DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF LASMIDITAN”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of lasmiditan and salts thereof. The present invention also relates to a process for the preparation lasmiditan intermediates
BACKGROUND OF THE INVENTION
Lasmiditan is a 5-HT 1F agonist is a first-in-class neurally acting anti-migraine agent (NAAMA) in phase III clinical trials at CoLucid Pharmaceuticals for the treatment of acute migraine. The chemical name of lasmiditan is 2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula IIA wherein X is halogen, with a compound of formula III in the presence of Grignard reagent to obtain a compound of formula I; and

IIA III
b) optionally converting the compound of formula I to a salt of the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process as depicted in scheme I for the preparation of lasmiditan, a compound of formula I.
Scheme I
The term X is a halogen, selected from the group consisting of F, Cl, Br, I.
The term C1-C6 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl.
The term aryl includes phenyl, naphthyl and the like.
The term C1-C6 alkyl aryl includes benzyl, ethylphenyl and the like.
In one embodiment, the present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula IIA wherein X is halogen, with a compound of formula III to obtain a compound of formula I; and
b) optionally converting the compound of formula I to a salt of the compound of formula I.
In one embodiment, the present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula IIA wherein X is halogen, with a compound of formula III in the presence of a base to obtain a compound of formula I; and
b) optionally converting the compound of formula I to a salt of the compound of formula I.
In one embodiment, the base may be alkyl lithium or Grignard reagents.
In one embodiment, the alkyl lithium is butyl lithium.
In one embodiment the Grignard reagent is alkyl magnesium halide.
In one embodiment, an alkyl magnesium halide, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.
In one embodiment, an alkyl magnesium halide is isopropyl magnesium chloride.
In one embodiment, the present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula IIA wherein X is halogen, with a compound of formula III in the presence of Grignard reagent to obtain a compound of formula I; and
b) optionally converting the compound of formula I to a salt of the compound of formula I.
In one embodiment the Grignard reagent is alkyl magnesium halide.
In one embodiment, an alkyl magnesium halide, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.
In one embodiment, an alkyl magnesium halide is isopropyl magnesium chloride.
In one embodiment, the compound of formula IIA is prepared by the reaction of a compound of formula VA, wherein X is halogen, with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl.

VA IV
In one embodiment, the compound of formula IIA is prepared by the reaction of a compound of formula VA, wherein X is halogen, with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl, in the presence of an activating agent.
In one embodiment, the compound of formula IIA is prepared by the reaction of a compound of formula VA, wherein X is halogen, with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl, in the presence of a suitable coupling additives.
In one embodiment, the compound of formula IIA is prepared by the reaction of a compound of formula VA, wherein X is halogen, with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl, in the presence of a suitable activating agent and a suitable coupling additives.
In one embodiment, the activating agent may be selected from a group consisting of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC HCl), N, N'-Dicyclohexylcarbodiimide (DCC), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), 1- Benzotriazolol; 1-hydroxybenzotriazole (HOBt), 1,1'-Carbonyldiimidazole (CDI), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate(TBTU), O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU).
In one embodiment, the coupling additives may selected from the group consisting of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat), 4-Dimethylaminopyridine (DMAP).
In one embodiment, a compound of formula VA wherein X is halogen, is prepared by reacting compound of formula VIA with base.

VIA
In one embodiment, the base is an inorganic base.
In one embodiment base is ammonium hydroxide or ammonia.
In one embodiment base is ammonium hydroxide.
In one embodiment, the present invention provides a process as depicted in scheme II for the preparation of lasmiditan, a compound of formula I.
Scheme II
In one embodiment, the present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula II with a compound of formula III to obtain a compound of formula I; and

II III
b) optionally converting the compound of formula I to a salt of the compound of formula I.
In one embodiment, the present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula II with a compound of formula III in the presence of a base to obtain a compound of formula I; and
b) optionally converting the compound of formula I to a salt of the compound of formula I.
In one embodiment, the base may be alkyl lithium or Grignard reagents.
In one embodiment, the base is butyl lithium.
In one embodiment, the Grignard reagent is alkyl magnesium halide.
In one embodiment, an alkyl magnesium halide, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.
In one embodiment, an alkyl magnesium halide is isopropyl magnesium chloride.
In one embodiment, the present invention provides a process for the preparation of a compound of formula I or salt thereof comprising
a) reacting a compound of formula II with a compound of formula III in the presence of Grignard reagent to obtain a compound of formula I; and
b) optionally converting the compound of formula I to a salt of the compound of formula I.
In one embodiment the Grignard reagent is alkyl magnesium halide.
In one embodiment, an alkyl magnesium halide, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.
In one embodiment, an alkyl magnesium halide is isopropyl magnesium chloride.
In one embodiment, the compound of formula II is prepared by the reaction of a compound of formula V with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl.

