WO2020095171A1

WO2020095171A1 - Process for preparation of lasmiditan

Info

Publication number: WO2020095171A1
Application number: PCT/IB2019/059438
Authority: WO
Inventors: Dinesh DEORE; Shekhar Bhaskar Bhirud; Prem Chand; Samir Naik; Santosh Badgujar; Deepak BAVISKAR
Original assignee: Glenmark Life Sciences Limited, Glenmark Pharmaceuticals Limited
Priority date: 2018-11-05
Filing date: 2019-11-04
Publication date: 2020-05-14

Abstract

The present invention relates to a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof, the process comprising reacting a compound of formula IX with N-methoxymethylamine or salt thereof to obtain a compound of formula VII; reacting the compound of formula VII with a compound of formula XIV to obtain lasmiditan or salts thereof.

Description

PROCESS FOR PREPARATION OF LASMIDITAN

PRIORITY

[0001] This application claims the benefit of Indian Provisional Application 201821041819 filed on November 5, 2018, entitled “PROCESS FOR THE PREPARATION OF LASMIDITAN”, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

[0002] 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.

Description of the Related Art

[0003] Lasmiditan, also known as 2,4,6-trifluoro-/V-[6-(l-methylpiperidine-4- carbonyl)pyridine -2-yl]benzamide, is represented by the structure of formula I.

[0004] Lasmiditan hemi succinate, compound of formula IB, is a serotonin (5-HT) 1F receptor agonist indicated for the acute treatment of migraine with or without aura in adults.

IB

SUMMARY OF THE INVENTION

[0005] The present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,

the process comprising: (a) reacting a compound of formula IX with l-methoxymethyl amine or salt thereof to obtain a compound of formula VII;

(b) reacting the compound of formula VII with a compound of formula XIV

wherein R is MgX, Li, ZnX, Sn(Ci-6 alkyl)-; X is selected from the group consisting of

Cl, Br, I, to obtain lasmiditan, the compound of formula I; and

(c) optionally, converting lasmiditan to a pharmaceutically acceptable salt.

[0006] In another embodiment, the present invention provides a compound selected from the following:

[0007] In another embodiment, the present invention provides use of a compound selected from the following

in the preparation of lasmiditan or pharmaceutically acceptable salt thereof.

[0008] In another embodiment, the present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,

the process comprising the step of reacting a compound of formula IX with N- methoxymethylamine or salt thereof to obtain a compound of formula VII,

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is a characteristic XRPD of lasmiditan hemisuccinate as obtained in example 30.

[0010] Figure 2 is a DSC thermogram of lasmiditan hemisuccinate as obtained in example 30.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,

the process comprising:

(a) reacting a compound of formula IX with l-methoxymethyl amine or salt thereof to obtain a compound of formula VII;

(b) reacting the compound of formula VII with a compound of formula XIV

wherein R is MgX, Li, ZnX, Sn(Ci-6 alkyl)-; X is selected from the group consisting of Cl, Br, I, to obtain lasmiditan, the compound of formula I; and

(c) optionally, converting lasmiditan to a pharmaceutically acceptable salt.

[0012] In the present application, the term“room temperature” means a temperature of about 25°C to about 30°C.

[0013] The term“Ci-6 alkyl” means alkyl groups having 1 to 6 carbon atoms and includes groups such as methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, /er/-butyl, «-pentyl. In (a) of the above process, the compound of formula IX is reacted with N- methoxymethylamine or salt thereof to obtain the compound of formula VII.

[0014] In one embodiment, the reaction of the compound of formula IX is reacted with l-methoxymethyl amine or salt thereof occurs in the presence of a coupling agent.

[0015] In one embodiment, the coupling agent may be selected from the group consisting of HATU ( 1 - [bi s(di methyl ami no)methylene]- l //- l ,2,3-triazolo[4,5-/ ]pyridinium 3-oxid hexafluorophosphate), EDCI ( A-(3 -di methyl a i nopropyl )-A"-ethyl carbodii mi de hydrochloride), HOBt (hydroxybenzotriazole), CDI (l, l'-carbonyldiimidazole), DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate), PyBOP (benzotriazol-l- yl-oxytripyrrolidinophosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazol-l- yloxy)tripyrrolidinophosphonium hexafluorophosphate), PyBroP (bromo-tris- pyrrolidino-phosphonium hexafluorophosphate), TBTU (O-(benzotriazol-l-yl)- A^f,A^f,A",A"-tetramethyluronium tetrafluorob orate), TATU ( ()-( 7-azabenzotri azol e- 1 -y 1 )- l,l,3,3-tetramethyluronium tetrafluoroborate), HCTU (2-(6-chl oro- 1 //-benzotri azol e- 1 - yl)-l, l,3,3-tetramethylaminium hexafluorophosphate), TsCl (p-toluenesulfonyl chloride), HBTU (A^f,A^f,A",A"-tetramethyl-(A-( l //-benzotriazol- 1 -yl)uronium hexafluorophosphate), COMU ((l-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate),

Oxyma (ethyl (hydroxyimino)cyanoacetate), PyBOP ((benzotriazol-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate), HOTT fV-fl -oxido-2-pyridyl)-

A^f,A^f,A",A"-tetramethylthiuronium hexafluorophosphate), FDPP (pentafluorophenyl diphenylphosphinate), T3P (propylphosphonic anhydride), DMTMM (4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluorob orate), PyOxim ([ethyl cyano(hydroxyi mi no)acetato-(A2]tri- l -pyrrol idinylphosphonium hexafluorophosphate),

TSTU ( A^f, A^f, A^f, A-tetram ethyl -(A-(A-succi ni mi dyl)uroni urn tetrafluoroborate), TDBTU

(0-( 3 ,4-dihydro-4-oxo- 1 ,2,3 -benzotriazin-3 -yl)-A^f,A(A" A"-tetram ethyl uronium tetrafluoroborate), TPTU (0-(2-oxo-l (2//)pyridyl)-A^f,A^f,A^f',A"-tetramethyluronium tetrafluoroborate), TOTU (t/-[(ethoxycarbonyl)cyanomethylenamino]-A^f,A^f,A^f',A"- tetramethyluronium tetrafluoroborate), IIDQ (isobutyl l,2-dihydro-2-isobutoxy-l- quinolinecarboxylate), PyCIU (chlorodipyrrolidinocarbenium hexafluorophosphate),

DIC (diisopropylcarbodiimide), TOTT (A^f,A^f,A^f',A"-tetramethyl-S-(l -oxido-2- pyridyl)thiouronium tetrafluoroborate), EEDQ (A -Ethoxy carbonyl-2-ethoxy-l ,2- dihydroquinoline), HDMC (A^f-[(5-Chloro-3-oxido-l //-benzotriazol-l -yl)-4- morphol i nyl methyl ene]-A-methylmethanaminium hexafluorophosphate), DEPBT (3-

(diethoxyphosphoryloxy)-l ,2,3-benzotriazin-4(3//)-one), PyOxim (ethyl cyano(hydroxyimino)acetato-0²]tri-l-pyrrolidinylphosphonium hexafluorophosphate),

HOOBt (hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine), HOSu (N- hydroxysuccinimide), HOAt (l-hydroxy-7-azabenzotriazole), TFFH

(tetramethylfluoroformamidinium hexafluorophosphate), and mixtures thereof.

