceptable carrier in suitable solvent(s),
b) isolating a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carrier.
In the fourth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers comprising the steps of:
a) physically blending Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers;
b) isolating solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers.
In the fifth embodiment, the present application provides a process for preparation of amorphous Lasmiditan hemi-succinate, which comprises;
a) providing a solution of Lasmiditan hemi-succinate in suitable solvent(s),
b) isolating an amorphous form of Lasmiditan hemi-succinate.
In the sixth embodiment, the present application provides a process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) methylation of piperidine-carboxylic acid or its salts under suitable reaction conditions to afford a compound of Formula II,

b) converting the compound of Formula II to a compound of Formula III, under suitable reaction conditions,

R1 and R2 can be same or different and are selected from C1-C4 alkyl, aryl, substituted aryl etc.
c) reacting the compound of Formula III with 2,6-dibromopyridine to afford a compound of Formula IV or its salts,

d) converting the compound of Formula IV or its salts to a compound of Formula V or its salts,

e) reacting the compound of Formula V or its salts with activated 2,4,6-triflurobenzoic acid under suitable reaction conditions to afford a compound of Formula I,

f) reacting the compound of Formula I with succinic acid in suitable solvent to afford Lasmiditan hemi-succinate of Formula Ia.

In the seventh embodiment, the present application provides a process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) converting 2,4,6-triflurobenzoic acid to a compound of Formula VI under suitable reaction conditions,

b) reacting the compound of Formula VI with a compound of Formula IV under suitable reaction conditions to afford compound of Formula I or its salts.

c) reacting the compound of Formula I with a pharmaceutically acceptable acid, optionally with succinic acid in suitable solvent to afford Lasmiditan hemi-succinate of Formula Ia.
In the eighth embodiment, the present application provides a process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) methylation of piperidine-carboxylic acid or its salts without using metal catalyst under suitable reaction conditions to afford a compound of Formula II,

b) converting the compound of Formula II to a compound of Formula III, under suitable reaction conditions,

R1 and R2 can be same or different and are selected from C1-C4 alkyl, aryl, substituted aryl etc.
In the ninth embodiment, the present application provides an improved process for preparation of crystalline Form A of Lasmiditan hemi-succinate, comprising;
a) providing a solution of Lasmiditan hemi-succinate in suitable solvents selected from methanol, C3-C5 alcohols, ketones, ethers, cyclic ethers, esters, nitriles and mixtures thereof,
b) crystallizing Form A of Lasmiditan hemi-succinate under suitable conditions; and
c) isolating crystalline Form A of Lasmiditan hemi-succinate.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and PVP-K30 prepared according to Example 20.
Figure 2 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and hydroxypropyl cellulose (HPC) prepared according to Example 21.
Figure 3 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and hydroxypropyl methyl cellulose (HPMC) prepared according to Example 22.
Figure 4 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and Co-Povidone prepared according to Example 23.
Figure 5 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of Lasmiditan hemi-succinate prepared according to Example 18.
Figure 6 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of Lasmiditan hemi-succinate prepared according to Example 19.
Figure 7 is powder X-ray power diffraction ("PXRD") pattern of Lasmiditan hemi-succinate prepared according to Example 16.
Figure 8 is powder X-ray power diffraction ("PXRD") pattern of Lasmiditan prepared according to Example 5.
Figure 9 is powder X-ray power diffraction ("PXRD") pattern of Lasmiditan hemi-succinate prepared according to Example 6.
Figure 10 is powder X-ray power diffraction ("PXRD") pattern of Lasmiditan hemi-succinate prepared according to Example 11.
Figure 11 is powder X-ray power diffraction ("PXRD") pattern of Lasmiditan prepared according to Example 24.

DETAILED DESCRIPTION
In the first embodiment, the present application provides a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The increase in solubility of the drug in solid dispersion is mainly because the drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve.
A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a carrier matrix. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the carrier dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles.
In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "amorphous solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and a carrier matrix. By "amorphous drug substance," it is meant that the amorphous solid dispersion contains drug substance in a substantially amorphous solid state form i.e. at least 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least 90% and most preferably at least 95% of the drug substance in the dispersion is in amorphous form.
The solid dispersions of Lasmiditan hemi-succinate of the present invention can be made by any of numerous methods that result in an amorphous solid dispersion of Lasmiditan hemi-succinate. Several approaches can be used for the preparation of solid dispersion which includes spray drying, fusion method, solvent evaporation, hot-melt extrusion, particle size reduction, supercritical fluid (SCF) processes, kneading, inclusion complexes, electrostatic spinning method and surface-active carriers.
Lasmiditan hemi-succinate can be incorporated in the dispersion in amorphous form.
The dispersing agent is typically composed of a pharmaceutically acceptable substance that does not substantially interfere with the pharmaceutical action of Lasmiditan hemi-succinate. The phrase "pharmaceutically acceptable" is employed herein to refer to those substances which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, the carrier is a solid at room temperature (e.g., about 25oC). In further embodiments, the carrier melts at a temperature between about 30 and 100oC. In further embodiments, the carrier is soluble in an organic solvent.
Non-limiting examples of suitable polymers or carriers such as celluloses (e.g., carboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses); polysaccharides, heteropolysaccharides (pectins); poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid; mixtures of two or more thereof, copolymers thereof, derivatives thereof, and the like. Further examples of carriers include copolymer systems such as polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyvinylpyrrolidone-polyvinylalcohol (PVP-PVA), and derivatized copolymers such as copolymers of N-vinyl purine (or pyrimidine) derivatives and N-vinylpyrrolidone.
An enteric coating polymer can also be used according to the present invention. Specific examples of the enteric coating polymers include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate and hydroxypropylmethyl trimellitate.
In an aspect of the invention, the polymer is polyvinylpyrrolidone (PVP) or a derivative thereof. PVP is a polyamide that forms complexes with a wide variety of substances and is considered to be chemically and physiologically inert. Examples of suitable PVPs include polyvinylpyrrolidones having an average molecular weight from about 10,000 to about 50,000. In some embodiments, the polyvinylpyrrolidone has an average molecular weight of about 10,000 to about 20,000. In further embodiments, the polyvinylpyrrolidone has a molecular weight of about 15,000 to about 20,000.
In the second embodiment, the present application provides a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by any of the Figures 1-4.
In the third embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of Lasmiditan hemi-succinate and pharmaceutically acceptable carrier in suitable solvent(s),
b) isolating a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carrier.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Lasmiditan hemi-succinate that is obtained in the course of its synthesis; or
ii) direct use of a reaction mixture containing Lasmiditan hemi-succinate that is obtained by treating Lasmiditan with succinic acid; or
iii) dissolving Lasmiditan hemi-succinate in suitable solvent(s).
Any physical form of Lasmiditan or Lasmiditan hemi-succinate may be utilized for providing the solution of Lasmiditan hemi-succinate in step a). More particularly, any polymorph reported in the literature can be utilized as an input material for providing a solution of step a).
Suitable pharmaceutically acceptable carriers that are dispersing agents which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide (Syloid, Aerosil, Cab-o-sil etc.) and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Suitable solvents which can be used for preparing amorphous solid dispersion of Lasmiditan hemi-succinate can be selected from the list of solvents provided in this application. In a preferred embodiment, alcohols, halogenated hydrocarbons, water and their mixtures are employed.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves isolation of amorphous solid dispersion of Lasmiditan hemi-succinate from a solution obtained in step a);
The isolation of amorphous solid dispersion of Lasmiditan hemi-succinate can be done by removing solvent from a solution obtained in step (a) or by addition of suitable anti-solvent in a solution obtained in step (a) or by cooling to appropriate temperature resulting in formation of amorphous form. Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art.
The solvent can be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 75°C, less than about 60°C, less than about 50°C, less than about 40°C or any other suitable temperatures.
Suitable anti-solvent that can be employed can be chosen by the person skilled in the art from the list of solvents provided in this application.
Suitable temperature at which the mixture of step a) can be cooled include but not limited to any temperature less than 60oC, preferably less than 40oC, more preferably less than 20oC.
The amorphous solid dispersion of Lasmiditan hemi-succinate can be recovered by using the processes as described in this application or any other technique known in the art.
In the fourth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers comprising the steps of:
a) physically blending Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers;
b) isolating solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers.
Lasmiditan hemi-succinate substantially in amorphous form may be utilized for physical blending in step (a).
Suitable pharmaceutically acceptable polymers or carriers that are dispersing agents which can be used in step (a) are the same as defined herein above.
Physical blending as used in step a) involves dry blending in motor pistol, flask or any other suitable container or any other technique known in the art.
Step (b) involves isolation of solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers or carriers which can be carried out by any technique known in the art.
The recovery of solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers or carriers of the present application, can be carried out by methods as described in this application or any other technique known in the art.
Although the solid dispersions of the present invention are preferably prepared using conventional techniques, it will be understood that suitable solid dispersions may be formed utilizing other conventional techniques known to those skilled in the art, such as vacuum drying, ATFD, fluid-bed drying, freeze-drying, rotary evaporation, drum drying, or other rapid solvent evaporation process.
Another aspect of the invention involves preparation of solid dispersions of Lasmiditan hemi-succinate by melt processing, wherein the compound and a carrier are heated to a temperature above the melting point of both the carrier and compound, which results in the formation of a fine colloidal (as opposed to molecular) dispersion of compound particles, with some solubilization of the compound in the carrier matrix. Processing of such a molten mixture often includes rapid cooling, which results in the formation of a congealed mass which must be subsequently milled to produce a powder which can be filled into capsules or made into tablets.
The amount of Lasmiditan hemi-succinate in the solid dispersions of the present invention ranges from about 0.1% to about 90%, by weight, of the solid dispersion; or from about 10% to about 70%, by weight, of the solid dispersion; or from about 20% to about 60%, by weight, of the solid dispersion; or from about 20% to about 40%, by weight, of the solid dispersion; or about 30%, by weight, of the solid dispersion. In some aspects, the weight ratio of Lasmiditan hemi-succinate to carrier is about 1:99 to about 99:1. In some aspects, the weight ratio of Lasmiditan hemi-succinate to carrier is about 1:99 to about 75:25 or about 1:99 to about 60: 40. In further aspects, the weight ratio of Lasmiditan hemi-succinate to carrier is about 1:99 to about 15:85; about 1:99 to about 10:90; or about 1:99 to about 5:95. In further aspects, the weight ratio of Lasmiditan hemi-succinate to carrier is about 25:75 to about 75:25, about 40:60 to about 60:40 or about 1:1 or about 2:1. Typically, Lasmiditan hemi-succinate and carrier medium are present in a ratio by weight with the solvent of 1:0.1 to 1:20.
In the fifth embodiment, the present application provides a process for preparation of amorphous Lasmiditan hemi-succinate, which comprises;
a) providing a solution of Lasmiditan hemi-succinate in suitable solvent(s),
b) isolating an amorphous form of Lasmiditan hemi-succinate.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Lasmiditan hemi-succinate that is obtained in the course of its synthesis; or
ii) direct use of reaction mixture containing Lasmiditan hemi-succinate that is obtained by treating Lasmiditan with succinic acid; or
iii) dissolving Lasmiditan hemi-succinate in suitable solvent(s).
Any physical form of Lasmiditan hemi-succinate may be utilized for providing the solution of Lasmiditan hemi-succinate in step a).
Suitable solvents which can be used for dissolving the hemi-succinate salt of Lasmiditan can be selected from the list provided in the instant application.
After dissolution in step (a), the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art or as described above.
Step (b) involves isolation of amorphous Lasmiditan hemi-succinate.
The isolation of amorphous Lasmiditan hemi-succinate can be done by removing solvent from a solution obtained in step (a) or by addition of suitable anti-solvent in a solution obtained in step (a) or by cooling to appropriate temperature resulting in formation of amorphous form. Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art.
The solvent can be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 75°C, less than about 60°C, less than about 50°C, less than about 40°C or any other suitable temperatures.
Suitable anti-solvent that can be employed can be chosen by the person skilled in the art, from the list of solvents provided in this application, in such a way in which amorphous Lasmiditan hemi-succinate is either insoluble or very less soluble.
Suitable temperature at which the mixture of step a) can be cooled include but not limited to any temperature less than 60oC, preferably less than 40oC, more preferably less than 20oC.
The recovery of an amorphous form Lasmiditan hemi-succinate can be carried out by methods as described in this application or any other technique known in the art.
The amorphous form Lasmiditan hemi-succinate prepared according to present application are illustrated by any of the Figures 5 & 6.
The dried product be it Form A, amorphous Lasmiditan hemi-succinate or solid dispersion comprising amorphous Lasmiditan hemi-succinate may be optionally subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
In another general aspect, there is provided Form A, amorphous form of Lasmiditan hemi-succinate or solid dispersion comprising amorphous form of Lasmiditan hemi-succinate having particle size distributions wherein D90 is less than about 100 microns or less than about 50 microns or less than about 20 microns or less than about 10 microns or any other suitable particle sizes.
In an aspect, the present application provides pharmaceutical formulations comprising an amorphous form of Lasmiditan hemi-succinate or solid dispersion comprising amorphous form of Lasmiditan hemi-succinate, together with one or more pharmaceutically acceptable excipients. Lasmiditan hemi-succinate together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
In an aspect, the present application provides pharmaceutical formulations comprising an amorphous form of Lasmiditan hemi-succinate or solid dispersion comprising amorphous form of Lasmiditan hemi-succinate, together with one or more pharmaceutically acceptable excipients. Lasmiditan hemi-succinate together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release.
Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
The pharmaceutical dosage form according to the present invention may be is coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
In the sixth embodiment, the present application provides a process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) methylation of piperidine-4-carboxylic acid or its salts under suitable reaction conditions to afford a compound of Formula II or a pharmaceutically acceptable salt thereof,