V IV
In one embodiment, the compound of formula II is prepared by the reaction of a compound of formula V with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl, in the presence of an activating agent.
In one embodiment, the compound of formula II is prepared by the reaction of a compound of formula V with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl, in the presence of a suitable coupling additives.
In one embodiment, the compound of formula II is prepared by the reaction of a compound of formula V with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl, in the presence of a suitable activating agent and a suitable coupling additives.
In one embodiment, the activating agent may be selected from a group consisting of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC HCl), N, N'-Dicyclohexylcarbodiimide (DCC), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), 1- Benzotriazolol; 1-hydroxybenzotriazole (HOBt), 1,1'-Carbonyldiimidazole (CDI), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate(TBTU), O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU).
In one embodiment, the coupling additives may selected from the group consisting of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat), 4-Dimethylaminopyridine (DMAP).
In one embodiment, a compound of formula V is prepared by reacting compound of formula VI with base.

VI
In one embodiment, the base is inorganic base.
In one embodiment, the base is ammonium hydroxide or ammonia.
In one embodiment, the base is ammonium hydroxide.
In one embodiment, the compound of formula III is prepared by reacting 1-methylisonipecotic acid with N,O-dimethylhydroxylamine.
In one embodiment, the compound of formula III is prepared by reacting 1-methylisonipecotic acid with N,O-dimethylhydroxylamine in the presence of a base.
In one embodiment, the compound of formula III is prepared by reacting 1-methylisonipecotic acid with N,O-dimethylhydroxylamine in the presence of a chlorinating agent.
In one embodiment, the compound of formula III is prepared by reacting 1-methylisonipecotic acid with N,O-dimethylhydroxylamine in the presence of a base and a coupling additive.
In one embodiment, the compound of formula III is prepared by reacting 1-methylisonipecotic acid with N,O-dimethylhydroxylamine in the presence of a chlorinating agent and a coupling additive
In one embodiment, the base may be an organic amine.
In one embodiment, the organic amines may be selected from the group consisting of triethyl amine, isopropylethyl amine, diisopropylethyl amine.
In one embodiment, the coupling additive may be imidazole.
In one embodiment, the coupling additives may selected from a group consisting of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat), 4-Dimethylaminopyridine (DMAP).
In one embodiment, the chlorinating reagents may be selected from a group consisting of thionyl chloride, oxalyl chloride.
In one embodiment, the present invention provides a compound of formula II.

In one embodiment, the present invention provides a compound of formula IIA.

wherein X is halogen, selected from F, Cl, Br, I.
In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention may be converted to suitable acid addition salt.
In one embodiment, lasmiditan a compound of formula I is converted to lasmiditan hydrochloride, a compound of formula IA.

In one embodiment, lasmiditan hydrochloride, a compound of formula IA is prepared by reacting lasmiditan, a comp of formula I with hydrochloric acid.
In one embodiment, lasmiditan hydrochloride, a compound of formula IA is prepared by dissolving lasmiditan, a comp of formula I in a suitable solvent and treating the reaction mixture with hydrochloric acid.
In one embodiment, lasmiditan, a compound of formula I is converted to lasmiditan hemi succinate, a compound of formula IB.

In one embodiment, the lasmiditan hemi succinate, a compound of formula IB is prepared by reacting lasmiditan, a comp of formula I with succinic acid.
In one embodiment, lasmiditan hydrochloride, a compound of formula IA is prepared by dissolving lasmiditan, a comp of formula I in a suitable solvent and treating the reaction mixture with succinic acid.
In one embodiment, lasmiditan and salt thereof are purified by the purification methods known in the art.
In one embodiment, lasmiditan and salt thereof are purified by dissolving in a suitable solvent and recrystallizing.
In one embodiment, lasmiditan and salt thereof are purified by dissolving in a suitable solvent and adding an anti-solvent.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example-1: Synthesis of compound of formula V
2,6-Dibromopyridine is dissolved in ammonia and mixture is heated in autoclave at about 120°C to about 150°C till reaction complies. After completion of reaction, the reaction mass is allowed to cool and diluted with water. Product is extracted in dichloromethane which on evaporation gives compound of formula-V in crude stage. The crude compound of formula V is purified in mixture of ethyl acetate and hexane to obtain a white solid.