[0016] In one embodiment, the reaction of the compound of formula IX is reacted with A-methoxymethyl amine or salt thereof occurs in the presence of a coupling agent, wherein the coupling agent is HATE1.

[0017] In one embodiment, the reaction of the compound of formula IX is reacted with A-methoxymethyl amine or salt thereof occurs in the presence of a base selected from organic base or inorganic base.

[0018] The organic base includes but is not limited to diisopropylethylamine, trimethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (l,4-diazabicyclo[2.2.2]octane), DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), A^f,A^f,AfA^f'-tetramethyl-l ,8- naphthalenediamine, oxyma (ethyl cyanohydroxyiminoacetate), or mixtures thereof.

[0019] The inorganic base includes but is not limited to lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or mixtures thereof.

[0020] In one embodiment, the reaction of the compound of formula IX is reacted with A-methoxymethyl amine or salt thereof occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6- trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4- diazabicyclo[2.2.2]octane), DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5- diazabicyclo[4.3.0]non-5-ene), A^f,A^f,A^f',A"-tetramethyl- l ,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0021] In one embodiment, the reaction of the compound of formula IX is reacted with A-methoxymethyl amine or salt thereof occurs in the presence of a base, wherein the base is triethylamine.

[0022] In one embodiment, the reaction of the compound of formula IX is reacted with A-methoxymethyl amine or salt thereof occurs in the presence of a solvent.

[0023] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof.

[0024] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, /cvV-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, «-propyl acetate, /cvv-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; and mixtures thereof. In (b) of the above process, the compound of formula VII is reacted with the compound of formula XIV.

[0025] In one embodiment, the compound of formula VII is reacted with the compound of formula XIV, wherein R is MgX and X is Cl.

[0026] In one embodiment, step (b) is carried out at a temperature of about -20°C to about 20°C.

[0027] In one embodiment, step (b) is carried out at a temperature of about -20°C to about l0°C.

In (c) of the above process, lasmiditan is converted to a pharmaceutically acceptable salt.

[0028] In one embodiment, lasmiditan is converted to lasmiditan hydrochloride.

[0029] In one embodiment, lasmiditan is converted to lasmiditan hemisuccinate.

[0030] In one embodiment, the compound of formula IX is prepared by a process comprising:

(x) hydrolyzing a compound of formula XA; or

(y) hydrogenating a compound of formula XA,

wherein Rl is Ci-6 alkyl, Ci-6 alkylaryl.

[0031] In one embodiment, hydrolysis of the compound of formula XA is carried out in the presence of an acid.

[0032] In one embodiment, the acid hydrolysis may be carried out by using hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid and the like.

[0033] In one embodiment, hydrolysis of the compound of formula XA is carried out in the presence of a base.

[0034] In one embodiment, the base hydrolysis may be carried out using sodium hydroxide, potassium hydroxide or lithium hydroxide or by using carbonates or bicarbonates of alkali metal or alkaline earth metals.

[0035] In one embodiment, hydrolysis of the compound of formula XA is carried out in the presence of a solvent selected from a group consisting of tetrahydrofuran, methanol, ethanol, propanol, isopropyl alcohol, butanol, tert-butanol.

[0036] In one embodiment, solvent is tetrahydrofuran. [0037] In one embodiment, hydrogenation of the compound of formula XA is carried out in the presence of a catalyst.

[0038] In one embodiment, the catalyst is selected from the group consisting of platinum, palladium, Raney nickel.

[0039] In one embodiment, the compound of formula XA is prepared by a process comprising reacting a compound of formula XIA with a compound of formula IV A,

wherein Rl is Ci-6 alkyl, Ci-6 alkylaryl; R is Cl, OH, OR1.

[0040] In one embodiment, the compound of formula IVA wherein R is OH is converted to the compound of formula IVA wherein R is Cl in the presence of chlorinating reagent selected from the group consisting of thionyl chloride, oxalyl chloride, phophoprous oxychloride.

[0041] In one embodiment, the compound of formula XIA is reacted with the compound of formula IVA in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, DMAP (4-(dimethylamino)pyridine), lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0042] In one embodiment, the compound of formula XIV, wherein R is MgX and X is Cl, is prepared by a process comprising reacting a compound of VIII with magnesium,

[0043] In one embodiment, the present invention provides a process as depicted in scheme III for the preparation of lasmiditan, a compound of formula I.

R= Cl, OH, OR1

R1 = C1 -C6 alkyl, C1-C6 Alkylaryl

Scheme III

[0044] In one embodiment, the present invention provides a process as depicted in scheme IV for the preparation of lasmiditan, a compound of formula I.

Scheme IV

[0045] In one embodiment, a compound of formula I is prepared by reacting a compound of formula VII with a compound of formula VIII.

[0046] In one embodiment, a compound of formula I is prepared by reacting a compound of formula VII with a compound of formula VIII in the presence of base.

[0047] In one embodiment, the base may be selected from the group consisting of alkyl lithium, Grignard reagent, naphthalene, zinc chloride, calcium hydroxide, t-butoxide, lithium halide, tributyl tin chloride.

[0048] In one embodiment, the base is butyl lithium.

[0049] In one embodiment, a compound of formula I is prepared by reacting a compound of formula VII with a compound of formula VIII in the presence Grignard reagent or turbo Grignard reagent. [0050] In one embodiment, the Grignard reagent is selected from the group consisting of methyl magnesium halide, ethyl magnesium halide, propyl magnesium halide, isopropyl magnesium halide, butyl magnesium halide, t-butyl magnesium halide.

[0051] In one embodiment, the Grignard reagent is isopropyl magnesium chloride, lithium chloride complex.

[0052] In one embodiment, the Grignard reagent is alkyl magnesium halide.

[0053] In one embodiment, compound of formula I is prepared by reacting compound of formula X with compound of formula VIII.

[0054] In one embodiment, compound of formula I is prepared by reacting compound of formula X with compound of formula VIII in the presence of base.

[0055] In one embodiment, the base may be selected from the group consisting of alkyl lithium, Grignard reagent, naphthalene, zinc chloride, calcium hydroxide, t-butoxide, lithium halide, tributyl tin chloride.

[0056] In one embodiment, the base is butyl lithium.

[0057] In one embodiment, a compound of formula I is prepared by reacting a compound of formula X with a compound of formula VIII in the presence Grignard reagent or turbo Grignard reagent

[0058] In one embodiment, the Grignard reagent is as discussed supra.

[0059] In one embodiment, compound X is prepared by reacting compound IVA with compound XI.

[0060] In one embodiment, compound X is prepared by reacting compound IVA with compound XI in the presence of a chlorinating agent.

[0061] In one embodiment, chlorinating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phophoprous oxychloride.

[0062] In one embodiment, chlorinating agent is oxalyl chloride.

[0063] In one embodiment, compound X is prepared by reacting compound IVA with compound XI in the presence of a base.

[0064] In one embodiment, base is selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, DMAP (4-(dimethylamino)pyridine), lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. [0065] In one embodiment, compound X is prepared by reacting compound IV with compound XI in the presence of a solvent.

[0066] In one embodiment, solvent is selected from the group consisting of methylene chloride, ethylene chloride, tetrahydrofuran and toluene.

[0067] In one embodiment, solvent is methylene chloride.

[0068] In one embodiment, the present invention provides a compound selected from the following:

[0069] In one embodiment, the present invention provides a compound of formula X characterized by a proton NMR spectrum having peaks at d 3.94 (s, 3H) 6.69 (m, 2H) 7.88 (m, 1H) 7.95 (t, 1H) 8.61 (d, 1H) 9.34 (s, 1H).

[0070] In one embodiment, the present invention provides a compound of formula X characterized by a ¹³C NMR spectrum having peaks at d 165.10, 164.72, 162.57, 161.80, 161.71, 161.65, 161.56, 159.27, 159.17, 159.12, 159.02, 158.32, 151.06, 145.79, 139.81,

121.76, 118.31, 110.82, 110.77, 101.29, 101.25, 101.03, 100.99, 100.77, 100.74, 52.91.

[0071] In one embodiment, the present invention provides a compound of formula IX characterized by a proton NMR spectrum having peaks at d 7.33 (m, 2H), 7.86 (d, 1H), 8.05 (t, 1H), 8.39 (d, 1H), 11.74 (s, 1H), 13.33 (s, 1H).

[0072] In one embodiment, the present invention provides a compound of formula IX characterized by a ¹³C NMR spectrum having peaks at d 166.19, 164.50, 162.02, 161.26, 161.10, 160.99, 159.27, 158.78, 158.67, 158.62, 158.51, 151.61, 147.65, 140.37, 121.69, 117.81, 112.42, 101.79, 101.52, 101.49, 101.22.

[0073] In one embodiment, the present invention provides a compound of formula VII characterized by a proton NMR spectrum having peaks at d 3.37 (s, 3H), 3.69 (s, 3H), 6.80 (m, 2H), 7.44 (d, 1H), 7.87 (t, 1H), 8.42 (d, 1H), 8.53 (s, 1H). [0074] In one embodiment, the present invention provides a compound of formula VII characterized by a ¹³C NMR spectrum having peaks at d 165.41, 165.26, 165.10, 162.87, 162.72, 162.57, 162.13, 162.04, 161.98, 61.89, 159060, 159.50, 159.45, 159.35, 157.97, 151.18, 149.79, 139.31, 119.74, 115.61, 110.73, 110.54, 110.49, 110.35, 101.62, 101.58, 101.36, 101.32, 101.10, 101.06, 61.50.

[0075] In one embodiment, the present invention provides use of a compound selected from the following

[0076] In the preparation of lasmi ditan or pharmaceutically acceptable salt thereof.

[0077] In one embodiment, the present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,

The reaction conditions are as discussed supra. [0078] 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

[0079] 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

[0080] In one embodiment, the compound of formula I is prepared by reacting compound of formula II with l-methylisonipecotic acid or salt thereof.

[0081] In one embodiment, the compound of formula I is prepared by reacting compound of formula II with l-methylisonipecotic acid or salt thereof in the presence of a chlorinating agent. [0082] In one embodiment, the chlorinating agent may be selected from the group consisting of thionyl chloride, oxalyl chloride, phophoprous oxychloride.

[0083] In one embodiment, the chlorinating agent is oxalyl chloride.

[0084] In one embodiment, the compound of formula I is prepared by reacting compound of formula II with l-methylisonipecotic acid or salt thereof in the presence of a base.

[0085] In one embodiment, the base may be selected from the group consisting of alkyl lithium, Grignard reagent, naphthalene, zinc chloride, calcium hydroxide, t-butoxide, lithium halide, tributyl tin chloride.

[0086] In one embodiment the base is butyl lithium.

[0087] In one embodiment, the compound of formula I is prepared by reacting compound of formula II with l-methylisonipecotic acid in the presence of a Grignard reagent, turbo Grignard reagent.

[0088] In one embodiment, the Grignard reagent is selected from the group consisting of methyl magnesium halide, ethyl magnesium halide, propyl magnesium halide, isopropyl magnesium halide, butyl magnesium halide, t-butyl magnesium halide.

[0089] In one embodiment, the compound of formula I is prepared by reacting compound of formula II with l-methylisonipecotic acid in the presence of a solvent.

[0090] In one embodiment, the solvent may be selected from the group consisting of dimethyl formamide, dimethyl sulphoxide, tetrahydrofuran, methylene chloride, acetonitrile.

[0091] In one embodiment, the present invention provides a process as depicted in scheme V for the preparation of lasmi ditan, a compound of formula I.

Scheme V [0092] In one embodiment, the present invention provides a process as depicted in scheme VI for the preparation of lasmiditan, a compound of formula I.

Scheme VI

[0093] In one embodiment, a compound of formula I is prepared by reacting a compound of formula III with a compound of formula XII.

[0094] In one embodiment, a compound of formula I is prepared by reacting a compound of formula III with a compound of formula XII in the presence of base.

[0095] In one embodiment, the base may be selected from the group consisting of alkyl lithium alkyl lithium, Grignard reagent, naphthalene, zinc chloride, calcium hydroxide, t- butoxide, lithium halide, tributyl tin chloride.

[0096] In one embodiment, the base is butyl lithium.

[0097] In one embodiment, a compound of formula I is prepared by reacting a compound of formula III with a compound of formula XII in the presence of a solvent.

[0098] In one embodiment, the solvent may be selected from the group consisting of tetrahydrofuran, ether, n-hexane, n-heptane.

[0099] In one embodiment, the solvent is tetrahydrofuran.

[0100] In one embodiment compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid or salt thereof.

[0101] In one embodiment compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid or salt thereof in the presence of base.

[0102] In one embodiment the base may be selected from the group consisting of alkyl lithium, Grignard reagent, naphthalene, zinc chloride, calcium hydroxide, t-butoxide, lithium halide, tributyl tin chloride [0103] In one embodiment the base is butyl lithium.

[0104] In one embodiment compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid or salt thereof in the presence of Grignard reagent.

[0105] In one embodiment, the Grignard reagent is alkyl magnesium halide.

[0106] In one embodiment, the Grignard reagent is selected from the group consisting of as discussed supra.

[0107] In one embodiment, the Grignard reagent is isopropyl magnesium chloride.

[0108] In one embodiment, the compound of formula III is prepared by reacting 1- methylisonipecotic acid or salt thereof with N,O-dimethylhydroxylamine.

[0109] In one embodiment, the compound of formula III is prepared by reacting 1- methylisonipecotic acid or salt thereof with N,O-dimethylhydroxylamine in the presence of a base.

[0110] In one embodiment, the base may be selected from the group consisting of alkyl lithium, Grignard reagent, naphthalene, zinc chloride, calcium hydroxide, t-butoxide, lithium halide, tributyl tin chloride.

[0111] In one embodiment, the compound of formula III is prepared by reacting 1- methylisonipecotic acid or salt thereof with N,O-dimethylhydroxylamine in the presence of a chlorinating agent.

[0112] In one embodiment, chlorinating agent may be selected from the group consisting of thionyl chloride, oxalyl chloride, and phophoprousoxychloride.

[0113] In one embodiment, chlorinating agent is oxalyl chloride.

[0114] In one embodiment, the compound of formula III is prepared by reacting 1- methylisonipecotic acid or salt thereof with N,O-dimethylhydroxylamine in the presence of a base and a coupling additive.

[0115] In one embodiment, the compound of formula III is prepared by reacting 1- methylisonipecotic acid or salt thereof with N,O-dimethylhydroxylamine in the presence of a chlorinating agent and a coupling additive.

[0116] In one embodiment, the base may be selected from a group consisting of organic amines, imidazoles.

[0117] In one embodiment, the organic amines may be selected from the group consisting of triethyl amine, isopropylethyl amine, diisopropylethyl amine. [0118] In one embodiment, the imidazoles is l, l'-Carbonyldiimidazole (CDI).

[0119] In one embodiment, the chlorinating reagents may be selected from a group consisting of thionyl chloride, oxalyl chloride thionyl chloride, oxalyl chloride, phophoprous oxychloride.

[0120] In one embodiment, the coupling additives may selected as discussed supra.

[0121] In one embodiment, a compound of formula XII is prepared by reacting compound IVa with compound XIII.

[0122] In one embodiment, a compound of formula XII is prepared by reacting compound IVa with compound XIII in the presence of chlorinating agent.

[0123] In one embodiment, chlorinating agent may be selected from the group consisting of as discussed supra.

[0124] In one embodiment, chlorinating agent is oxalyl chloride.

[0125] In one embodiment, a compound of formula XII is prepared by reacting compound IVa with compound XIII in the presence of a base.

[0126] In one embodiment, the base is as discussed supra.

[0127] In one embodiment, a compound of formula XII is prepared by reacting compound IVa with compound XIII in the presence of a solvent.

[0128] In one embodiment, solvent is selected from the group consisting of methylene chloride, ethylene chloride, tetrahydrofuran and toluene.

[0129] In one embodiment, the compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid.

[0130] In one embodiment, the compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid in the presence of chlorinating agent.

[0131] In one embodiment the chlorinating agent may be selected from the group consisting of as discussed supra.

[0132] In one embodiment, the compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid in the presence of a base.

[0133] In one embodiment, the base may be selected from the group consisting of as discussed supra.

[0134] In one embodiment the base is butyl lithium.

[0135] In one embodiment, the compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid in the presence of a Grignard reagent. [0136] In one embodiment, the Grignard reagent is selected from the group consisting of as discussed supra.

[0137] In one embodiment, the compound of formula I is prepared by reacting compound of formula XII with l-methylisonipecotic acid in the presence of a solvent.

[0138] In one embodiment, the solvent may be selected from the group consisting of as discussed supra.

[0139] In one embodiment, present invention provides compound of formula XII.

XII

[0140] In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention is obtained as a solid.

[0141] In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention is obtained as a crystalline solid.

[0142] In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention is obtained as an amorphous solid.

[0143] In one embodiment, lasmiditan a compound of formula I is obtained as a solid by isolating from a suitable solvent.

[0144] The solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0145] 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.

[0146] In one embodiment, lasmiditan a compound of formula I is converted to lasmiditan hydrochloride, a compound of formula IA.

[0147] In one embodiment, lasmiditan hydrochloride, a compound of formula IA is prepared by reacting lasmiditan, a comp of formula I with hydrochloric acid.

[0148] 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.

[0149] In one embodiment, lasmiditan, a compound of formula I is converted to lasmiditan hemi succinate, a compound of formula IB.

[0150] In one embodiment, the lasmiditan hemi succinate, a compound of formula IB is prepared by reacting lasmiditan, a compound of formula I with succinic acid.

[0151] In one embodiment, lasmiditan hydrochloride, a compound of formula IA is prepared by dissolving lasmiditan, a compound of formula I in a suitable solvent and treating the reaction mixture with succinic acid.

[0152] The solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0153] In one embodiment, lasmiditan and salt thereof are purified by the purification methods known in the art.

[0154] In one embodiment, lasmiditan and salt thereof are purified by dissolving in a suitable solvent and recrystallizing. [0155] In one embodiment, lasmiditan and salt thereof are purified by dissolving in a suitable solvent and adding an anti-solvent.

[0156] In one embodiment, the lasmiditan obtained by the process described herein, has a purity of >99%, as determined by HPLC.

[0157] In one embodiment, the present invention provides lasmiditan free of any of the below listed impurities A - G.

[0158] In one embodiment, the present invention provides pharmaceutical compositions comprising lasmiditan or salt thereof obtained by the processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.

[0159] In one embodiment, the present invention provides pharmaceutical compositions comprising lasmiditan or salt thereof obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.

[0160] The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state lasmiditan or salt thereof into any of the foregoing desired particle size range.

[0161] 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

[0162] Example-1: Synthesis of compound of formula V

2,6-Dibromopyridine was dissolved in ammonia and mixture was heated in autoclave at about l20°C to about l50°C till reaction complies. After completion of reaction, the reaction mass was allowed to cool and diluted with water. Product was extracted in dichloromethane which on evaporation gives compound of formula-V in crude stage. The crude compound of formula V was purified in mixture of ethyl acetate and hexane to obtain a pale yellow solid.

[0163] Example-2: Synthesis of compound of formula III

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

[0164] Example-3: Synthesis of compound of formula II

Methylene chloride was added to 2,4,6-trifluoro benzoic acid, dimethyl formamide was added to the reaction mass and the reaction mass was cooled to about 5°C to l0°C. Oxalyl chloride was added to the reaction mass, the temperature of the reaction mass was raised to 25°C to 30°C and reaction mass was stirred at about 25°C to 30°C for about 2 hours. The solvent was distilled out under vacuum to obtain 2,4,6-trifluoro benzoyl chloride as an oil. Compound of formula V was dissolved in tetrahydrofuran and trimethylamine was added to the obtained reaction mass. The reaction mass was then cooled to about l5°C to 20°C. To the reaction mass was added 2,4,6-trifluoro benzoyl chloride dissolved in tetrahydrofuran. The temperature of the reaction mass was raised to about l5°C to 20°C and the reaction mass was stirred for about 1 hour. The mixture of water and ethyl acetate was added to the reaction mass to obtain organic and aqueous layers. Organic layer was washed with water sodium chloride solution. The solvent was distilled out completely to obtain an oil. The obtained oil was crystallized using diisopropylether. The obtained solid was dried. [0165] Example-4: 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 MgS04 and then concentrated in vacuum to get compound of formula-I.

[0166] Example-5: Synthesis of compound of formula I

l-methylisonipecotic acid hydrochloride is dissolved in methylene chloride and dimethyl formamide is added to the reaction mass. The reaction mass is then cooled to about 5°C to l0°C. Oxalyl chloride is slowly added to the reaction mass and the temperature of the reaction mass is raised to about 25°C to 30°C and the reaction mass is stirred for about 2 hours. The solvent is distilled out to obtain l-methylpiperidine-4-carboxylic acid chloride; the obtain product is then dissolved in tetrahydrofuran and compound of formula II is added to thereaction mass. The reaction mass is stirred and n-butyl lithium is added to the reaction mixture at about -78°C. The mass is stirred for about 15 to 30 minutes. The reaction mass is quenched with aqueous hydrochloric acid and extracted with dichloromethane. The extract is washed with water and brine and dried over MgS04 and then concentrated in vacuum to obtain compound of formula I.

[0167] Example-6: Synthesis of compound of formula X

2,4,6-trifluoro benzoic acid was added to dichloromethane and dimethyl formamide was added to the reaction mass. Oxalyl chloride was added to the reaction mass and the reaction mass was stirred at about 25°C to 30°C for about 30 to 40minutes. The solvent was distilled off to get an oil. The obtained oil was dissolved in dichloromethane to obtain 2,4,6-trifluoro benzoyl chloride. Compound of formula XI was dissolved in dichloromethane and triethylamine was adde to the reaction mass. The reaction mass was then cooled to about 0°C to 5°C. 2,4,6-trifluoro benzoyl chloride in dichloromethane was added to the reaction mass and reaction mass was stirred at about 0°C to 5°C for about 30 minutes. The temperature of the reaction mass was raised to about 25°C 30°C. Aqueous hydrochloric acid was added to the reaction mass and reaction mass was stirred for about l0-l5min and organic and aqueous layer were separated. Organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was distilled off to obtain a solid. The obtained solid was crystalized using methanol.

[0168] Example-7: Synthesis of compound of formula IX

Lithium hydroxide was dissolved in water and added to the compound of formula X dissolved in tetrahydrofuran to obtain a reaction mass. The reaction mass was stirred at about 20°C to 25°C for about 20 to 30minutes. Aqueous hydrochloric acid and ethyl acetate were added to the reaction mass and reaction mass was stirred. Aqueous and organic layers were separated. Organic layer was washed with water and aqueous sodium chloride solution. The solvent was distilled off to get solid compound of formula IX.

[0169] Example-8: Synthesis of compound of formula VII

Compound of formula IX was added to dimethyl formamide and triethyl amine and N,O- dimethyl hydroxylamine hydrochloride and HATU were added to the reaction mass the reaction mass was stirred at about 25°C to 30°C for about 5 hours to 6 hours. Water and ethyl acetate were added to the reaction mass and organid and aqueous layers were separated. Aqueous layer was extracted with ethyl acetate. Organic layer washed with water and aqueous sodium chloride solution. The solvent was distilled out completely to obtain an oil; the oil was crystallized using diisopropyl ether to obtain compound of formula VII.

[0170] Example-9: Synthesis of compound of formula I

4-chloro-l -methyl piperidine is added to tetrahydrofuran to obtain a reaction mass. The reaction mass is cooled to about l0°C to 20°C, solution of isopropyl magnesium chloride lithium chloride complex in tetrahydrofuran is added to the reaction mass at about l0°C to 20°C. The reaction mass is stirred for about 30 minutes to 60 minutes. Compound of formula VII is dissolved in tetrahydrofuran and added to the reaction mass. Obtained reaction mass is stirred for about 1 hour to 2 hours. Aqueous ammonium chloride solution and ethyl acetate is added to the reaction mass. The organic and aqueous layers are separated. Organic layer is washed with water and aqueous sodium chloride solution. Organis layer is distilled out to obtain compound of formula I.

[0171] Example-10: Synthesis of compound of formula I

4-chloro-l -methyl piperidine is dissolved in tetrahydrofuran, the reaction mass is cooled to about l0°C to 20°C; isopropyl magnesium chloride lithium chloride complex dissolved in tetrahydrofuran is added to the reaction mass at about lO°C to 20°C. The reaction mass is stirred at about lO°C to 20°C for about 30 minutes to 60 minutes. Compound of formula X dissolved in tetrahydrofuran is added to reaction mass and reaction mass is stirred at about l0°C to 20°C for about 60 minutes to 120 minutes. Aqueous ammonium chloride solution and ethyl acetate is added to the reaction mass, the reaction mass is stirred and aqueous and organic layers are separated. Organic layer is washed with water and aqueous sodium chloride solution. Organic layer is distilled out to obtain compound of formula I.

[0172] Example-11: Synthesis of compound of formula XII

2,4,6-trifluoro benzoic acid was dissolved in dichloromethane and dimethylformamide was added to the reaction mass. The reaction mass was cooled to about 0°C to l0°C, oxalyl chloride was slowly added to the reaction mass and the temperature of the reaction mass was raised to about 20°C to 30°C and stirred for about 30 minutes to 40 minutes. The solvent was distilled off to obtain anoil; the oil was dissolved in tetrahydrofuran to obtained a solution of 2,4,6-trifluoro benzoyl chloride. 2-amino pyridine was dissolved in tetrahydrofuran and triethylamine was added to the reaction mass; a solution of 2,4,6- trifluoro benzoyl chloride in THF was added to the reaction mass and the reaction mass was cooled to about 0°C to 5°C. Water and ethylacetate were addd to the reaction mass and the temperature of reaction mass was raised to about 20°C to 30°C. The reaction mass was stirred and organic and aqueous layers were separated. Organic layer was washed with water and sodium chloride solution. Organic layer was distilled off completely to get an oil, the obtained oil was crystallized using diisopropyl ether and methanol to obtain compound of formula XII.

[0173] Example-12: Synthesis of compound of formula I

Compound of formula XII is dissolved in tetrahydrofuran and N-butyl lithium is added to the reaction mixture at about -78°C. The reation mass is stirred for about 15 minutes to 30 minutes. Compound of formula III is added to the reaction mass and the reaction mass is stirred at about -78°C to -50°C for 2 hours. The reaction mass is quenched with aqueous hydrochloric acid and extracted with dichloromethane. The extract is washed with water and brine, dried over MgS04 and then concentrated in vacuum to get compound of formula I.

[0174] Example-13: Synthesis of compound of formula I l-methylisonipecotic acid hydrochloride is dissolved in methylene chloride and dimethylformamide is added to the reaction mass. The reaction mass is to about 5°C to l0°C and oxalyl chloride is added to the reaction mass, the temperature of the reaction mass is raised to about 25°C to 30°C and reaction mass is stirred for about 2 hours. The solvent is distilled off to obtain l-methylpiperidine-4-carboxylic acid chloride. 1- methylpiperidine-4-carboxylic acid chloride is dissolved in tetrahydrofuran and compound of formula XII dissolved tin tetrahydrofuran is added to it; the reaction mass is stirred. N-butyl lithium is added to the reaction mixture at about -78°C. The mixture is stirred for about 15 minutes to 30 minutes. The reaction mass is quenched with aqueous hydrochloric acid and extracted with dichloromethane. The extract is washed with water and brine, dried over MgS04 and then concentrated in vacuum to get compound of formula I.

[0175] Example-14: Synthesis of compound of formula X

To a mixture of 2,4,6-trifluorobenzoic acid (23. l3g), dichloromethane (260mL) and dimethylformamide (0.2mL) was added oxalyl chloride (25.08g) at about 25°C and the reaction mixture was stirred for about lh. The reaction mixture was concentrated and methylene chloride (75mL) was added to the obtained residue. The resulting solution was added to a mixture of compound of formula XI (15g), methylene dichloride (l50mL) and triethylamine (12.9g) cooled to about 0°C and stirred for about 30min. The temperature of the reaction mixture was raised to about 25°C and 1M aqueous hydrochloric acid was added to it. The two layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in methanol and dried. Yield: l8g Mass spectrum: m/z= 309(M-l); ¾ NMR (CDCh) ppm 3.94(s, 3H) 6.69(m, 2H) 7.88(m, 1H) 7.95(t, 1H) 8.6l(d, 1H) 9.34(s, 1H); ¹³C NMR (CDCh) ppm: 165.10, 164.72, 162.57,

161.80, 161.71, 161.65, 161.56, 159.27, 159.17, 159.12, 159.02, 158.32, 151.06, 145.79,

139.81, 121.76, 118.31, 110.82, 110.77, 101.29, 101.25, 101.03, 100.99, 100.77, 100.74, 52.91

[0176] Example-15: Synthesis of compound of formula X

To a mixture of 2,4,6-trifluorobenzoic acid (20g), methylene chloride (200mL) and dimethylformamide (0.2mL) was added oxalyl chloride (l9.24g) at about 25°C for about lh. The reaction mixture was concentrated and methylene chloride (60mL) was added to the obtained residue. The resulting solution was added to a mixture of compound of formula XI (l2g), methylene chloride (l40mL) and triethylamine (lOg) cooled to about 0°C and stirred for about 30min. The temperature of the reaction mixture was raised to about 25°C and 1M aqueous hydrochloric acid was added it. The two layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystalized in methanol and dried. Yield: l8g; HPLC Purity: 99.89%

[0177] Example-16: Synthesis of compound of formula X

To a mixture of 2,4,6-trifluorobenzoic acid (lOg), methylene chloride (lOOmL) and dimethylformamide (0.2mL) was added oxalyl chloride (9.6g) at about 25°C and stirred for about lh. The reaction mixture was concentrated and methylene chloride (50mL) was added to the obtained residue. The resulting solution was added to a compound of formula XI (6g), methylene chloride (50mL) and triethylamine (5g) cooled to about 0°C and stirred for about 30min. The temperature of the reaction mass was raised to about 25°C and 1M aqueous hydrochloric acid was added to it. The two layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in methanol and dried. Yield: 9. lg; HPLC Purity: 99.72%

[0178] Example-17: Synthesis of compound of formula X

To a mixture of 2,4,6-trifluorobenzoic acid (5g) in dimethylformamide (25mL) was added compound of formula XI (4.75g) and triethylamine (5.73g) and the reaction mixture was stirred for about l5min. HATU (l3g) was portion wise added to the reaction mixture at about 25°C and the reaction mixture was stirred at about room temperature for about 15h. Water was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in methanol and dried. Yield: 2.0lg; HPLC Purity: 97.68%

[0179] Example-18: Synthesis of compound of formula X

A mixture of 2,4,6-trifluorobenzoic acid (lOg) and thionyl chloride (30ml) was heated to about 70 to 75°C and maintained for about lh. The reaction mixture was concentrated and methylene chloride (50mL) was added to the obtained residue. The resulting solution was added to a mixture of compound of formula XI (9.5g), triethylamine (l l .47g) and methylene chloride (50ml) cooled to about 0°C and stirred for about lh. The temperature of the reaction mass was raised to about 25°C and 1M aqueous hydrochloric acid (lOOmL) was added to the reaction mixture. The two layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in methanol and dried. Yield: 8.7g; HPLC Purity: 92.64%

[0180] Example-19: Synthesis of compound of formula IX

To a solution of lithium hydroxide (3.35g) in water (75mL), was added compound of formula X (15g) and tetrahydrofuran (150mL) at about 25°C and the reaction mixture was stirred for about 15h. Aqueous hydrochloric acid and ethyl acetate were added to the reaction mixture and the two layers were separated. The organic layer was washed with aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in diisopropyl ether. Yield: 12.7g

Mass spectrum: m/z= 297(M+l); ¾ NMR (DMSO) ppm 7.33(m, 2H), 7.86(d, 1H), 8.05(t, 1H), 8.39(d, 1H), l l .74(s, 1H), l3.33(s, 1H)

¹³C NMR (CDCb) ppm: 166.19, 164.50, 162.02, 161.26, 161.10, 160.99, 159.27, 158.78, 158.67, 158.62, 158.51, 151.61, 147.65, 140.37, 121.69, 117.81, 112.42, 101.79, 101.52, 101.49, 101.22

[0181] Example-20: Synthesis of compound of formula IX

To a solution of lithium hydroxide (2.35g) in water (75mL), was added compound of formula X (15g) and tetrahydrofuran (150mL) at about 25°C and the reaction mixture was stirred for about 15h. Aqueous hydrochloric acid and ethyl acetate were added to the reaction mixture and the two layers were separated. The organic layer was washed with aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in diisopropyl ether. Yield: 13. lg; HPLC Purity: 97.64%

[0182] Example-21: Synthesis of compound of formula IX

To a solution of sodium hydroxide (7.74g) in water (l50mL), was added compound of formula X (30g) and tetrahydrofuran (300mL) at about 25°C and the reaction mixture was stirred for about 2h. Aqueous hydrochloric acid and ethyl acetate were added to the reaction mixture and the two layers were separated. The organic layer was washed with aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in diisopropyl ether. Yield: 27.3g; HPLC Purity: 98.14%

[0183] Example-22: Synthesis of compound of formula VII

To a mixture of compound of formula IX (lOg) in dimethylformamide (40mL) was added and triethylamine (l0.23g), A^f/7-dimethyl hydroxyl amine hydrochloride (3.22g) and HATU (l5.4g) and the reaction mixture was stirred at about 25 °C for about 15h. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture and the two layers were separated. The aqueous layer was extracted with ethyl acetate and tetrahydrofuran. The combined organic layer was washed with aqueous sodium bicarbonate, water and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in ethyl acetate. Yield: 5.5g

Mass spectrum: m/z= 340(M+l); ¹HNMR (CDCb) ppm 3.37(s, 3H), 3.69(s, 3H), 6.80(m, 2H), 7.44(d, 1H), 7.87(t, 1H), 8.42(d, 1H), 8.53(s, 1H)

¹³C NMR (CDCb) ppm: 165.41, 165.26, 165.10, 162.87, 162.72, 162.57, 162.13, 162.04, 161.98, 61.89, 159060, 159.50, 159.45, 159.35, 157.97, 151.18, 149.79, 139.31, 119.74, 115.61, 110.73, 110.54, 110.49, 110.35, 101.62, 101.58, 101.36, 101.32, 101.10, 101.06, 61.50

[0184] Example-23: Synthesis of compound of formula VII

To a mixture of compound of formula IX (20g) in dimethylformamide (l25mL), was added triethylamine (25.6g), A^f/7-dimethyl hydroxyl amine hydrochloride (9.05g) and HATU (38.5g) and the reaction mixture was stirred at about 25 °C for about 15h. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture and the two layers were separated. The aqueous layer was extracted with ethyl acetate and tetrahydrofuran. The combined organic layer was washed with aqueous sodium bicarbonate and aqueous sodium chloride solution. The organic layer was concentrated and the residue was crystallized in ethyl acetate. Yield: 20.2g; HPLC Purity: 99.35%

[0185] Example-24: Synthesis of compound of formula VII

To a mixture of compound of formula IX (lOg) in dimethylformamide (50mL), was added triethylamine (l0.23g), A^f,U-dimethyl hydroxylamine hydrochloride (3.6g) and HATU (l5.4g) and the reaction mass was stirred at about 25°C for about 3h. Water was added to the reaction mixture. The reaction mixture was stirred at about 25°C for about 30min and filtered. The solid was washed with water and dried under vacuum. Yield: l0.07g; HPLC Purity: 99.33%

[0186] Example-25: Synthesis of lasmiditan hemisuccinate

(a) To a mixture of 4-chloro-l-methylpiperidine hydrochloride (25g) in water (75mL) was added potassium carbonate (25g). The reaction mixture was extracted with methyl

/cvv-butyl ether. The organic layer was washed with aqueous sodium chloride solution and concentrated to give 4-chloro-l-methylpiperidine free base. Yield: l4g

(b) To a mixture of magnesium turnings (12.5g), pinch of iodine and ethylene dibromide (lmL) in tetrahydrofuran (40mL) was added a mixture of 4-chloro-l -methyl piperidine (20g) in tetrahydrofuran (lOOmL). The reaction mixture was heated to reflux for about 2h and cooled to about 25°C. The reaction mixture was added to a mixture of compound of formula VII (lOg) in tetrahydrofuran (l50mL) at about 0°C. The reaction mixture was stirred for about lh at about 0°C and aqueous ammonium chloride solution and MTBE was added to it. The temperature of the reaction mixture was raised to about 25°C and the two layers were separated. The organic layer was washed with aqueous sodium chloride solution and concentrated. The residue was dissolved in ethanol (lOOmL) and succinic acid (3.5g) was added to it at about 25°C. The reaction mixture was heated to about 75°C. The reaction mixture was cooled to about 20°C and stirred overnight. The solid obtained was filtered, washed with ethanol and dried under vacuum. Yield: 6.5g

[0187] Example-26: Synthesis of lasmiditan hemisuccinate

To a mixture of compound of formula VII (5g) in tetrahydrofuran (50mL) cooled to about 0°C, was slowly added 1M solution of l-methylpiperidine-4-yl-magnesium chloride in THF (75mL) and the reaction mixture was stirred for about lh. Water was added slowly at about 0-5°C and then ethyl acetate and the temperature was raised to about 25°C. The two layers were separated and the organic layer was washed with aqueous sodium chloride solution and concentrated. The residue was dissolved in isopropyl alcohol (50mL) and succinic acid (1 75g) was added to it at about 25°C. The reaction mixture was heated to about 75°C. The reaction mixture was cooled to about 20°C and stirred for 2h. The solid obtained was filtered, washed with isopropyl alcohol and dried. Yield: 4. l2g; HPLC purity: 99.10%

[0188] Example-27: Synthesis of lasmiditan hemisuccinate To a mixture of compound of formula VII (lOg) in tetrahydrofuran (50mL) cooled to about 0°C, was added 1M solution of l-methylpiperidine-4-yl-magnesium chloride in tetrahydrofuran (l80mL) slowly at about 0°C and the reaction mixture was stirred for about 2h. 10% aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture at about 0-5°C and the temperature was raised to about 25°C. The two layers were separated. The organic layer was washed with aqueous sodium chloride solution and concentrated. The residue was dissolved in isopropyl alcohol (lOOmL) and succinic acid (3.4g) was added to it at about 25°C. The reaction mixture was heated to about 70°C. The reaction mixture was cooled to about 20°C and stirred for 30min. The solid obtained was filtered, washed with isopropyl alcohol and dried. Yield: 9g; HPLC Purity: 99.45%

[0189] Example-28: Synthesis of lasmiditan hemisuccinate

To a mixture of compound of formula VII (8g) in tetrahydrofuran (50mL) cooled to about 0°C, was added 1M solution of l-methylpiperidine-4-yl-magnesium chloride in tetrahydrofuran (H8mL) slowly at about 0°C and the reaction mixture was stirred for about lh. 10% aqueous hydrochloric acid and ethyl acetate were added to the reaction mixtures at about 0-5°C and the temperature was raised to about 25°C. The two layers were separated and the organic layer was washed with aqueous sodium chloride solution and concentrated. The residue was dissolved in isopropyl alcohol (80ml) and succinic acid (2.73g) was added to it at about 25°C. The reaction mixture was heated to about 70°C. The reaction mixture was cooled to about 20°C and stirred for about lh. The solid obtained was filtered, washed with isopropyl alcohol and dried. Yield: 6.35g; HPLC Purity: 98.25%

[0190] Example-29: Synthesis of lasmiditan hemisuccinate

To a mixture of compound of formula VII (l8g) in tetrahydrofuran (l80mL) cooled to about 0°C to about -l0°C, was added 1M solution of l-methylpiperidine-4-yl-magnesium chloride in tetrahydrofuran (l80mL) slowly at about -5°C to about -l0°C and the reaction mixture was stirred for about lh. Water was added slowly at about 0-5°C and then ethyl acetate and the temperature was raised to about 25°C. The two layers were separated and the organic layer was washed with aqueous sodium chloride solution and concentrated. The residue was dissolved in isopropyl alcohol (l80mL) and succinic acid (6g) was added to it at about 25°C. The reaction mixture was heated to about 50°C. The reaction mixture was cooled to about 20°C. The solid was filtered, washed with isopropyl alcohol and dried. Yield: 14.6g

[0191] Example-30:

A mixture of lasmiditan hemisuccinate (3g) in isopropyl alcohol (30mL) was heated to about 65-70°C and stirred for about 30min. The reaction mixture was cooled to about 25°C and stirred for about lh. The solid obtained was filtered, washed with isopropyl alcohol and dried. Yield: 2.6g; HPLC Purity: 99.38%

XRPD peaks of lasmiditan hemisuccinate

[0192] Example-31:

To a mixture of lasmiditan hemisuccinate (8g) in water (80mL) was added 10% aqueous sodium carbonate solution (40mL) at about 25°C followed by addition of ethyl acetate (80mL). The two layers were separated and the organic layer was washed with aqueous sodium chloride solution and concentrated. The residue was dissolved in isopropyl alcohol (40mL) at about 45°C and succinic acid (2.59g) in isopropyl alcohol (40mL) was added to it. The reaction mixture was cooled to about 25°C and stirred for about lh. The solid was filtered, washed with isopropyl alcohol and dried. Yield: 5.45g; HPLC Purity: 99.69% [0193] Example-32:

A mixture of lasmiditan hemisuccinate (5g) in isopropyl alcohol (50mL) was heated to about 65-70°C and stirred for about 30min. The mixture was cooled to about 25°C and stirred for about lh. The solid was filtered, washed with isopropyl alcohol and dried. Yield: 4.7g; HPLC purity: 99.77%

The following examples follow similar process as described in Example-32.

Claims

CLAIMS:

1. A process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,

the process comprising:

(b) reacting the compound of formula VII with a compound of formula XIV

wherein R is MgX, Li, ZnX, Sn(Ci-₆ alkyl)-; X is selected from the group consisting of

Cl, Br, I, to obtain lasmiditan, the compound of formula I; and

(c) optionally, converting lasmiditan to a pharmaceutically acceptable salt.

2. The process of claim 1, wherein step (a) is carried out in the presence of a coupling agent.

3. The process of claim 2, wherein the coupling agent is selected from the group consisting of HATU, EDCI, HOBt, CDI, DCC, BOP, PyBOP, PyAOP, PyBroP, TBTU, TATU, HCTU, TsCl, HBTU, COMU, Oxyma, PyBOP, HOTT, FDPP, T3P, DMTMM, PyOxim, TSTU, TDBTU, TPTU, TOTU, IIDQ, PyCIU, DIC, TOTT, EEDQ, HDMC, DEPBT, PyOxim, HOOBt, HOSu, HO At, TFFH, and mixtures thereof.

4. The process of claim 1, wherein step (a) is carried out in the presence of a base.

5. The process of claim 4, wherein the base is selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine, collidine, imidazole, DMAP, DABCO, DBE1, DBN, N,N,N',N'- tetramethyl-l,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

6. The process of claim 1 , wherein the step (b) is carried out at a temperature of about -20°C to about lO°C.

7. The process of claim 1, wherein in step (c), lasmiditan is converted to lasmi ditan hydrochloride.

8. The process of claim 1, wherein in step (c), lasmiditan is converted to lasmiditan hemi succinate.

9. The process of claim 1, wherein the compound of formula IX is prepared by a process comprising:

(x) hydrolyzing a compound of formula XA; or

(y) hydrogenating a compound of formula XA,

wherein Rl is Ci-₆ alkyl, Ci-₆ alkylaryl.

10. The process of claim 9, wherein hydrolysis is carried out in the presence of an acid.

11. The process of claim 9, wherein the hydrolysis is carried out in the presence of a base.

12. The process of claim 9, wherein the hydrogenation is carried out in the presence of catalyst selected from platinum, palladium, Raney nickel.

13. The process of claim 9, wherein the compound of formula XA is prepared by a process comprising reacting a compound of formula XIA with a compound of formula IV A,

wherein Rl is Ci-₆ alkyl, Ci-₆ alkylaryl; R is Cl, OH, OR1.

14. The process of claim 1, wherein R is MgX and X is Cl.

15. The process of claim 1 , wherein the compound of formula XIV, wherein R is MgX and X is Cl, is prepared by a process comprising reacting a compound of VIII with magnesium,

A compound selected from the following

Use of a compound selected from the following

in the preparation of lasmiditan or pharmaceutically acceptable salt thereof.

16. A process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,