FIELD OF THE INVENTION
The present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, with high purity
.

Present invention further provides a novel compound of Formula IV or its salt and use of said compound in preparation of lasmiditan and pharmaceutically acceptable salt thereof,
.

BACKGROUND OF THE INVENTION
Lasmiditan is a 5-HT1F agonist, chemically known as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-yl carbonyl)-pyridin-2-yl]-benzamide, and is represented by compound of Formula I
.

US 7,423,050 B2 (US’050) discloses the preparation of lasmiditan and salts thereof, specifically hydrochloride & hemisuccinate as mentioned in the Scheme 1 & Scheme 2 below:

Scheme 1:
.

Scheme 2:

US’050 further discloses a method for the preparation of hydrochloride salt and hemisuccinate salt of Lasmiditan using acetone as crystallization solvent.

US 8,697,876 B2 (US’876) discloses a method for preparation of lasmiditan and salts thereof as mentioned in the Scheme 3 below:

Scheme 3:

US’876 further discloses an anhydrous solid crystalline form (Form A) of lasmiditan hemisuccinate wherein said Form A is obtained by crystallization with ethanol. US’876 describes two additional XRPD patterns designated Form B and Form C of lasmiditan hemisuccinate as well as amorphous form of lasmiditan free base and hemisuccinate salt.

Although there are some processes known in the literature for preparation of lasmiditan and its intermediate(s), there is a need to develop a process that is high yielding, reproducible and economical at large scale production.

Based on aforesaid, the present invention provides a novel process for the preparation of lasmiditan & its pharmaceutically acceptable salts which is simple, reproducible and well suited on commercial scale.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof wherein said process is high yielding, simple and cost effective at large scale production.

Another object of the present invention is to develop an improved process for preparing lasmiditan wherein said process involves use of novel intermediates of Formula IV.

SUMMARY OF THE INVENTION
In main aspect, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent,
,
wherein X is a leaving group; and
b) optionally converting compound of Formula I to its salt(s).

In another aspect, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula VI with compound of Formula VII in a suitable solvent to give compound of Formula IV,
,
wherein, X and Y are independently selected from any leaving group;
b) optionally converting compound of Formula IV to its salts; and
c) converting compound of Formula IV or its salt to lasmiditan or salt thereof.

In another aspect, the present invention provides a process for the preparation of lasmiditan salt comprising the steps of;
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent to give lasmiditan of Formula I, wherein said lasmiditan is optionally isolated;
;
b) adding suitable acid to give a salt of lasmiditan of Formula I; and
c) isolating the salt of lasmiditan of Formula I.

In another aspect, the present invention provides compounds of Formula IV or salt thereof,

wherein X is a leaving group.

DETAILED DESCRIPTION
The term "about" as used in the context of the present invention, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value.

The term “substantially free” or “substantially pure” used in the context of the present invention means lifitegrast having each impurity less than about 0.2% by area percentage of HPLC. In particular, less than about 0.15% by area percentage of HPLC. More particular, not in detectable amount by area percentage of HPLC.

As used herein, the term “solution” or “reaction mixture” does not limit to a clear solution only and includes any hazy or opaque mass obtained.

“Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like.

The term “suitable solvent” as used in the context of the present invention is selected from, but not limited to, methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, glycols, toluene, acetonitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), methyl tetrahydrofuran, dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dicholoromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, hexane, n-heptane, cyclohexane, petroleum benzine, water and mixture thereof.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

In one embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent,

,
wherein, X is a leaving group; and
b) optionally converting compound of Formula I to its pharmaceutically acceptable salt(s).

In another embodiment, the said leaving group represents compounds that can easily be replaced by other groups during condensation reaction.

In another embodiment, the present invention provides an improved process for the preparation of lasmiditan of Formula I or its pharmaceutically acceptable salt, wherein said process comprises reaction of compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V without isolating the compound of Formula IV or its salt from the reaction mass.

In another embodiment, the present invention provides an improved process for the preparation of lasmiditan of Formula I or its pharmaceutically acceptable salt, wherein said process comprises isolation and purification of compound of Formula IV before proceeding with conversion to lasmiditan of Formula I or its salt.

In another embodiment, the suitable solvent used for condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V is selected from, but not limited to, methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, glycols, toluene, acetonitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), methyl tetrahydrofuran, dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dicholoromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, water and mixture thereof.

In another embodiment, compound of Formula IV can be taken as free base or salt wherein said salt is selected from, but not limited to, succinic acid salt, tartaric acid salt, oxalic acid salt, phosphoric acid salt, acetic acid salt, hydrochloric acid salt, hydrobromic acid salt, and the like.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula VI with compound of Formula VII in a suitable solvent to give compound of Formula IV,
,
wherein, X and Y are independently selected from any leaving group;
b) optionally converting compound of Formula IV to its salts; and
c) converting compound of Formula IV or its salt to lasmiditan or pharmaceutically acceptable salt thereof.

In another embodiment, groups X and Y in compounds of Formula VI and VII respectively, represents leaving group which are easily replaceable.

In another embodiment, the compound of Formula IV or its salt is prepared by condensing compound of Formula VI with compound of Formula VIII with or without isolation of intermediate of Formula XV as represented in the Scheme 4 below:
Scheme 4:
.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof by using compound of Formula IV or its salt wherein said compound of Formula IV is prepared by a process comprising the steps of:
a) converting 1-methylpiperidine-4-carboxylic acid of Formula IX to give compound of Formula X,
,
wherein, R is a straight or branched chain alkyl group;
b) reacting the compound of Formula X with compound of Formula XI to give compound of Formula IV,
,
wherein R and X are as defined above, Z is independently selected from any leaving group; and
c) optionally converting compound of Formula IV to its salts.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof by using compound of Formula IV or its salt wherein said compound of Formula IV is prepared by a process comprising the steps of:
a) reacting N-methoxy-N,1-dimethylpiperidine-4-carboxamide of Formula XII with compound of Formula XIII to give compound of Formula IV,
,
wherein X is as defined above; and
b) optionally converting compound of Formula IV to its salts.

In another embodiment, the present invention provides an improved process for the preparation of lasmiditan of Formula I or salt thereof, as represented in the scheme 5 below:

Scheme 5:
.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or salt thereof, comprising the steps of;
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent to form a reaction mixture,
;
b) optionally isolating lasmiditan from the reaction mixture of step (a) to get a solid mass;
c) adding acid either to the reaction mixture of step (a) or solid mass of step (b) in a suitable solvent to form acid addition salt of lasmiditan;
d) treating the acid addition salt of lasmiditan with base and isolating to get pure lasmiditan of Formula I; and
e) optionally converting the lasmiditan of Formula I to its salt.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or salt thereof, comprising the steps of;
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent to form a reaction mixture,
;
b) isolating lasmiditan from the reaction mixture of step (a) to get a solid mass;
c) purifying the solid mass in a suitable solvent to get pure lasmiditan of Formula I; and
d) optionally converting the lasmiditan of Formula I to its salt.

In another embodiment, the present invention provides a process for the preparation of lasmiditan salt comprising the steps of;
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent to give lasmiditan of Formula I, wherein said lasmiditan is optionally isolated;
;
b) adding suitable acid to give a salt of lasmiditan of Formula I; and
c) isolating the salt of lasmiditan of Formula I.

In another embodiment, the acid used for preparing salt of lasmiditan is selected from, but not limited to, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, oxalic acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, and p-toluenesulfonic acid.

In another embodiment, the present invention provides a substantially pure lasmiditan free base wherein said lasmiditan is purified either by acid base treatment or by any conventional method.

In another embodiment, the suitable solvent used for purification of lasmiditan free base or salt thereof, or used for preparation of lasmiditan salt(s) are selected from, but not limited to, alcohol such 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, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

In another embodiment, the present invention further provides a substantially pure crystalline form of Lasmiditan free base.

In another embodiment, the present invention provides substantially pure lasmiditan and its salt wherein said lasmiditan and its salts are substantially free from compound of Formula IV and its salts,

wherein X is a leaving group.

In another embodiment, the present invention provides substantially pure lasmiditan and its pharmaceutically acceptable salt wherein said lasmiditan and its salts are substantially free from compound of Formula XIV and its salts;
.

In another embodiment, the present invention provides pure lasmiditan and its pharmaceutically acceptable salt, substantially free from impurities wherein each impurity is less than about 0.3% w/w, and wherein total impurity is less than about 1.0% w/w.

In another embodiment, the present invention provides pure lasmiditan and its pharmaceutically acceptable salt, substantially free from impurities wherein said lasmiditan and its salt is characterized by purity of 99.0% and above.

In another preferred embodiment, the lasmiditan or its pharmaceutically acceptable salt prepared as per the process of the present invention is characterized by the particle size distribution wherein, d90 is between 0.1µm to 200µm.

In still another embodiment, the present invention provides a pharmaceutical composition comprising of lasmiditan or its salt along with at least one pharmaceutical acceptable excipient thereof, wherein said lasmiditan or its salt is prepared as per the process of the present invention.

EXAMPLES
Example 1: Preparation of 1-Methylpiperidine-4-carboxylic acid Hydrochloride, Formula IXa
To a stirred solution of Isonipecotic acid (50 g, 0.38mol) in formic acid (105.0 ml) at ambient temperature was added 67.5 ml of 37.0% formaldehyde solution dropwise over 30.0 min. The reaction mixture was stirred under reflux and evaporated the solvent under vacuum to give a syrup. The syrup was dissolved in conc. HCl (25.0 ml) and distilled out the solvent under vacuum to give a semisolid. The semisolid was dissolved in acetone, filtered and washed with acetone to give 1-methylpiperidine-4-carboxylic acid hydrochloride (66.0g, 95% yield).

Example 2: Preparation of N,N-Diethyl-1-methylpiperidine-4-carboxamide, Formula X (R=Et)
To a stirred solution of 1-methylpiperidine-4-carboxylic acid (30g, 0.209mol) in dichloromethane (450.0 ml) at ambient temperature was added DMF (3.16 ml, 0.041mol). The reaction mixture was cooled over ice bath to 10°C, and added 24.1 ml of oxalyl chloride. After completion of addition the temperature was allowed to rise to 40°C for 2.0 hrs. The solution was cooled over ice bath at 0°C and a solution of triethyl amine (47.5 ml), and 2M Diethyl amine (153.36 ml) was added. The reaction mixture gradually allowed to come to ambient temperature and stirring was continued for 10.0 hrs. To the reaction mixture was added 250.0 ml of DM-water, basified and separated the layer×3. The combined organic layer were dried over sodium sulfate and evaporated to give N,N,1-trimethylpiperidine-4-carboxamide (32.0g, 96.0% yield).

Example 3: Preparation of (6-Bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone Hydrobromide, Formula IVb
Charged 2,6-dibromopyridine (10 g, 0.0423 mol) to a reaction vessel followed by addition of tetrahydrofuran (100.0ml) at 25°C. Charged iPrMgCl/LiCl (1.3 M) in THF (32.5 ml, 0.0423) while maintaining the temperature at 18 to 25° C. Added N,N-Diethyl-1-methylpiperidine-4-carboxamide (8.3g, 0.0425mol) to the former reaction mixture at 18 to 25°C. Added ammonium chloride solution (100.0ml) while maintaining the temperature at 18 to 25°C. Adjusted the pH of the biphasic layer to 7.6 to 7.9 with HCl at 18 to 25°C and stirred for 20 to 40 minutes. Allowed to settle for at least 60 minutes and removed the lower aqueous phase. Charged tetrahydrofuran (50.0 ml) to the aqueous phase at 18 to 25°C, combined the organic layer and added heptane (50.0ml) to the mixture at 18 to 25°C. Charged conc. HCl to the mixture until a pH 1.0 to 1.5 is reached. Separated the organic layer and concentrated the combined organic phases under vacuum at 20 to 30°C to give crude product (8.9g). Charged isopropyl alcohol in above crude product and added HBr (5.5 ml), filtered the solid and dried under vacuum to give desired compound (13.5g, 90.0% yield).