Example-2: Synthesis of compound of formula III
1-Methylisonipecotic acid, Diisopropylethylamine, 1-hydroxybenzotriazole and N,O-dimethylhydroxylamine hydrochloride are added in dimethylformamide and the reaction mixture is stirred for about 15 minutes. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) is then added to the reaction mixture and the reaction mass is stirred at ambient temperature to complete the reaction. The solvent is removed by vacuum distillation. Water is added to obtained residue and the pH of the reaction mixture is adjusted to 8. The obtained aqueous reaction mixture is extracted with dichloromethane and evaporated to get compound of formula III as an oil.

Example-3: Synthesis of compound of formula II
To a solution of 6-bromopyridine-2-amine in THF, triethyl amine is added and reaction mass is stirred for about 15 minutes. A solution of 2,4,6-trifluorobenzoyl chloride in THF is added to the reaction mass and stirred at ambient temperature to complete the reaction. The reaction mass is quenched with water and extracted in dichloromethane. The organic layer is washed with water and concentrated to get compound of formula-II

Example-4: Synthesis of compound of formula II
To a solution of 6-bromopyridine-2-amine and 2,4,6-trifluorobenzoic acid in dichloromethane is added 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC HCl), and 1-hydroxybenzotriazole and the reaction mass is stirred at about ambient temperature to complete the reaction. The reaction mass is quenched with water and organic layer is separated. The organic layer is washed with water and concentrated to get compound of formula-II

Example-5: Synthesis of compound of formula I
The compound of formula II is added to THF and the reaction mass is stirred. N-BuLi is added to the reaction mixture at about -78°C. The mixture is stirred for about 15 to about 30 minutes. The compound of formula-III is added to the reaction mass and the reaction mass is stirred at about -78°C to about -50°C for about 2h. The reaction mass is quenched with aqueous hydrochloric acid and extracted with dichloromethane. The extract is successively washed with water and brine, dried over MgSO4 and then concentrated in vacuum to get compound of formula-I.

Example-6: Synthesis of compound of formula I
Isopropyl magnesium chloride is dissolved in THF and stirred. The compound of fomula II is added dropwise to the reaction mass at about 5°C to about 10°C and the reaction is stirred for about 1h. The reaction mass is cooled to about 0°C to about 5°C and the compound of formula-III is added drop-wise to the reaction mass. The reaction mass is stirred at 5°C to about 10°C till reaction complies. The reaction is quenched with a solution of ammonium chloride in water and warmed to ambient temperature. The organic layer is concentrated under vacuum to obtain the compound of formula-I.

,CLAIMS:We Claim
1] A process for the preparation of lasmiditan, a compound of formula I or salt thereof, comprising:

I
a) reacting a compound of formula IIA wherein X is halogen, with a compound of formula III in the presence of a Grignard reagent to obtain lasmiditan, a compound of formula I; and

IIA III
b) optionally converting the compound of formula I to a salt of the compound of formula I
2] The process as claimed in claim 1, wherein in step a) the Grignard reagent is alkyl magnesium halide.
3] The process as claimed in claim 1, wherein the compound of formula IIA is prepared by the reaction of a compound of formula VA, wherein X is halogen, with a compound of formula IV, wherein R is selected from the group consisting of chloro, hydroxyl and OR1 wherein R1 is C1-C6 alkyl or C1-C6 alkylaryl,

VA IV
in the presence of an activating agent.
4] The process as claimed in claim 3, wherein an activating agent is selected from the group consisting of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDC HCl) and N, N'-Dicyclohexylcarbodiimide (DCC), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), 1- Benzotriazolol; 1-hydroxybenzotriazole (HOBt), 1,1'-Carbonyldiimidazole (CDI), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate(TBTU), O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU).
5] The process as claimed in claim 3, wherein the compound of formula VA is prepared by reacting compound of formula VIA wherein X is halogen, with a base.

VIA
6] The process as claimed in claim 5, wherein the base is an inorganic base.
7] A compound of formula IIA

IIA
wherein X is halogen.
8] The compound of formula IIA as claimed in claim 7 wherein X is Br

II
9] The process as claimed in claim 1, wherein in step b) the compound of formula I is reacted with an acid in the presence of a solvent.
10] The process as claimed in claim 1, wherein in step b) the salt is hydrochloride salt or hemisuccinate salt.

Dated this 31st day of July, 2019

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE S