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 Life Sciences Limited,
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
[0001] 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
[0002] Lasmiditan, also known as 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine -2-yl]benzamide, is represented by the structure of formula I.
I.
[0003] Lasmiditan hemisuccinate, 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
[0004] The present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
the process comprising:
(a) reacting a compound of formula IX with N-methoxymethylamine or salt thereof to obtain a compound of formula VII;
IX VII
(b) reacting the compound of formula VII with a compound of formula XIV
XIV
wherein R is MgX, Li, ZnX, Sn(C1-6 alkyl)3; 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.
[0005] In another embodiment, the present invention provides a compound selected from the following:
X IX
VII.
[0006] In another embodiment, the present invention provides use of a compound selected from the following
X IX
VII
in the preparation of lasmiditan or pharmaceutically acceptable salt thereof.
[0007] In another embodiment, the present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
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,
IX VII.

BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Figure 1 is a characteristic XRPD of lasmiditan hemisuccinate as obtained in example 22.
[0009] Figure 2 is a DSC thermogram of lasmiditan hemisuccinate as obtained in example 22.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
the process comprising:
(a) reacting a compound of formula IX with N-methoxymethylamine or salt thereof to obtain a compound of formula VII;
IX VII
(b) reacting the compound of formula VII with a compound of formula XIV
XIV
wherein R is MgX, Li, ZnX, Sn(C1-6 alkyl)3; 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.
[0011] In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C.
[0012] The term “C1-6 alkyl” means alkyl groups having 1 to 6 carbon atoms and includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-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.
[0013] In one embodiment, the reaction of the compound of formula IX is reacted with N-methoxymethylamine or salt thereof occurs in the presence of a coupling agent.
[0014] In one embodiment, the coupling agent may be selected from the group consisting of HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), HOBt (hydroxybenzotriazole), CDI (1,1'-carbonyldiimidazole), DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TATU (O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), HCTU (2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate), TsCl (p-toluenesulfonyl chloride), HBTU (N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate), COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), Oxyma (ethyl (hydroxyimino)cyanoacetate), PyBOP ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), HOTT (S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium hexafluorophosphate), FDPP (pentafluorophenyl diphenylphosphinate), T3P (propylphosphonic anhydride), DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate), PyOxim ([ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), TSTU (N,N,N,N-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate), TDBTU (O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TPTU (O-(2-oxo-1 (2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TOTU (O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate), IIDQ (isobutyl 1,2-dihydro-2-isobutoxy-1-quinolinecarboxylate), PyCIU (chlorodipyrrolidinocarbenium hexafluorophosphate), DIC (diisopropylcarbodiimide), TOTT (N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl)thiouronium tetrafluoroborate), EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), HDMC (N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), PyOxim (ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), HOOBt (hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine), HOSu (N-hydroxysuccinimide), HOAt (1-hydroxy-7-azabenzotriazole), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), and mixtures thereof.
[0015] In one embodiment, the reaction of the compound of formula IX is reacted with N-methoxymethylamine or salt thereof occurs in the presence of a coupling agent, wherein the coupling agent is HATU.
[0016] In one embodiment, the reaction of the compound of formula IX is reacted with N-methoxymethylamine or salt thereof occurs in the presence of a base selected from organic base or inorganic base.
[0017] 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 (1,4-diazabicyclo[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, oxyma (ethyl cyanohydroxyiminoacetate), or mixtures thereof.
[0018] 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.
[0019] In one embodiment, the reaction of the compound of formula IX is reacted with N-methoxymethylamine 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 (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
[0020] In one embodiment, the reaction of the compound of formula IX is reacted with N-methoxymethylamine or salt thereof occurs in the presence of a base, wherein the base is triethylamine.
[0021] In one embodiment, the reaction of the compound of formula IX is reacted with N-methoxymethylamine or salt thereof occurs in the presence of a solvent.
[0022] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof.
[0023] 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, tert-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, n-propyl acetate, tert-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.
[0024] In one embodiment, the compound of formula VII is reacted with the compound of formula XIV, wherein R is MgX and X is Cl.
[0025] In one embodiment, step (b) is carried out at a temperature of about -20°C to about 20°C.
[0026] In one embodiment, step (b) is carried out at a temperature of about -20°C to about 10°C.
In (c) of the above process, lasmiditan is converted to a pharmaceutically acceptable salt.
[0027] In one embodiment, lasmiditan is converted to lasmiditan hydrochloride.
[0028] In one embodiment, lasmiditan is converted to lasmiditan hemisuccinate.
[0029] 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,
XA
wherein R1 is C1-6 alkyl, C1-6 alkylaryl.
[0030] In one embodiment, hydrolysis of the compound of formula XA is carried out in the presence of an acid.
[0031] In one embodiment, the acid hydrolysis may be carried out by using hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid and the like.
[0032] In one embodiment, hydrolysis of the compound of formula XA is carried out in the presence of a base.
[0033] 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.
[0034] 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.
[0035] In one embodiment, solvent is tetrahydrofuran.
[0036] In one embodiment, hydrogenation of the compound of formula XA is carried out in the presence of a catalyst.
[0037] In one embodiment, the catalyst is selected from the group consisting of platinum, palladium, Raney nickel.
[0038] 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 IVA,
XIA IVA
wherein R1 is C1-6 alkyl, C1-6 alkylaryl; R is Cl, OH, OR1.
[0039] 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.
[0040] 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.
[0041] 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,
VIII.
[0042] In one embodiment, the present invention provides a process as depicted in scheme III for the preparation of lasmiditan, a compound of formula I.

Scheme III
[0043] 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
[0044] In one embodiment, a compound of formula I is prepared by reacting a compound of formula VII with a compound of formula VIII.
[0045] 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.
[0046] 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.
[0047] In one embodiment, the base is butyl lithium.
[0048] 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.
[0049] 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.
[0050] In one embodiment, the Grignard reagent is isopropyl magnesium chloride, lithium chloride complex.
[0051] In one embodiment, the Grignard reagent is alkyl magnesium halide.
[0052] In one embodiment, compound of formula I is prepared by reacting compound of formula X with compound of formula VIII.
[0053] 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.
[0054] 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.
[0055] In one embodiment, the base is butyl lithium.
[0056] 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
[0057] In one embodiment, the Grignard reagent is as discussed supra.
[0058] In one embodiment, compound X is prepared by reacting compound IVA with compound XI.
[0059] In one embodiment, compound X is prepared by reacting compound IVA with compound XI in the presence of a chlorinating agent.
[0060] In one embodiment, chlorinating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phophoprous oxychloride.
[0061] In one embodiment, chlorinating agent is oxalyl chloride.
[0062] In one embodiment, compound X is prepared by reacting compound IVA with compound XI in the presence of a base.
[0063] 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.
[0064] In one embodiment, compound X is prepared by reacting compound IV with compound XI in the presence of a solvent.
[0065] In one embodiment, solvent is selected from the group consisting of methylene chloride, ethylene chloride, tetrahydrofuran and toluene.
[0066] In one embodiment, solvent is methylene chloride.
[0067] In one embodiment, the present invention provides a compound selected from the following:
X IX
VII.
[0068] 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).
[0069] 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.
[0070] 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).
[0071] 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.
[0072] 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).
[0073] 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.
[0074] In one embodiment, the present invention provides use of a compound selected from the following
X IX
VII
[0075] In the preparation of lasmiditan or pharmaceutically acceptable salt thereof.
[0076] In one embodiment, the present invention provides a process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
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,
IX VII.
The reaction conditions are as discussed supra.
[0077] In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention is obtained as a solid.
[0078] In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention is obtained as a crystalline solid.
[0079] In one embodiment, lasmiditan a compound of formula I obtained by the process of the present invention is obtained as an amorphous solid.
[0080] In one embodiment, lasmiditan a compound of formula I is obtained as a solid by isolating from a suitable solvent.
[0081] 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.
[0082] 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.
[0083] In one embodiment, lasmiditan a compound of formula I is converted to lasmiditan hydrochloride, a compound of formula IA.
IA
[0084] In one embodiment, lasmiditan hydrochloride, a compound of formula IA is prepared by reacting lasmiditan, a comp of formula I with hydrochloric acid.
[0085] 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.
[0086] In one embodiment, lasmiditan, a compound of formula I is converted to lasmiditan hemi succinate, a compound of formula IB.
IB
[0087] 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.
[0088] 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.
[0089] 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.
[0090] In one embodiment, lasmiditan and salt thereof are purified by the purification methods known in the art.
[0091] In one embodiment, lasmiditan and salt thereof are purified by dissolving in a suitable solvent and recrystallizing.
[0092] In one embodiment, lasmiditan and salt thereof are purified by dissolving in a suitable solvent and adding an anti-solvent.
[0093] In one embodiment, the lasmiditan obtained by the process described herein, has a purity of =99%, as determined by HPLC.
[0094] In one embodiment, the present invention provides lasmiditan free of any of the below listed impurities A – G.



