The present invention provides an economic and industrially advantageous process for preparation of lasmiditan & pharmaceutically acceptable salt thereof, by using novel intermediates of Formula II, pharmaceutically acceptable salts and polymorphs thereof,
.
Present invention also relates to process for preparation of novel intermediates of Formula II, pharmaceutically acceptable salts and polymorphs thereof.

BACKGROUND OF THE INVENTION
Lasmiditan is a 5-HT1F agonist constituting a class of drugs, “ditans” and chemically known as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-yl carbonyl)-pyridin-2-yl]-benzamide, 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 below:

Scheme 1:
.

US’050 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:
.

Although there are several 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. Also, it is apparent from above disclosure, there are several polymorphs of lasmiditan known from the prior published applications. However, there is always a need for the development of a stable polymorph of lasmiditan and its pharmaceutically acceptable salts having high stability and can be easily formulated. Therefore, the present invention provides a 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 and its pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide novel compounds of Formula II wherein said compounds are used in the preparation of lasmiditan and pharmaceutical acceptable salts thereof.

Another object of the present invention is to provide a process for preparing novel polymorphs of lasmiditan and its pharmaceutically acceptable salts, and a composition comprising said polymorphs along with atleast one pharmaceutical acceptable excipients.

SUMMARY OF THE INVENTION
In main aspect, the present invention provides a process for the preparation of lasmiditan of Formula I or its pharmaceutically acceptable salts thereof by using compounds of Formula II, and/ or V or pharmaceutically acceptable salts, polymorphs thereof.

In another aspect, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salts thereof, comprising the steps of:
a) preparing (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI by treating compound of Formula V with metal azide in presence of suitable solvent,
,
wherein R5 is a suitable leaving group;
b) converting (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII in presence of suitable solvent,
;
c) protecting compound of Formula VII with suitable amine protecting group to give compound of Formula II;
,
wherein R3 is as defined above; and
d) converting compound of Formula II to lasmiditan of Formula I or its salts thereof.

In another aspect, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) deprotecting compound of Formula II to give (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII,
,
wherein R3 is as defined above;
b) optionally isolating compound of Formula VII;
c) reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with compound of Formula VIII to give lasmiditan,

wherein,
A is selected from halogens, hydroxy, alkoxy, aryloxy, tosylate, and mesylate; and
d) optionally converting lasmiditan to its pharmaceutically acceptable salt.

In another aspect, the present invention provides compounds of Formula II, salts and polymorphs thereof,

wherein R3 is an amine protecting group.

In another aspect, the present invention provides substantially pure lasmiditan free base or salt thereof, wherein said lasmiditan free base or its salt is substantially free from impurities.

In another aspect, the present invention provides substantially pure lasmiditan free base or salt thereof, substantially free from impurities wherein each impurity is less than about 0.3% w/w.

In another aspect, the present invention provides a process for the preparation of lasmiditan hydrochloride salt, comprising the steps of:
a) adding lasmiditan of Formula I or salt thereof in suitable solvent to get a reaction mixture;
b) optionally adding base to the reaction mixture of step a);
c) adding hydrochloric acid either to the reaction mixture of step a) or b) to obtain hydrochloride salt of lamiditan of Formula Ia,
; and
d) isolating the hydrochloride salt of lamiditan compound of Formula Ia.

In another aspect, the present invention provides a process for the preparation of lasmiditan hemisuccinate salt, comprising the steps of:
a) adding lasmiditan of Formula I or salt thereof in suitable solvent to get a reaction mixture;
b) optionally adding suitable base to the reaction mixture of step a);
c) adding succinic acid to reaction mixture of step a) or b) to obtain succinate salt of lamiditan of Formula Ib,
; and
d) isolating the succinate salt of lamiditan of Formula Ib.

In another aspect, the present invention provides a process for the preparation of lasmiditan of Formula I and salts thereof, wherein said process comprising the steps of:
a) reacting compound of Formula V with amine source in presence of aprotic solvent to give compound of Formula II,
,
wherein R5 and R3 are as defined above; and
b) reacting compound of Formula II with compound of Formula VIII and isolating lasmiditan of Formula I, wherein compound of Formula II is optionally not isolated,

wherein A is as defined above.

In another aspect, the present invention provides a process for the preparation of lasmiditan of Formula I and salts thereof, wherein said process comprising the steps of:
a) reacting compound of Formula V with amine source to give compound of Formula VII,
;
b) optionally protecting compound of Formula VII to give compound of Formula II; and
c) reacting compound of Formula VII or II with compound of Formula VIII and isolating lasmiditan of Formula I, wherein compound of Formula VII is optionally not isolated,

wherein A is as defined above.

DETAILED DESCRIPTION
The term “substantially free” or “substantially pure” used in the context of the present invention means lasmiditan 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.

“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, 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; pharmaceutically acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium or zinc salts, ammonium salts; and the like.

In context of the present invention, the term “suitable solvent” or “solvent” provides solvents that are used for preparing lasmiditan and its intermediates and are selected from the group comprising of, but not limited to, C1-C6 alcohols, C1-C8 hydrocarbons, halogenated hydrocarbons, ethers, C3-C8 ketones, esters, nitriles, sulphonamides, acetamides, pyrrolidines, formamides, water and mixture thereof. For Example, some of the suitable solvents comprises of methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, pentanol, glycols, toluene, chlorobenzene, 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.

Accordingly, in main embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or its pharmaceutically acceptable salts thereof.

In one embodiment, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) preparing (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI by treating compound of Formula V with metal azide in presence of suitable solvent,
,
wherein R5 is a suitable leaving group;
b) converting (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII in presence of suitable solvent,
; and
c) optionally protecting compound of Formula VII with suitable amine protecting group to give compound of Formula II;
,
wherein R3 is as defined above; and
d) converting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or N-protected compound of Formula II to lasmiditan of Formula I or its salts thereof.

In another embodiment, the present invention provides process for the preparation of lasmiditan wherein said process comprises reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl)methanone of Formula VII with compound of Formula VIII
,
wherein, A is selected from halogen, hydroxy, alkoxy, aryloxy, tosylate, and mesylate.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) deprotecting compound of Formula II to give (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII,
,
wherein R3 is as defined above;
b) optionally isolating compound of Formula VII;
c) reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with compound of Formula VIII to give lasmiditan,

wherein, A is selected from halogen, hydroxy, alkoxy, aryloxy, tosylate, and mesylate; and
d) optionally converting lasmiditan to its pharmaceutically acceptable salt.

In another embodiment, the preparation of lasmiditan may be carried out in one pot without isolation of intermediates.

In another embodiment, the present invention provides compounds of Formula II, pharmaceutically acceptable salts and polymorphs thereof,

wherein R3 is an amine protecting group and R5 is a suitable leaving group.

In another embodiment, the said amine protecting group in compound of Formula II, represents a suitable moiety that protect amine group from taking part in the reaction. The said amine protecting groups are selected from any carbon containing moiety, silyl containing moiety or sulphur containing moiety.

In another embodiment, the present invention further provides compound of Formula II or its pharmaceutically acceptable salt wherein said compound of Formula II or salt can be isolated in amorphous form.

In another embodiment, the present invention further provides compound of Formula II or its pharmaceutically acceptable salt wherein said compound of Formula II or salt can be isolated in crystalline form.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I and salts thereof, wherein said process comprising the steps of:
a) reacting compound of Formula V with amine source in presence of aprotic solvent to give compound of Formula II,
,
wherein R5 and R3 are as defined above; and
b) reacting compound of Formula II with compound of Formula VIII and isolating lasmiditan of Formula I, wherein compound of Formula II is optionally not isolated,

wherein A is as defined above.

In another aspect, the present invention provides a process for the preparation of lasmiditan of Formula I and salts thereof, wherein said process comprising the steps of:
a) reacting compound of Formula V with amine source to give compound of Formula VII,
;
b) optionally protecting compound of Formula VII to give compound of Formula II; and
c) reacting compound of Formula VII or II with compound of Formula VIII and isolating lasmiditan of Formula I, wherein compound of Formula VII is optionally not isolated,

wherein A is as defined above.

In a specific embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I and salts thereof, wherein said process comprising the steps of:
a) reacting compound of Formula Va with amine source to give compound of Formula VII,

b) optionally isolating compound of Formula VII;
c) reacting compound of Formula VII with compound of Formula VIIIa and isolating lasmiditan of Formula I,
;and
d) optionally converting lasmiditan to its pharmaceutically acceptable salt.

In another embodiment, the present invention provides substantially pure lasmiditan free base or salt thereof, wherein said lasmiditan free base or its salt is substantially free from impurities.

In another embodiment, the present invention provides substantially pure lasmiditan free base or salt thereof, substantially free from impurities wherein each impurity is less than about 0.3% w/w.

In another embodiment, the present invention provides substantially pure lasmiditan free base or salt thereof, substantially free from impurities of Formula A-K, wherein each impurity is less than about 0.3% w/w,
, ,
, ,
, , ,
, , and
.

In another embodiment, the present invention provides substantially pure lasmiditan free base or salt thereof, substantially free from compound of Formula II, wherein the total purity of lasmiditan and its salts is about 99.0% and more.

In another embodiment, the present invention provides a process for the preparation of lasmiditan hemisuccinate salt, comprising the steps of:
a) adding lasmiditan of Formula I or salt thereof in suitable solvent to get a reaction mixture;
b) optionally adding suitable base to the reaction mixture of step a);
c) adding succinic acid to reaction mixture of step a) or b) to obtain succinate salt of lamiditan of Formula Ib,
; and
d) isolating the succinate salt of lamiditan of Formula Ib.

In another embodiment, the suitable solvent used for preparing salts of lasmiditan free base are selected from, but not limited to, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, glycols, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl t-butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, propenyl acetate, butyl acetate, t-butyl acetate, petroleum benzine, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran; dioxane, acetonitrile, propionitrile, butanenitrile, diethyl ether, dioxane, tetrahydrofuran, methyl tetrahydrofuran, dipropyl ether, ethyl methyl ether, dialkyl ether, water, and mixture thereof.

In another embodiment, the suitable base used during preparation of lasmiditan and its pharmaceutically acceptable salt is selected from, but not limited to, organic and inorganic base selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates, bicarbonates; and organic base such as primary, secondary and tertiary amines; and mixture thereof.

In another embodiment, the present invention provides a process for the preparation of lasmiditan or salt thereof, comprising the steps of:
a) reacting 6-bromopyridin-2-amine of Formula IX with Boc-anhydride in the presence of suitable solvent to get tert-butyl (6-bromopyridin-2-yl)carbamate of Formula IVa;
b) reacting tert-butyl (6-bromopyridin-2-yl)carbamate of Formula IVa with N,N,1-trimethylpiperidine-4-carboxamide of Formula IIIa to get tert-butyl (6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)carbamate of Formula IIa, wherein said compound of Formula IVa is optionally not isolated;
c) reacting the compound of Formula IIa with 2,4,6-trifluorobenzoyl chloride of Formula VIIIa in presence of acid to get lasmiditan of Formula I, wherein said compound of Formula IIa is optionally not isolated;
d) isolating the lasmiditan of Formula I; and
e) optionally converting lasmiditan of Formula I to its salt.

In another embodiment, the lasmiditan or its salts are prepared as per the scheme 4 as mentioned below:
Scheme 4:

In another embodiment, the suitable reagent used for deprotecting amine group of compound of Formula II is selected from, but not limited to, acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, fuming acid and the like; base such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I and salts thereof, wherein said process comprising the steps of:
a1) reacting compound of Formula II with compound of Formula VIII and isolating protected lasmiditan of Formula XII, wherein compound of Formula XII is optionally not isolated,

wherein A is as defined above, and
a2) deprotecting compound of Formula XII to get lasmiditan of Formula I,
;
Or,
b1) deprotecting compound of Formula II to give compound of Formula VII,
, and
b2) converting compound of Formula VII to lasmiditan of Formula I.

In another embodiment, the isolation of lasmiditan and its intermediates from the reaction mixture may be done by using techniques such as extraction, direct filtration or by scraping, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or other techniques specific to the equipment used.

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 4-Methyl-isonipecotic acid hydrochloride:
Charged 210 ml of formic acid and 135 ml of formaldehyde to piperidine-4-carboxylic acid (100 g) at room temperature. Raised the temperature to 60-100°C. After completion of reaction, distilled out the reaction mass completely. Charged 100 ml of conc. HCl followed by cooling the reaction mass at room temperature and charged 200 ml of acetone at room temperature. Stirred and filtered the product and washed with acetone. Dried the solid so obtained to give desired compound.

EXAMPLE 2: Preparation of N,N’-Dimethyl-N-methylisonipecotamide:
Charged 100g of 4-Methyl-isonipecotic acid hydrochloride to 1 L of dichloromethane followed by slow addition of 95.4 g of oxalyl chloride (drop wise) at 5-10°C. Raised the temperature up to 40°C for 1-2 hours. After completion of reaction, cooled the reaction mass at 20-35°C. Distilled out dichloromethane under vacuum at 25-35°C. Charged 1200 ml of tetrahydrofuran at 20-25°C. Cooled to 0-10°C. Added a mixture of triethyl amine and dimethylamine THF solution (116 ml & 278 ml respectively) and maintained the reaction mass at room temperature for 1-2 hours. After reaction completion added 144 ml of 30% NaOH solution drop wise at 5-10°C. Added 160 ml of DM water to dissolve solid part in reaction mass at 20°C. Settled and separated the layer at 20-30°C. Extracted the aqueous layer with 2*300 ml of dichloromethane. Combined all organic layers, and distilled out completely under vacuum at 50°C.

EXAMPLE 3: Preparation of 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine:
In a clean and dry RBF, charged 700 ml of tetrahydrofuran under nitrogen atmosphere. Cooled to -80°C. Slowly added n-Butyl Lithium (2.5 M) 185.8 ml at -80°C. Stirred for 10-15 minutes. Slowly added 2,6-dibromopyridine (100 g solution in 400 ml THF) at -65 to -80°C. Maintained the reaction mass at this temperature for 1-2 hours. Added N,N’-Dimethyl-N-methylisonipecotamide in 400 ml THF drop wise in reaction mass at -65 to -80°C under nitrogen. After completion of reaction slowly raised the temperature up to room temperature and added 450 ml of saturated ammonium chloride solution. Adjusted the pH to 1-2 with conc. HCl solution at 20-30°C. Separated out the layer. Basified the aqueous layer with 30% NaOH solution and adjusted the pH 9-10 at RT. Extracted the reaction mass with 2*300 ml of dichloromethane. Distilled the organic layer under vacuum at 40-45°C.

EXAMPLE 4: Preparation of 2-Amino-6-(1-methylpiperidin-4ylcarbonyl)-pyridine:
In an autoclave, charged 100 g of 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine followed by addition of 20 ml Methanol. Charge 1.0 Lt. aqueous ammonia and 2.5 g copper (I) Oxide at 20-30°C. Raised the temperature up to 100-120°C. Maintained the reaction mass for 10-12 hours After completion of reaction, cooled the mass at 20-30°C. Extracted the reaction mass with 2*300 ml of MDC. Combined all the organic layers and concentrated under vacuum at 40-45°C completely. Added 120 ml of ethanol to 60 g freebase oil at 20-30°C. Slowly added 210 ml of ethanolic HCl at 20-30°C. Distilled out ethanol completely and charged 150 ml of isopropanol. Raised the temperature at 80°C under reflux for 30 minutes. Cooled to 20-30°C, filtered the product and washed with 60 ml of isopropanol. Dried the product under vacuum at 50°C. Added 132 ml of DM water at room temperature. Adjusted the pH to 11-12 with 30% NaOH solution. Extracted the aqueous layer with 2*200 ml of ethyl acetate at 20-30°C. Distilled out the organic layer completely under vacuum at 45-50°C.

EXAMPLE 5: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide (Lasmiditan) of Formula I:
Synthesis of 2,4,6-Triflorobenzoyl chloride: In a clean and dry RBF charged 100 g of 2,4,6-Trifluorobenzoic acid followed by 1.0 L of dichloromethane at room temperature. Slowly added 178.6 g of oxalyl chloride at room temperature. Raised the temperature at 30-35°C. Maintained for 1.0 hour and concentrated the organic layer under vacuum at 40°C. In a clean and dry RBF charged 100g of 2-Amino-6-(1-methylpiperidin-4ylcarbonyl)-pyridine followed by 1.0 L of anhydrous tetrahydrofuran and 110.8 g of triethyl amine at room temperaure under nitrogen atmosphere. Slowly added 133 g of 2,4,6-Triflorobenzoyl chloride at 20-30°C. Stirred for 1-2 hours under nitrogen at 20-30°C. After completion of reaction, added 220 ml of 30% NaOH solution and 150 ml of DM water at RT. Stirred for 2-4 hours. Extracted aqueous layer with 200 ml of ethyl acetate. Concentrated the organic layer to give desired compound (Yield: 82%, Purity: 99.96%).

EXAMPLE 6: Preparation of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone:
Stirred the magnesium turning (1.3g 0.0549mol) and 150.0 ml of THF at 50 °C for 1 hrs. The (15.0g 0.0549 mol) of tert-butyl (6-bromopyridin-2-yl)carbamate was dissolved in 15.0 ml of THF, added dropwise and stirred for 2.0 hrs. The (11.2g, 0.0659mol) N,N,1-trimethylpiperidine-4-carboxamide was dissolved in 15.0 ml of THF and added in to above reaction mixture. Quenched the reaction mixture with sat. NH4Cl solution, acidified with conc. HCl solution and stirred for 2.0 hrs at 50°C. The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic layer were dried over sodium sulfate and evaporated to give (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

EXAMPLE 7: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hydrochloride:
To the solution of 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide (5.0g , 01326 mol) in isopropanol (50.0ml) at ambient temperature and added a solution of 3.3 M diethyl ether/HCl (8.0 ml). 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 (Yield: 91%, purity: 99.95%).

EXAMPLE 8: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate salt:
To a solution of 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) was added succinic acid (0.25g, 0.0021 mol) at ambient temperature. 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 off the resulting white solid and washed with acetone (5.0 ml). Dried the residual solid under reduce pressure to give 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide hemisuccinate salts (yield: 89%, purity: 99.6%).

EXAMPLE 9: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide:
To a stirred solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (10g, 0.045mol) in dichloromethane (100.0 ml) at ambient temperature was added 8.37g of EDCl, 7.29g of HOBT and 7.92g (0.045 mol) of 2,4,6-trifluorobenzoic acid. The reaction mixture was stirred for 4.0 hrs at ambient temperature. To the reaction mixture was added 100.0 ml of DM-water and separated the layer×3. The combined organic layer were dried over sodium sulfate and evaporated the organic layer under reduced pressure to give 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide.

EXAMPLE 10: Preparation of (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone:
To a suspension of magnesium chips (1.8g, 0.0751mol) in THF (100.0ml) was added 1.2 ml of Red-Al (65% solution of sodium bis (2-methoxy) aluminium hydride in toluene). The reaction mixture was heated under reflux for 1.0 hrs and then cooled to ambient temperature. 4-chloro-1-methylpiperidine (10.0g, 0.0751mol) was added to the reaction mixture and heated to reflux for 1.0 hrs and then cooled to -5 to 0°C. A solution of 6-chloropyridine-2-carbonitrile (10.3g, 0.0751mol) was added dropwise at -5 to 0°C and stirred for 1.0 hrs. The reaction mixture was poured into conc. HCl and ice water. The Organic layer was separated out and aqueous layer was washed with THF. Organic layer was then combined and distilled under reduced pressure to give the desired product (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

EXAMPLE 11: Preparation of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone:
To a stirred solution of (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone (9.5g, 0.0402mol), benzophenone imine (8.75g, 0.048 mol), tris (dibenzylideneacetone) dipalladium(0) (0.66g, 0.00072mol), (±) racemic-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene(1.0g,0.00161mol) in toluene was added sodium t-butoxide (5.41g, 0.056mol) for 2 hour. Evaporated the solvent and re-dissolved in ethyl acetate followed by washing with water. Distilled out the solvent to give imine intermediate. Added 1N HCl into a solution of imine intermediate in THF and stirred at ambient temperature for 2 hrs. Basified the aqueous phase, extracted with dichloromethane, dried the organic layer and distilled to give (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

EXAMPLE 12: Preparation of (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone:
To a stirred solution of (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone (5.5g, 0.0231mol) in dimethyl formamide (44.0 ml) was added sodium azide (1.8g, 0.027mol) at ambient temperature. The reaction mixture was heated to 80-90°C for 5.0 hrs and then cooled to room temperature. Added DM water and extracted with dichloromethane, dried and distilled under vacuum to give (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone

EXAMPLE 13: Preparation of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone:
Stirred a solution of (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (5.0g), Zn powder (1.0g), acetic acid (30.0ml) and acetone (35.0ml) at 0-5°C for 2.0 hrs. The reaction mass was filtered and distilled out under vacuum. Basified the aqueous phase, extracted with dichloromethane, dried the organic layer and distilled out to give (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

CLAIMS:WE CLAIM

1. A process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) preparing (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI by treating compound of Formula V with metal azide in presence of suitable solvent,
,
wherein R5 is a suitable leaving group;
or,
reacting compound of Formula V with amine source in presence of aprotic solvent to give compound of Formula II,
,
wherein R5 is a suitable leaving group and R3 is an amine-protecting group;
b) converting (6-azidopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII in presence of suitable solvent,
;
c) protecting compound of Formula VII with suitable amine protecting group to give compound of Formula II;
,
wherein R3 is as defined above; and
d) converting compound of Formula II obtained from step a) or c) to lasmiditan of Formula I or its salts thereof.

2. The process as claimed in claim 1, wherein said process of conversion of compound of Formula II to lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) deprotecting compound of Formula II to give (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII,
,
wherein R3 is as defined above;
b) optionally isolating compound of Formula VII;
c) reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with compound of Formula VIII to give lasmiditan,

wherein,
A is selected from halogen, hydroxy, alkoxy, aryloxy, tosylate, and mesylate; and
d) optionally converting lasmiditan to its pharmaceutically acceptable salt.

3. The process as claimed in claim 1, wherein said process of conversion of compound of Formula II to lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula II with compound of Formula VIII and isolating protected lasmiditan of Formula XII, wherein compound of Formula XII is optionally not isolated,

wherein A is as defined above, and
b) deprotecting compound of Formula XII to get lasmiditan of Formula I,
.

4. The process as claimed in claims 1-3, wherein said process is optionally carried out in one pot without isolation of intermediates.

5. Compounds of Formula II, pharmaceutically acceptable salts and polymorphs thereof,

wherein R3 is an amine protecting group and R5 is a suitable leaving group.

6. Substantially pure lasmiditan free base or pharmaceutically acceptable salt thereof, substantially free from compound of Formula II, wherein the total purity of lasmiditan and its salts is about 99.0% and more.

7. A process for the preparation of lasmiditan hemisuccinate salt, comprising the steps of:
a) adding lasmiditan of Formula I or salt thereof in suitable solvent to get a reaction mixture;
b) optionally adding suitable base to the reaction mixture of step a);
c) adding succinic acid to reaction mixture of step a) or b) to obtain succinate salt of lamiditan of Formula Ib,
; and
d) isolating the succinate salt of lamiditan of Formula Ib.

8. The process as claimed in claims 7 and 8, wherein said suitable solvent is selected from methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, glycols, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl t-butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, propenyl acetate, butyl acetate, t-butyl acetate, petroleum benzine, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran; dioxane, acetonitrile, propionitrile, butanenitrile, diethyl ether, dioxane, tetrahydrofuran, methyl tetrahydrofuran, dipropyl ether, ethyl methyl ether, dialkyl ether, water, and mixture thereof.

9. Composition comprising lasmiditan or pharmaceutically acceptable salt along with atleast one pharmaceutically acceptable excipient wherein said lasmiditan or salt is prepared as per the process of any of the preceding claim.

10. The process as claimed in any of the preceding claim, wherein said lasmiditan or pharmaceutically acceptable salt is isolated with purity 99.0% and above.