The step a) involves converting piperidine-4-carboxylic acid to 1-methylpiperidine-4-carboxylic acid of Formula II or a pharmaceutically acceptable salt thereof. The said conversion can be materialized by using formaldehyde at ambient pressure under transfer hydrogenation conditions or by catalytic hydrogenation using Palladium/Charcoal, Raney-Nickel, etc. in presence of suitable hydrogen source like formic acid or by transition metal free reductive amination using borohydride based reducing agents like sodium borohydride, Vitride, optionally in presence of acids like sulfonic acid such as methanesulfonic acid, p-toluenesulfonic, acid and the like.
Compounds of Formula II can be isolated in the form of a salt to enhance the purity. A suitable salt of compound of Formula II can be a salt of a mineral or organic acid. Suitable mineral acids for salt formation include hydrochloric, hydroiodic, nitric, phosphoric and sulphuric acid. Suitable organic acids include acetic, trifluoroacetic, oxalic, maleic, fumaric, malic, succinic acid, formic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, gluconic, glutamic, isethionic, lactic, mandelic, methanesulfonic, p-toluenesulphonic acids, L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid.
b) converting the compound of Formula II to a compound of Formula III, under suitable reaction conditions,

R1 and R2 can be same or different and are selected from C1-C4 alkyl, aryl, substituted aryl etc.
The said step involves activation of the compound of Formula II with acid activating agents like thionyl chloride, pivaloyl chloride, oxalyl chloride, acetic anhydride, alkyl chloroformate, NHS ester followed by reaction with suitable organic amine.
Suitable activating agents will be familiar to the person skilled in the art. In a preferred embodiment, compound of Formula II is converted to its acid chloride or mixed anhydride before reacting with a suitable organic amine to afford a compound of Formula III.
Organic amine can be selected from but not limited to organic bases such as dimethyl amine, diethyl amine, di-isopropyl amine, dicyclohexylamine, morpholine, N,O-dimethylhydroxylamine or the like. In a preferred embodiment, dimethylamine is employed.
A suitable solvent which is inert to the reaction conditions can be selected from the list provided in the application.
c) reacting the compound of Formula III with 2,6-dibromopyridine to afford a compound of Formula IV or its salts,

The said step involves reaction of a compound of Formula III with a solution of 2,6-dibromopyridine in the presence of a suitable organolithium compound such as methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, n-hexyl lithium or the like, or a suitable Grignard reagent. In a preferred embodiment, n-butyl lithium is employed.
A suitable solvent which is inert to the reaction conditions can be selected from the list provided in the application.
The compound of Formula IV can be converted to its suitable salts in order to enhance the purity at intermediate stage.
A suitable salt of compound of Formula IV can be a salt of a mineral or organic acid. Suitable mineral acids for salt formation include hydrochloric, hydroiodic, nitric, phosphoric and sulphuric acid. Suitable organic acids include acetic, trifluoroacetic, oxalic, maleic, fumaric, malic, succinic acid, formic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, gluconic, glutamic, isethionic, lactic, mandelic, methanesulfonic, p-toluenesulphonic acids, L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid.
d) converting the compound of Formula IV to a compound of Formula V or its salts,

The said step involves reaction of 6-(bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (Formula IV) with a suitable source of ammonia optionally in presence of copper or a suitable copper salt promoter and an organic additive, to afford a compound of Formula V.
Suitable sources of ammonia include, but are not limited to, ammonia gas, solutions of ammonia such as aqueous ammonia, BocNH2, (Boc)2NH, BnNH2, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine and metal salts of bis(trimethylsilyl)amide such as LiHMDS. Suitable copper salt promoters include, but are not limited to, Cu2O, CuI, CuCl, CuCl2, CuI(OTf) and Cu(OAc)2. Suitable organic additives include, but are not limited to, N,N'-Dimethylethylenediamine (DMEDA), trans-N,N‘-dimethyl-1,2-cyclohexanediamine (DMCDA), 1,10-phenanthroline and N,N,N',N'-tetramethylethylenediamine.
The compound of Formula V can be converted to its suitable salts in order to enhance the purity at intermediate stage. The suitable salts can be selected from the list provided above.
e) reacting the compound of Formula V or its salts with activated 2,4,6-triflurobenzoic acid under suitable reaction conditions to afford a compound of Formula I,

Suitable activating agents will be familiar to the person skilled in the art. In a preferred embodiment, 2,4,6-triflurobenzoic acid is converted to its acid chloride before reacting with the compound of Formula V or its salts.
f) reacting compound of Formula I with succinic acid in suitable solvent(s) to afford Lasmiditan hemi-succinate of Formula Ia.

A suitable solvent which is inert to the reaction conditions can be selected from the list provided in the application. In a preferred embodiment, acetone is employed for the said step.
Some suitable temperatures for conducting this step are about 0oC to the boiling point of solvent.
In seventh embodiment, the present application provides a process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) converting 2,4,6-triflurobenzoic acid to a compound of Formula VI under suitable reaction conditions,

The said step involves in situ activation of 2,4,6-triflurobenzoic acid under suitable reaction conditions. Suitable activating agents will be familiar to the person skilled in the art. In a preferred embodiment, 2,4,6-triflurobenzoic acid is converted to its acid chloride by using thionyl chloride followed reaction with a suitable source of ammonia. In a preferred embodiment, aqueous ammonia or ammonia gas is employed.
A suitable solvent which is inert to the reaction conditions can be selected from the list provided in the application. In a preferred embodiment, acetonitrile, or dichloromethane is employed for the said step.
Some suitable temperatures for conducting this step are about -50oC to 10°C.
b) reacting the compound of Formula VI with the compound of Formula IV under suitable reaction conditions to afford compound of Formula I or its salts.
The compound of Formula IV can be prepared by using an adaptation of literature methods, such as described in US7423050, US8697876 or the method described in the instant application.

The reaction is carried out under conditions of Buchwald-Hartwig coupling in presence of a suitable palladium catalyst, ligand, base and solvent.
Suitable palladium catalysts include, but are not limited to, Pd2(dba)3, Pd(OAc)2, PdCl2, (PPh3)2PdCl2, Pd(dppf)Cl2, Pd(PPh3)4, Pd(Josiphos)Cl2 and Pd(acac)2.
Suitable ligands include, but are not limited to, Xanthphos, tris-o-tolylphosphine, X-Phos, PPh3, t-Bu3P, BINAP, dppf, dppb, dppe and S-Phos.
Suitable bases include, but are not limited to, alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like; organic bases, such as triethylamine, diisopropylethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,6-dimethylpyridine, N,N-dimethylaminopyridine or the like; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide or the like; alkali metal hydrides, such as, sodium hydride, lithium hydride, potassium hydride or the like; organometallic bases, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide or the like.
A suitable solvent which is inert to the reaction conditions can be selected from the list provided in the application. In a preferred embodiment, toluene is employed for the said step.
Some suitable temperatures for conducting this step are about 50oC-150°C.
c) reacting compound of Formula I with succinic acid in a suitable solvent(s) to afford Lasmiditan hemi-succinate of Formula Ia.
A suitable solvent which is inert to the reaction conditions can be selected from the list provided in the application. In a preferred embodiment, acetone is employed for the said step.
Some suitable temperatures for conducting this step are about 0oC to the reflux temperature.
In the eighth embodiment, the present application provides a process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) reductive amination of piperidine-carboxylic acid or its salts using formaldehyde under suitable reaction conditions to afford a compound of Formula II,

Step a) involves reaction of piperidine-carboxylic acid or its salts with formaldehyde followed by reduction in presence of hydride source, hydrogen and/or reducing agent to afford compound of Formula II.
The said hydride source can be selected from formic acid, ammonium formate and reducing agents can be selected from sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydide, vitride, sodium cyanoborohydride.
The said reaction can optionally be done in presence of acid as explaind above.
b) converting the compound of Formula II to a compound of Formula III, under suitable reaction conditions,

R1 and R2 can be same or different and are selected from C1-C4 alkyl, aryl, substituted aryl etc.
Step b) involves conversion of the compound of Formula II to a compound of Formula III under suitable conditions. Such conversion can be carried out by the methods reported in literature or as described in the present application.
In the ninth embodiment, the present application provides an improved process for preparation of crystalline Form A of Lasmiditan hemi-succinate, comprising;
a) providing a solution of Lasmiditan hemi-succinate in suitable solvents selected from methanol, C3-C5 alcohols, ketones, ethers, cyclic ethers, esters, nitriles and mixtures thereof,
b) crystallizing Form A of Lasmiditan hemi-succinate under suitable conditions; and
c) recovering crystalline Form A of Lasmiditan hemi-succinate.
The step a) involves providing a solution of Lasmiditan hemi-succinate in suitable solvent(s) selected from methanol, C3-C5 alcohols, ketones, ethers, cyclic ethers, esters, nitriles and mixtures thereof.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Lasmiditan hemi-succinate that is obtained in the course of its synthesis; or
ii) direct use of reaction mixture containing Lasmiditan hemi-succinate that is obtained by treating Lasmiditan with succinic acid; or
iii) dissolving Lasmiditan hemi-succinate in suitable solvent(s) selected from methanol, C3-C5 alcohols, ketones, ethers, cyclic ethers, esters, nitriles, and mixtures thereof.
Any physical form of Lasmiditan hemi-succinate may be utilized for providing the solution of Lasmiditan hemi-succinate in step a).
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques or by means as described in the present application.
The isolation of crystalline Form A Lasmiditan hemi-succinate can be done by removing solvent from a solution obtained in step (a) or by addition of suitable anti-solvent in a solution obtained in step (a) or by cooling to appropriate temperature resulting in formation of said form.
Suitable anti-solvent that can be employed can be chosen by the person skilled in the art, from the list of solvents provided in this application, in such a way in which crystalline Form A of Lasmiditan hemi-succinate is either insoluble or very less soluble.
Suitable temperature at which the mixture of step a) can be cooled include but not limited to any temperature less than 60oC, preferably less than 40oC, more preferably less than 20oC.
In aforementioned embodiment, once obtained, the crystals of Form A of Lasmiditan hemi-succinate may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
The crystalline Form A of Lasmiditan hemi-succinate can be done recovered by using the processes known in the art, such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The present application also includes aspects wherein one or more intermediate compounds are isolated as solids, preferably as crystalline solids and their use for preparation of Lasmiditan or its pharmaceutically acceptable salts.
The present application also includes embodiments, wherein the Lasmiditan and its hemi-succinate salt has high purity, such as at least about 99%, at least about 99.5%, or at least about 99.9%, by weight as determined using high performance liquid chromatography (HPLC). Correspondingly, the level of impurities may be less than about 1%, less than about 0.5%, or less than about 0.1%, by weight, as determined using HPLC.
The chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at ambient temperatures, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, many of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, or any of their combinations.
Suitable solvents inert to the reaction conditions include but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, tert-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof.
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
Lasmiditan hemi-succinate obtained by literature adopted methods can be subjected to purification process using conventional techniques known in the art. For example, useful techniques include, but are not limited to, slurrying, crystallization using single or mixture of solvents, by addition of suitable anti-solvent and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Anti-solvent refers to a liquid that, when combined with a solution of Lasmiditan hemi-succinate, reduces its solubility in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.
The compounds at various stages of the process may be recovered using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, by addition of suitable anti-solvent, centrifugation, gravity filtration, suction filtration, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
In aforementioned aspects of the invention wherever solid is getting crystallized or precipitated. To ease the filtration of product, step-wise cooling, optionally with seeding, can be performed. For example, the reaction mixture can first be cooled from about reflux temperature of solvent to ambient temperature followed by -10°C to 10°C over a period of about 10 mins to about 1 hour, to about 10 hours or longer.
A recovered solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
The solid form of Lasmiditan hemi-succinate of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1.5406 Å and were obtained using a Rigaku Desktop X-ray diffractometer (Model: MiniFlex600). For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.20. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.20. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.20. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.20) of 7.9?" means "having a diffraction peak at a diffraction angle (2?) of 7.7? to 8.1?”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
DSC analysis was carried out in a Discovery DSC instrument with a ramp of 10°C/ minute. The starting temperature was 25°C and ending temperature was 250°C.
The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise, D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D50, and D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.
Although the exemplified procedures herein illustrate the practice of the present invention in some of its embodiments, the procedures should not be construed as limiting the scope of the invention. Modifications from consideration of the specification and examples within the ambit of current scientific knowledge will be apparent to one skilled in the art.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, or instrument error for a given technique used to measure a value.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that crystalline form, salt and/or optical isomer, within any associated and recited margin of error, for purposes of identification.
The term “anti-solvent” refers to a liquid that, when combined with a solution of Lasmiditan or its hemisuccinate salt, reduces solubility of the Lasmiditan or its hemisuccinate salt in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.
Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc.
Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
The "carrier" as used herein, refers to any substance or mixture of substances that acts as a dispersing medium for molecules/particles of Lasmiditan hemi-succinate.
The term “dispersed” means random distribution of a therapeutically active substance throughout the carrier.
“Amorphous form” as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds.
A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include, but are not limited to, isopentane, neopentane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example 1: Preparation of 1-Methylpiperidine-4-carboxylic acid
A hydrogenation flask is charged with isonipecotic acid (100 g), formaldehyde (37%, 72.26 mL), 10% Pd/Charcoal (10 g) and water. The reaction mixture was maintained at room temperature for 16 hours under hydrogen pressure of 45 psi. After completion of the reaction, the mixture was filtered through Celite bed and washed with water (2x100 mL). The filtrate was subjected to complete distillation under reduced pressure at 55 oC followed by co-distillation with ethanol (3x100 mL). The solid obtained was dried under vacuum at ~50 oC for 5 hours to afford the title compound as off white solid in ~97% yield.

Example 2: Preparation of N,N-diethyl-1-methylpiperidine-4-carboxamide
A flask was charged with 1-methylpiperidine-4-carboxylic acid (50 g) and dry DCM (400 mL) and then cooled to ~20 oC. To the mixture, catalytic amount of DMF (0.67 mL) was added followed by slow addition of oxalyl chloride (48 mL) at the same temperature. The mixture was heated to 40-45oC and maintained at the same temperature for ~ 2 hours. After completion of the reaction as monitored by TLC, solvents were distilled off from the mixture followed by co-distillation with toluene (3x100 mL) under reduced pressure at 50 oC. Then to the above residue dry THF (400 mL) was added and the mixture was cooled to 0-5oC. To this mixture, sequentially, a solution of N,N-dimethylamine in THF (2M, 350 mL), then triethylamine (244 mL) were slowly added at the same temperature followed by maintenance of the mixture for about ~3 hours. Then the mixture was warmed to ~20oC and maintained for overnight. After completion of the reaction as monitored by TLC, reaction mixture was quenched with slow addition of 30% NaOH solution (61 mL) at 0-5 oC and maintained for ~ 20 minutes. The desired compound was extracted in DCM (800 mL, 4x100 mL), the dichloromethane layer was separated and then sticky solid was dissolved in water (200 mL), then again extracted with dichloromethane (4x100 mL). The dichloromethane layer was subjected to distillation followed by co-distillation with MTBE (3x50 mL) to afford the title compound as brown solid in ~75% yield having ~99% HPLC purity.

Example 3: Preparation of (6-Bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone
A flask was charged with MTBE (200 mL) and cooled to -75oC followed by addition of n-butyl lithium (220 mL, 1.6 M in Hexane). To this mixture, a solution of 2,6-dibromopyridine (83.5g) in MTBE (800 mL) was drop-wise added at the same temperature followed by maintenance of the mixture for ~ 30 minutes. Then N,N-diethyl-1-methylpiperidine-4-carboxamide (40 g) dissolved in MTBE (320 mL) was drop-wise added to the above mixture at -75oC followed by maintenance of the mixture at the same temperature for ~1 hour. After completion of the reaction as monitored by TLC, mixture was allowed to attain 0oC and then quenched with drop-wise addition of saturated ammonium chloride solution (120 mL). The pH of the mixture was adjusted to ~7 by addition of 37% Hydrochloric acid followed by addition of water (200 mL). The organic layer was separated and aqueous layer was extracted with DCM (10x100 mL). The combined organic layer was washed with 6N aqueous hydrochloric acid solution (2x500 mL). The aqueous layer was basified with 30% sodium hydroxide solution (1000 mL) and then extracted with ethyl acetate (2x500 mL). The ethyl acetate layer was washed with brine solution (300 mL) and then subjected to complete distillation under vacuum at ~45oC to afford the title compound as brown residue in ~72% yield having ~94% HPLC purity.

Example 4: Preparation of (6-Aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride
A flask was charged with (6-Bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (20 g), aqueous ammonia (396 mL), copper (I) oxide (1 g), potassium carbonate (3.9 g), DMEDA (1.53 mL), ethylene glycol (135 mL). The mixture was heated to 60-65oC and maintained at the same temperature for about 20 hours. After completion of reaction as monitored by TLC, the mixture was concentrated at 50oC to remove ammonia. To the said mixture, water (70 mL) and 30% aqueous sodium hydroxide solution (40 mL) was added. The mixture was stirred for 10 minutes and extracted with ethyl acetate (3x200 mL), subjected to washing with brine solution (100 mL) followed by distillation of organic layer under reduced pressure at 45oC. To the obtained residue, ethanol (40 mL) was added and mixture was cooled to 0oC followed by drop-wise addition of 4M HCl in 1,4-dioxane (160 mL). The mixture was allowed to attain room temperature and stirred for 30 minutes. The mixture was concentrated followed by addition of isopropyl alcohol (200 mL) and maintenance at 80oC for 30 minutes. The mixture was cooled to room temperature and solid obtained was isolated by filtration, washed with isopropyl alcohol (2x20 mL) and dried at 50oC to afford the title compound as off white solid in ~73% yield having ~99% HPLC purity.

Example 5: Preparation of 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide
A flask was charged with 2,4,6-trifluorobenzoic acid (11 g), dry DCM (140 mL), N,N-dimethylformamide (0.10 mL), and then drop-wise oxalyl chloride (7.42 mL) was added. The mixture was stirred at room temperature for overnight. After completion of reaction as monitored by TLC, the mixture was concentrated and then subjected to co-distillation with toluene (2x30 mL). To the mixture, THF (140 mL) was added at the room temperature to make solution (I). In another flask, (6-Aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone free base (10.5 g, generated from 14 g of the dihydrochloride salt), THF (140 mL) and triethylamine (9.73 g) were charged under inert atmosphere at room temperature. This mixture was cooled to 5-10oC followed by drop-wise addition of the above solution (I).The mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, reaction was quenched with water (50 mL) and 30% aqueous NaOH solution (30 mL) and stirred for ~ 1hour. The organic layer was separated and extracted with water (150 mL), acetic acid (25 mL), cyclohexane (150 mL). The combined aqueous layer was basified with 30% NaOH solution followed by extraction with ethyl acetate (3x150 mL). The organic layer was subjected to complete distillation under reduced pressure at 45oC to afford the title compound as brown solid in ~ 78% yield having HPLC purity of ~98%.

Example 6: Preparation of Lasmiditan hemi-succinate
A flask was charged with 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide (23.1 g), acetone (231 mL) for dissolution followed by addition of succinic acid (3.61 g). The reaction mixture was stirred at 55-60oC for ~30 minutes. The solid obtained was isolated by filtration, washed with acetone (2x2 mL), dried under vacuum at 50oC to afford the title compound as white solid in ~82% yield having HPLC purity of ~99.62%.

Example 7: Preparation of 1-methylpiperidine-4-carboxylic acid hydrochloride
A flask was charged with isonipecotic acid (5 g), formic acid (10.5 mL), formaldehyde (aq. 37%, 15.7 mL). The reaction mixture was heated to about 100oC and maintained for 15-16 hours at the same temperature. After completion of reaction, the mixture was cooled to 45-50oC followed by concentration under reduced pressure below 50oC. Then conc. HCl (2.5 mL) was added to the above obtained crude material followed by distillation under reduced pressure. To the residue obtained, acetone (15 mL) was added and the mixture was stirred at room temperature. Then the white solid obtained was isolated by filtration to afford the title compound in ~73% yield.