[0095] 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.
[0096] 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.
[0097] 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.
[0098] 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
[0099] Example-1: 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 10-15min 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.
[0100] Example-2: 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.
[0101] Example-3: 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.
[0102] Example-4: Synthesis of compound of formula I
4-chloro-1-methyl piperidine is added to tetrahydrofuran to obtain a reaction mass. The reaction mass is cooled to about 10°C to 20°C, solution of isopropyl magnesium chloride lithium chloride complex in tetrahydrofuran is added to the reaction mass at about 10°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.
[0103] Example-5: Synthesis of compound of formula I
4-chloro-1-methyl piperidine is dissolved in tetrahydrofuran, the reaction mass is cooled to about 10°C to 20°C; isopropyl magnesium chloride lithium chloride complex dissolved in tetrahydrofuran is added to the reaction mass at about 10°C to 20°C. The reaction mass is stirred at about 10°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 10°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.
[0104] Example-6: Synthesis of compound of formula X
To a mixture of 2,4,6-trifluorobenzoic acid (23.13g), dichloromethane (260mL) and dimethylformamide (0.2mL) was added oxalyl chloride (25.08g) at about 25°C and the reaction mixture was stirred for about 1h. 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 (150mL) 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: 18g
Mass spectrum: m/z= 309(M-1); 1H NMR (CDCl3) ppm 3.94(s, 3H) 6.69(m, 2H) 7.88(m, 1H) 7.95(t, 1H) 8.61(d, 1H) 9.34(s, 1H); 13C NMR (CDCl3) 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
[0105] Example-7: 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 (19.24g) at about 25°C for about 1h. 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 (12g), methylene chloride (140mL) and triethylamine (10g) 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: 18g; HPLC Purity: 99.89%
[0106] Example-8: Synthesis of compound of formula X
To a mixture of 2,4,6-trifluorobenzoic acid (10g), methylene chloride (100mL) and dimethylformamide (0.2mL) was added oxalyl chloride (9.6g) at about 25°C and stirred for about 1h. 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: 9.1g; HPLC Purity: 99.72%
[0107] Example-9: 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 15min. HATU (13g) 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: 2.01g; HPLC Purity: 97.68%
[0108] Example-10: Synthesis of compound of formula X
A mixture of 2,4,6-trifluorobenzoic acid (10g) and thionyl chloride (30ml) was heated to about 70 to 75°C and maintained for about 1h. 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 (11.47g) and methylene chloride (50ml) cooled to about 0°C and stirred for about 1h. The temperature of the reaction mass was raised to about 25°C and 1M aqueous hydrochloric acid (100mL) 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%
[0109] Example-11: 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+1); 1H NMR (DMSO) ppm 7.33(m, 2H), 7.86(d, 1H), 8.05(t, 1H), 8.39(d, 1H), 11.74(s, 1H), 13.33(s, 1H)
13C NMR (CDCl3) 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
[0110] Example-12: 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: 13.1g; HPLC Purity: 97.64%
[0111] Example-13: Synthesis of compound of formula IX
To a solution of sodium hydroxide (7.74g) in water (150mL), 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%
[0112] Example-14: Synthesis of compound of formula VII
To a mixture of compound of formula IX (10g) in dimethylformamide (40mL) was added and triethylamine (10.23g), N,O-dimethylhydroxylamine hydrochloride (3.22g) and HATU (15.4g) 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+1); 1H NMR (CDCl3) 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 (CDCl3) 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