Example 4: Preparation of (6-Bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone Hydrobromide, Formula IVa
Charged 2,6-dibromopyridine (10 g, 0.0423 mol) (Formula XI, X and Y=Br) to a reaction vessel followed by addition of tetrahydrofuran (100.0ml) at 25°C. Charged 1.3 M iPrMgCl/LiCl (32.5 ml, 0.0423) in THF maintaining the temperature at 18 to 25°C. Added N,N-Diethyl-1-methylpiperidine-4-carboxamide (8.3g, 0.0425mol) to former solution at 18 to 25°C. Added ammonium chloride solution (100.0ml) while maintaining the temperature at 18 to 25°C. Adjusted the pH of the biphasic layer to 7.6 to 7.9 with HCl at 18 to 25°C and stirred for 20 to 40 minutes. Allowed to settle for at least 60 minutes and removed the aqueous phase. Charged tetrahydrofuran (50.0 ml) to the aqueous phase at 18 to 25°C. Combined the organic layer and added heptane (50.0ml) to the mixture at 18 to 25°C. Charged conc. HCl to the mixture until a pH 1.0 to 1.5 is reached. Separated the organic layer and concentrated the combined organic phases under vacuum at 20 to 30°C to give 8.9g of desired product with purity 99.6% by HPLC.

Example 5: Preparation of 6-chloro-(2-(1-methylpiperidin-4-ylcarbonyl)-pyridine, Formula IVc (X=Cl)
Charged 2,6-dichloropyridine (10 g, 0.068 mol) (Formula XI, X and Y=Cl) to a reaction vessel followed by addition of tetrahydrofuran (100.0ml) at 25°C. Charged 1.3 M iPrMgCl/LiCl (7.58 ml, 0.068) in THF maintaining the temperature at 18 to 25°C. Added N,N-Diethyl-1-methylpiperidine-4-carboxamide (8.3g, 0.0425mol) to former at 18 to 25°C. Added ammonium chloride solution (100.0ml) at 18 to 25°C and adjusted the pH of the biphasic layer to 7.6 to 7.9 with HCl at 18 to 25°C and stirred for 20 to 40 minutes. Allowed to settle for at least 60 minutes and removed the lower aqueous phase retaining any interfacial material in the aqueous phase. Charged tetrahydrofuran (50.0 ml) to the aqueous phase at 18 to 25°C. Combined the organic layer and added heptane (50.0ml) to the mixture at 18 to 25°C. Charged conc. HCl to the mixture until a pH 1.0 to 1.5 is reached. Separated the organic layer and concentrated the combined organic phases under vacuum at 20 to 30°C to give 8.1g of desired product (Yield: 81.0%, Purity: 99.56%).

Example 6: Preparation of 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide Free base, Formula I
To the mixture of potassium carbonate (8.0g, 0.0585 mol), 2,4,6-trifluorobenzamide (4.09g, 0.0234mol) and (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (5.5 g 0.0195) in dioxane (80.0 ml) and admixed at 80°C with a suspension of 0.436 g of palladium(II) acetate (0.1 mol %) and (0.200 g, 0.00047 mol) of 1,3-bis(diphenylphosphino)propane (2.5 mol %). The mixture was subsequently refluxed and the conversion was monitored by HPLC. After boiling overnight, the conversion was >98%. The work-up was carried out by addition of water to dissolve the precipitated salts, followed by addition of toluene. Separated the layers and evaporated the organic layer to get crude compound. Purified the product by chromatography to give 5.0 g (89.5%) of desired product with purity of 99.9% by HPLC.

Example 7: Preparation of 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide Hydrochloride, Formula II
To dissolved 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide (5.0g, 0.01326 mol) in isopropanol (50.0ml) at ambient temperature and added a solution of 3.3 M diethyl ether/HCl (8.0ml). The reaction mixture was stirred for 30.0 minutes under reflux. Cooled the reaction mixture up to room temperature and stirred for 2.0 hrs, filtered the resulting white solid and washed with isopropanol (5.0 ml). Dried the residual solid under reduced pressure to give 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide hydrochloride salts (5.1g).

Example 8: Preparation of 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide Hydrochloride, Formula II
Charged (6-Chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrochloride of Formula IVb (X=Cl) to the vessel. Charged TBME and stirred at 15 to 25° C under nitrogen. Charged 8% w/w sodium hydroxide solution (5.0 vol, 970 mL) to the reactor vessel at 15 to 25° C. Stirred the resulting biphasic solution for 20 to 25 minutes at 15 to 25° C. Separated the layers and recharged the lower aqueous layer to the reaction vessel followed by TBME, stirred the resulting biphasic mixture for 20 to 25 minutes at 15 to 25° C. Separated the layers and combined the organic layers and concentrated to give a wet mass. Charged chlorobenzene to a separate reaction vessel. Charged 2,4,6-trifluorobenzamide, Formula V and added the solution to former wet mass and heated the reaction mixture to 60 to 65°C. Stirred the reaction at 98 to 102° C for 230-250 minutes. Cooled the reaction mixture to 15 to 25°C for 70 to 80 minutes at an approximately constant rate. Filtered the suspension to give 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide Hydrochloride, Formula II with purity of 99.9% by HPLC.

Example 9: Preparation of 2,4,6-Trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide hemisuccinate salt, Formula III
To dissolved 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide (1.62g, 0.00429 mol) in acetone (16.2 ml) at ambient temperature was added succinic acid (0.25g, 0.0021 mol) at ambient temperature. The reaction mixture was stirred for 30.0 minutes at reflux temperature. Cooled the reaction mixture up to room temperature and stirred for 2.0 hrs. Filtered off the resulting white solid and washed with acetone (5.0 ml). Dried the residual solid under reduced pressure to give 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide hemisuccinate salt (1.91g).

CLAIMS:WE CLAIM
1. A process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) condensing compound of Formula IV or its salt with 2,4,6-trifluorobenzamide of Formula V in a suitable solvent,
,
wherein X is a leaving group; and
b) optionally converting compound of Formula I to its salt(s).

2. The process as claimed in claim 1, wherein said process further comprising the steps of:
a) reacting compound of Formula VI with compound of Formula VII in a suitable solvent to give compound of Formula IV,
,
wherein, X and Y are independently selected from any leaving group;
b) optionally converting compound of Formula IV to its salts; and
c) converting compound of Formula IV or its salt to lasmiditan or salt thereof by a process as claimed in claim 1.

3. The process as claimed in claims 1 and 2, wherein said suitable solvent is selected from methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, glycols, toluene, acetonitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), methyl tetrahydrofuran, dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dicholoromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, water and mixture thereof.

4. Compounds of Formula IV or salt thereof,

wherein X is a leaving group.

5. The compound as claimed in claim 1, wherein said compound is prepared by a process comprising the steps of:
a) reacting compound of Formula VI with compound of Formula VII in a suitable solvent to give compound of Formula IV,
,
wherein, X and Y are independently selected from any leaving group; and
b) optionally converting compound of Formula IV to its salts.

6. The compound as claimed in claim 1, wherein said compound is prepared by a process comprising the steps of:
a) converting 1-methylpiperidine-4-carboxylic acid of Formula IX to give compound of Formula X,
,
wherein, R is a straight or branched chain alkyl group;
b) reacting the compound of Formula X with compound of Formula XI to give compound of Formula IV,
,
wherein R and X are as defined above, Z is independently selected from any leaving group; and
c) optionally converting compound of Formula IV to its salts.

7. The compound as claimed in claim 1, wherein said compound is prepared by a process comprising the steps of:
a) reacting N-methoxy-N,1-dimethylpiperidine-4-carboxamide of Formula XII with compound of Formula XIII to give compound of Formula IV,
,
wherein X is as defined above; and
b) optionally converting compound of Formula IV to its salts.

8. Substantially pure lasmiditan or its pharmaceutically acceptable salt wherein said lasmiditan or its salts are substantially free from compound of Formula IV and XIV;
, and
wherein X is as defined above.

9. The process as claimed in claim 1, wherein said lasmiditan or its pharmaceutically acceptable salt is isolated with purity of 99.0% and above.

10. Lasmiditan or its pharmaceutically acceptable salt prepared as per the process claimed in claim 1, wherein said lasmiditan or its salt is characterized by the particle size distribution wherein, d90 is between 0.1µm to 200µm