Example 8: Preparation of N, N-1-trimethylpiperidine-4-carboxamide
A flask was charged with 1-methylpiperidine-4-carboxylic acid hydrochloride (5 g), dichloromethane (100 mL) under inert atmosphere at room temperature. The mixture was cooled to 0-5oC followed by addition of triethylamine (11.6 mL), pivaloyl chloride (4.1 mL) at the same temperature. The mixture was maintained for 30 min followed by slow addition of dimethylamine solution in THF (20.89 mL). The mixture was then maintained for 2-3 hours at room temperature. After completion of reaction, the mixture was cooled to 0-5oC and then 30% aqueous sodium hydroxide solution (6 mL) was added. The mixture was allowed to attain room temperature & organic layer was separated. The organic layer was concentrated under reduced pressure below 40oC followed by cooling to 0-5oC to afford solid. 6N hydrochloric acid (10 mL) was added to the above solid at 0-5oC and reaction mixture was stirred at 25-35oC followed by addition of ethyl acetate (25 mL). The aqueous layer was separated and washed with ethyl acetate (25 mL) followed by addition of 30% aq. sodium hydroxide (5 mL) and the desired product was extracted in DCM (25mL x 4) followed by evaporation under reduced pressure to afford the title compound in ~63% yield having HPLC purity of ~99.6%.

Example 9: Preparation of 2,4,6-trifluorobenzamide
Thionyl chloride (30 mL) was added to a flask containing 2,4,6-trifluorobenzoic acid (10 g), under inert atmosphere. The mixture was heated to ~80oC for 4-5 hours, after completion of reaction, the mixture was cooled to ~45oC. The mixture was subjected to concentration under reduced pressure followed by addition of toluene (20 mL) to the compound so obtained. The mixture was again subjected to distillation followed by addition of acetonitrile (100 mL). The mixture was cooled to ~-40oC before passing ammonia gas passed through it for 10 min. The mixture was then stirred for ~30 min. before allowing to attain room temperature at which it was again stirred for another 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford title compound as white solid in ~68% yield having HPLC purity of ~99.6%.

Example 10: Preparation of Lasmiditan
A flask was charged with 2,4,6-trifluorobenzamide (1 g), (6-Bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (0.68 g), toluene (10 mL), Cesium Carbonate (1.61 g) under inert atmosphere. Then Pd2(dba)3 [0.16 g] and Xantphos (0.1 g) were added to the above mixture. The mixture was degassed, heated to ~100oC and maintained for 16-18 hours. After completion of the reaction, mixture was cooled to ~25oC followed by filtration and washing of bed with ethyl acetate (5 mL). The filtrate was concentrated under reduced pressure to afford the crude compound which was purified by column chromatography using methanol:dichloromethane (~4%) as eluents. The pure fractions were combined and evaporated under reduced pressure to afford Lasmiditan as light brown solid in ~77% yield having HPLC purity of >91%.

Example 11: Preparation of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (~1 g), acetone (10.3 mL), succinic acid (0.162 g). The mixture was heated to 60-65oC and stirred for 30 min. at the same temperature followed by cooling to ~25oC. The solid obtained is filtered & washed with acetone (~15 mL) followed by drying at below 45oC to afford title compound in ~72% yield having HPLC purity >97%.

Example 12: Preparation of Form A of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (1 g), THF (8 mL) and was refluxed for clear solution. The mixture was allowed to attain room temperature followed by addition of succinic acid (0.156 g). The mixture was stirred for ~2 hours at the same temperature and solid obtained was isolated by filtration, washed & dried to afford the title compound in ~77% yield having HPLC purity of ~99.59%.

Example 13: Preparation of Form A of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (1 g), n-butanol (10 mL) and was refluxed for clear solution. The mixture was allowed to attain room temperature followed by addition of succinic acid (0.156 g). The mixture was stirred for ~2 hours at the same temperature and solid obtained was isolated by filtration, washed & dried to afford the title compound in ~79% yield having HPLC purity of ~99.72%.

Example 14: Preparation of Form A of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (1 g), 1,4-dioxane (10 mL) and was refluxed for clear solution. The mixture was allowed to attain room temperature followed by addition of succinic acid (0.156 g). The mixture was stirred for ~2 hours at the same temperature and solid obtained was isolated by filtration, washed & dried to afford the title compound in ~77% yield having HPLC purity of ~99.40%.

Example 15: Preparation of Form A of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (1 g), tert-butanol (10 mL) and was refluxed for clear solution. The mixture was allowed to attain room temperature followed by addition of succinic acid (0.156 g). The mixture was stirred for ~2 hours at the same temperature and solid obtained was isolated by filtration, washed & dried to afford the title compound in ~80% yield having HPLC purity of ~99.61%.

Example 16: Preparation of Form A of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (1 g), ethyl acetate (10 mL) and was refluxed for clear solution. The mixture was allowed to attain room temperature followed by addition of succinic acid (0.156 g). The mixture was stirred for ~2 hours at the same temperature and solid obtained was isolated by filtration, washed & dried to afford the title compound in ~76% yield having HPLC purity of ~99.79%, having D90 ~45microns and after micronization D90 ~15microns.

Example 17: Preparation of Form A of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan (1 g), methyl isobutyl ketone (10 mL) and was refluxed for clear solution. The mixture was allowed to attain room temperature followed by addition of succinic acid (0.156 g). The mixture was stirred for ~2 hours at the same temperature and solid obtained was isolated by filtration, washed & dried to afford the title compound in ~79% yield having HPLC purity of ~99.70%.

Example 18: Preparation of amorphous form of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan hemi-succinate (250 mg), methanol (0.5 mL), dichloromethane (4.5 mL) and stirred for clear solution. The mixture was filtered and filtrate was subjected to complete distillation under vacuum at ~45oC to afford title compound as off white solid having HPLC purity > 99%.

Example 19: Preparation of amorphous form of Lasmiditan hemi-succinate
A flask was charged with Lasmiditan hemi-succinate (250 mg), water (50 mL) and stirred for clear solution. The mixture was filtered and filtrate was subjected to freezing in dry ice acetone bath (-78oC) for ~1 hour. The frozen solution was lyophilized to afford the title compound as off white solid having HPLC purity >99%.

Example 20: Preparation of a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and PVP K-30
A flask was charged with Lasmiditan hemi-succinate (250 mg), PVP K-30 (250 mg), methanol (1 mL) and dichloromethane (9 mL) and stirred for clear solution. The mixture was filtered and the filtrate was subjected to complete distillation under reduced pressure at ~45oC. The solid obtained was dried under vacuum at ~45°C to afford the title compound.

Example 21: Preparation of a solid dispersion comprising an amorphous form of Lasmiditan hemisuccinate and hydroxypropyl cellulose
A flask was charged with Lasmiditan hemi-succinate (250 mg), hydroxypropyl cellulose (250 mg), methanol (10 mL) and dichloromethane (40 mL) and stirred for clear solution. The mixture was filtered and the filtrate was subjected to complete distillation under reduced pressure at ~45oC. The solid obtained was dried under vacuum at ~45°C to afford the title compound.

Example 22: Preparation of a solid dispersion comprising an amorphous form of Lasmiditan hemisuccinate and hydroxypropyl methylcellulose
A flask was charged with Lasmiditan hemi-succinate (250 mg), hydroxypropyl methylcellulose (250 mg), methanol (10 mL) and dichloromethane (40 mL) and stirred for clear solution. The mixture was filtered and the filtrate was subjected to complete distillation under reduced pressure at ~45oC. The solid obtained was dried under vacuum at ~45°C to afford the title compound.

Example 23: Preparation of a solid dispersion comprising an amorphous form of Lasmiditan hemisuccinate and Co-povidone
A flask was charged with Lasmiditan hemi-succinate (250 mg), co-povidone (250 mg), methanol (1 mL) and dichloromethane (9 mL) and stirred for clear solution. The mixture was filtered and the filtrate was subjected to complete distillation under reduced pressure at ~45oC. The solid obtained was dried under vacuum at ~45°C to afford the title compound.

Example 24: Preparation of Lasmiditan
A flask was charged with Lasmiditan hemisuccinate (2 g). Then pH was adjusted up to ~12 followed by stirring for 20 mins at room temperature. After completion of reaction, the reaction mixture was extracted with dichloromethane (~100 mL). The organic layer was separated and washed with brine solution (10 mL), then subjected to complete distillation under vacuum at ~45oC pressure to afford the crude compound which was purified by column chromatography using methanol:dichloromethane (~6%) as eluents. The pure fractions were combined and evaporated under reduced pressure to afford titled compound as off white solid in ~70% yield having HPLC purity of ~99.5%.

,CLAIMS:We Claim:

Claim 1: A solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers.

Claim 2: A solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by any of the Figures 1-4.

Claim 3: A process for preparing a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of Lasmiditan hemi-succinate and pharmaceutically acceptable carrier in suitable solvent(s),
b) isolating a solid dispersion comprising an amorphous form of Lasmiditan hemi-succinate and one or more pharmaceutically acceptable carrier.

Claim 4: A method for preparing a solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers comprising the steps of:
a) physically blending Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers;
b) isolating solid dispersion comprising amorphous Lasmiditan hemi-succinate and one or more pharmaceutically acceptable polymers.

Claim 5: A process for preparation of amorphous Lasmiditan hemi-succinate, which comprises;
a) providing a solution of Lasmiditan hemi-succinate in suitable solvent(s),
b) isolating an amorphous form of Lasmiditan hemi-succinate.

Caim 6: A process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) methylation of piperidine-carboxylic acid or its salts under suitable reaction conditions to afford a compound of Formula II,

b) converting the compound of Formula II to a compound of Formula III, under suitable reaction conditions,

R1 and R2 can be same or different and are selected from C1-C4 alkyl, aryl, substituted aryl etc.
c) reacting the compound of Formula III with 2,6-dibromopyridine to afford a compound of Formula IV or its salts,

d) converting the compound of Formula IV or its salts to a compound of Formula V or its salts,

e) reacting the compound of Formula V or its salts with activated 2,4,6-triflurobenzoic acid under suitable reaction conditions to afford a compound of Formula I,

f) reacting the compound of Formula I with succinic acid in suitable solvent to afford Lasmiditan hemi-succinate of Formula Ia.

Claim 6: A process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) converting 2,4,6-triflurobenzoic acid to a compound of Formula VI under suitable reaction conditions,

b) reacting the compound of Formula VI with a compound of Formula IV under suitable reaction conditions to afford compound of Formula I or its salts.

c) reacting the compound of Formula I with a pharmaceutically acceptable acid, optionally with succinic acid in suitable solvent to afford Lasmiditan hemi-succinate of Formula Ia.

Claim 7: A process for preparation of Lasmiditan and its pharmaceutically acceptable salts, comprising
a) methylation of piperidine-carboxylic acid or its salts without using metal catalyst under suitable reaction conditions to afford a compound of Formula II,

b) converting the compound of Formula II to a compound of Formula III, under suitable reaction conditions,

R1 and R2 can be same or different and are selected from C1-C4 alkyl, aryl, substituted aryl etc.

Claim 8: An improved process for preparation of crystalline Form A of Lasmiditan hemi-succinate, comprising;
a) providing a solution of Lasmiditan hemi-succinate in suitable solvents selected from methanol, C3-C5 alcohols, ketones, ethers, cyclic ethers, esters, nitriles and mixtures thereof,
b) crystallizing Form A of Lasmiditan hemi-succinate under suitable conditions; and
c) isolating crystalline Form A of Lasmiditan hemi-succinate.