[0113] Example-15: Synthesis of compound of formula VII
To a mixture of compound of formula IX (20g) in dimethylformamide (125mL), was added triethylamine (25.6g), N,O-dimethylhydroxylamine 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%
[0114] Example-16: Synthesis of compound of formula VII
To a mixture of compound of formula IX (10g) in dimethylformamide (50mL), was added triethylamine (10.23g), N,O-dimethyl hydroxylamine hydrochloride (3.6g) and HATU (15.4g) 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: 10.07g; HPLC Purity: 99.33%
[0115] Example-17: Synthesis of lasmiditan hemisuccinate
(a) To a mixture of 4-chloro-1-methylpiperidine hydrochloride (25g) in water (75mL) was added potassium carbonate (25g). The reaction mixture was extracted with methyl tert-butyl ether. The organic layer was washed with aqueous sodium chloride solution and concentrated to give 4-chloro-1-methylpiperidine free base. Yield: 14g
(b) To a mixture of magnesium turnings (12.5g), pinch of iodine and ethylene dibromide (1mL) in tetrahydrofuran (40mL) was added a mixture of 4-chloro-1-methyl piperidine (20g) in tetrahydrofuran (100mL). 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 (10g) in tetrahydrofuran (150mL) at about 0°C. The reaction mixture was stirred for about 1h 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 (100mL) 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
[0116] Example-18: 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 1-methylpiperidine-4-yl-magnesium chloride in THF (75mL) and the reaction mixture was stirred for about 1h. 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: 4.12g; HPLC purity: 99.10%
[0117] Example-19: Synthesis of lasmiditan hemisuccinate
To a mixture of compound of formula VII (10g) in tetrahydrofuran (50mL) cooled to about 0°C, was added 1M solution of 1-methylpiperidine-4-yl-magnesium chloride in tetrahydrofuran (180mL) 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 (100mL) 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%
[0118] Example-20: 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 1-methylpiperidine-4-yl-magnesium chloride in tetrahydrofuran (118mL) slowly at about 0°C and the reaction mixture was stirred for about 1h. 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 1h. The solid obtained was filtered, washed with isopropyl alcohol and dried. Yield: 6.35g; HPLC Purity: 98.25%
[0119] Example-21: Synthesis of lasmiditan hemisuccinate
To a mixture of compound of formula VII (18g) in tetrahydrofuran (180mL) cooled to about 0°C to about -10°C, was added 1M solution of 1-methylpiperidine-4-yl-magnesium chloride in tetrahydrofuran (180mL) slowly at about -5°C to about -10°C and the reaction mixture was stirred for about 1h. 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 (180mL) 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
[0120] Example-22:
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 1h. The solid obtained was filtered, washed with isopropyl alcohol and dried. Yield: 2.6g; HPLC Purity: 99.38%
XRPD peaks of lasmiditan hemisuccinate
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
7.67 11.52 9.46 21.55 4.12 20.25 30.07 2.97 7.77
9.58 9.22 25.77 22.17 4.00 45.97 30.42 2.93 6.18
9.71 9.10 10.82 23.18 3.83 45.60 30.87 2.89 10.96
11.04 8.00 8.86 23.41 3.79 51.17 31.47 2.84 17.73
13.37 6.61 13.81 23.60 3.76 47.21 32.68 2.73 14.82
14.08 6.28 44.76 23.88 3.72 21.08 32.96 2.71 13.55
15.10 5.86 66.69 24.80 3.58 28.15 33.71 2.65 7.43
15.32 5.78 48.55 25.06 3.55 14.76 34.22 2.61 5.12
16.17 5.47 53.26 25.62 3.47 25.49 35.40 2.53 8.10
16.43 5.39 100.00 25.81 3.45 38.13 37.45 2.40 2.93
16.90 5.24 51.83 25.95 3.43 38.19 38.59 2.33 5.29
18.50 4.79 36.62 26.69 3.33 9.98 39.38 2.28 4.70
19.20 4.62 35.92 26.90 3.31 6.46 39.79 2.26 3.54
19.40 4.57 67.76 28.39 3.14 6.75 41.40 2.18 2.37
19.59 4.52 13.91 28.66 3.11 8.32 42.80 2.11 5.09
20.10 4.41 1.05 29.32 3.04 1.76 43.77 2.06 2.74

[0121] Example-23:
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 1h. The solid was filtered, washed with isopropyl alcohol and dried. Yield: 5.45g; HPLC Purity: 99.69%
[0122] Example-24:
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 1h. 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.
Example No Solvent Temperature HPLC Purity
Example-33 Methanol 55°C 99.87%
Example-34 Ethyl acetate 65°C 98.92%
Example-35 Acetone 40°C 97.61%
Example-36 Toluene 100°C 98.75%
sExample-37 THF 60°C 99.50%
Example-38 IPA-methanol 55°C 99.35%

WE CLAIM
1. A process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
the process comprising:
(a) reacting a compound of formula IX with N-methoxymethylamine or salt thereof to obtain a compound of formula VII;
IX VII
(b) reacting the compound of formula VII with a compound of formula XIV
XIV
wherein R is MgX, Li, ZnX, Sn(C1-6 alkyl)3; 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 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, HOAt, TFFH, and mixtures thereof.
3. The process of claim 1, wherein step (a) is carried out in the presence of a base.
4. The process of claim 1, wherein the step (b) is carried out at a temperature of about -20°C to about 10°C.
5. The process of claim 1, wherein in step (c), lasmiditan is converted to lasmiditan hemisuccinate.
6. The process of claim 1, wherein the compound of formula IX is prepared by a process comprising:
(x) hydrolyzing a compound of formula XA, wherein hydrolysis is carried out in the presence of an acid or a base; or
(y) hydrogenating a compound of formula XA, wherein the hydrogenation is carried out in the presence of catalyst selected from platinum, palladium, Raney nickel;
XA
wherein R1 is C1-6 alkyl, C1-6 alkylaryl.
7. The process of claim 6, wherein the compound of formula XA is prepared by a process comprising reacting a compound of formula XIA with a compound of formula IVA,
XIA IVA
wherein R1 is C1-6 alkyl, C1-6 alkylaryl; R is Cl, OH, OR1.
8. The process of claim 1, wherein R is MgX and X is Cl.
9. 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,

VIII.
10. A process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
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,
IX VII.

Dated this 5th day of November, 2019

(Signed)____________________
DR. VARSHA SADEKAR
DEPUTY GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED
,CLAIMS:WE CLAIM
1. A process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
the process comprising:
(a) reacting a compound of formula IX with N-methoxymethylamine or salt thereof to obtain a compound of formula VII;
IX VII
(b) reacting the compound of formula VII with a compound of formula XIV
XIV
wherein R is MgX, Li, ZnX, Sn(C1-6 alkyl)3; 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 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, HOAt, TFFH, and mixtures thereof.
3. The process of claim 1, wherein step (a) is carried out in the presence of a base.
4. The process of claim 1, wherein the step (b) is carried out at a temperature of about -20°C to about 10°C.
5. The process of claim 1, wherein in step (c), lasmiditan is converted to lasmiditan hemisuccinate.
6. The process of claim 1, wherein the compound of formula IX is prepared by a process comprising:
(x) hydrolyzing a compound of formula XA, wherein hydrolysis is carried out in the presence of an acid or a base; or
(y) hydrogenating a compound of formula XA, wherein the hydrogenation is carried out in the presence of catalyst selected from platinum, palladium, Raney nickel;
XA
wherein R1 is C1-6 alkyl, C1-6 alkylaryl.
7. The process of claim 6, wherein the compound of formula XA is prepared by a process comprising reacting a compound of formula XIA with a compound of formula IVA,
XIA IVA
wherein R1 is C1-6 alkyl, C1-6 alkylaryl; R is Cl, OH, OR1.
8. The process of claim 1, wherein R is MgX and X is Cl.
9. 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,

VIII.
10. A process for the preparation of lasmiditan, a compound of formula I, or pharmaceutically acceptable salts thereof,
I
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,
IX VII.

Dated this 5th day of November, 2019

(Signed)____________________
DR. VARSHA SADEKAR
DEPUTY GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED