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

BACKGROUND OF THE INVENTION
Lasmiditan is a 5-HT1F agonist and is chemically known as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-yl carbonyl)-pyridin-2-yl]-benzamide, represented by compound of Formula I:
.
US 7,423,050 B2 (US’050) discloses the preparation of lasmiditan and salts thereof, specifically hydrochloride & hemi succinate as mentioned in the Scheme 1 & Scheme 2 below:
Scheme 1:
.
Scheme 2:
.
US’050 discloses a method for the preparation of hydrochloride salt of Lasmiditan using isopropyl alcohol and diethyl ether as crystallization solvent.

US’050 also discloses a method for the preparation of hemi succinate salt of Lasmiditan using acetone as crystallization solvent.

US 8,697,876 B2 (US’876) discloses a method for preparation of lasmiditan and salts thereof as mentioned in the scheme 3 below.
Scheme 3:
.
US’876 further discloses an anhydrous solid crystalline form (Form A) of lasmiditan hemi succinate wherein said Form A is obtained by crystallization with ethanol. US’876 describes two additional XRPD patterns designated Form B and Form C of lasmiditan hemi succinate as well as amorphous form of lasmiditan free base and hemi succinate salt.
PCT application, WO2018106657 A1 (WO’657) discloses the pseudo-polymorphs of lasmiditan hemi succinate selected from Form D, Form E, and Form F and mixtures thereof, either alone or in combination with Form A. Form D is also referred to as Hydrate 1 or the di-hydrate. Form E is also referred to as the dehydrated hydrate of Form D, and it may exist as a partially or fully dehydrated hydrate of Form D. Form F is also referred to as the tri-hydrate. The structure of Form F was determined based on weight-loss from a crystallization study.

PCT application, WO 2018010345 A1 (WO’345) discloses certain polymorphic forms of lasmiditan free base & hydrochloride salt. WO’345 discloses lasmiditan free base crystalline form selected from Form 1, Form 2 & Form 3. It further discloses crystalline form of hydrochloride salt of lasmiditan selected from Form A, Form B, Form C, Form E & Form G.

Although there are several processes known in the literature for the preparation of lasmiditan and its intermediate(s), the present invention is focussed to provide an improved process for the preparation of lasmiditan and its salt by using novel compounds as intermediates.

Based on aforesaid, the present invention provides a novel process for the preparation of lasmiditan & its pharmaceutically acceptable salts which is simple, reproducible and well suited on commercial scale. The present invention is directed towards the development of novel compounds and use of said compounds in the preparation of lasmiditan and salts thereof.

OBJECT OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide novel intermediates that can be used for the preparation of lasmiditan or pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula X or salt thereof,
,
wherein R4 is hydrogen or nitrogen protecting group selected from carbon containing moieties, silyl containing moieties and sulfur containing moieties, and
Rx is R or -CORx1 and wherein R is selected from suitable leaving group, hydroxyl, alkoxy, (un)substituted amine, protected amine; Rx1 is selected from hydroxyl, halogen, alkoxy, protected amine, (un) substituted amine, (un) substituted alkyl, (un) substituted cyclic ring optionally substituted with one or more heteroatom.

In another aspect, the present invention provides compounds of Formula VIII or salt thereof represented by Formula:
,
wherein R3 is independently selected from C1-C6 alkyl or R4; R4 is independently selected from hydrogen, nitrogen protecting group selected from carbon containing moieties, silyl containing moieties and sulfur containing moieties; wherein when R3 is alkyl then R4 is not hydrogen.

In another aspect, the present invention provides compounds of Formula VIII or salt thereof represented by Formulae VIII A and VIII B as mentioned below:
,
wherein R4 is as defined above.

In one aspect, the present invention provides novel compounds of Formula II, or salt thereof,

wherein Q is hydroxyl, (un)substituted amine, (un)substituted aryl, (un)substituted heteroaryl optionally substituted with halogen, amine, protected amine, N(R1)(OR2); wherein wherein R1 and R2 are independently selected from straight or branched chain alkyl, or R1, R2 together form (un)substituted cyclic ring optionally comprising one or more heteroatoms and R3 independently selected C1-C6 alkyl or R4; R4 is independently selected from hydrogen, nitrogen protecting group selected from carbon containing moieties, silyl containing moieties and sulfur containing moieties; wherein R3 is alkyl then R4 is not hydrogen.

In another aspect, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) converting compound of Formula III or salt thereof, to compound of Formula IV in presence of suitable solvent,
,
wherein R1, R2 and R3 are as defined above,
b) reacting compound of Formula IV or salt thereof with compound of Formula V B in presence of suitable solvent to give compound of Formula XII,
,
wherein X is selected from halogen, and R, R1, R2 and R3 are as defined above;
c1) converting compound of Formula XII to compound of Formula VIb in presence of suitable solvent; wherein compound of Formula VIb is optionally not isolated,
,
wherein R and R3 are as defined above;
OR
c2) preparing compound of Formula VIII by treating compound of Formula XII or VIb with compound of Formula VII in presence of suitable solvent; wherein compound of Formula VIII is optionally not isolated,
,
wherein A is selected from suitable leaving group, hydroxyl, alkoxy, amine or protected amine; R, R3 and R4 are as defined above; and
d) converting compound of Formula VIII to lasmiditan of Formula I or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula VII with compound of Formula VI to give compound of Formula VIII,
,
wherein, A is selected from suitable leaving group, R3 and R4 are as defined above; and
b) converting compound of Formula VIII to lasmiditan or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula V with compound of Formula VII in presence of suitable solvent to obtain compound of Formula X,
,
wherein A is selected from suitable leaving group, hydroxyl, alkoxy, amine or protected amine, Rx and R4 are as defined above;
b) converting compound of Formula X to lasmiditan or pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

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

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

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

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

The “suitable solvent” as used in the context of the present invention is selected from, but not limited to, protic solvents, aprotic solvents, C1-C6 alcohols, C1-C8 hydrocarbons, halogenated hydrocarbons, ethers, C3-C8 ketones, esters, nitriles, sulphonamides, acetamides, pyrrolidines, formamides, water and mixture thereof. For Example, some of the suitable solvents comprises of methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, pentanol, glycols, toluene, chlorobenzene, acetonitrile, propionitrile, butanenitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), methyl tetrahydrofuran, dioxane, dipropyl ether, diisopropyl ether, ethyl methyl ether, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dicholoromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, methyl acetate, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, isopropyl acetate, propenyl acetate, butyl acetate, hexane, n-heptane, cyclohexane, petroleum benzine, xylene, water and mixture thereof.

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

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

In one embodiment, the present invention provides novel compounds of Formula II, or salt thereof,

wherein Q and R3 are defined above.

In another embodiment, the present invention provides compound of Formula X, or salt thereof,
,
wherein Rx & R4 is hydrogen or nitrogen protecting group selected from carbon containing moieties, silyl containing moieties and sulfur containing moieties, and

In another embodiment, the present invention compound of Formula X or salt thereof represented as compound of Formula X B as mentioned below:

wherein B is selected from hydroxyl, halogen, C1-C6 alkoxy, protected amine, (un)substituted amine optionally independently substituted with C1-C6 alkyl, C1-C6 alkoxy, and
R4 is as defined above.

In another embodiment, the present invention provides compounds of Formula VIII or salt thereof represented by Formula:
,
wherein R3 and R4 are defined above.

In another embodiment, the present invention provides compounds of Formula VIII or salt thereof represented by compounds of Formulae VIII A and VIII B as mentioned below:
,
wherein R4 is as defined above.

In another embodiment, the present invention provides novel compounds or salt thereof represented by Formulae:
, , , , , , and
wherein X is halogen, R1, R2, R3 & R4 are as defined above.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof by using novel intermediates of Formula II, VIII and X.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof,

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising conversion of compound of formula VIII to lasmiditan of Formula I or pharmaceutically acceptable salt thereof in the presence of solvent.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof,

comprising the steps of:
a) converting compound of Formula III or salt thereof to compound of Formula IV in presence of suitable solvent,
,
wherein R1, R2 and R3 are as defined above,
b) reacting compound of Formula IV or salt thereof with compound of Formula V B in presence of suitable solvent to give compound of Formula XII,
,
wherein X, R, R1, R2 and R3 are as defined above;
c1) converting compound of Formula XII to compound of Formula VIb in presence of suitable solvent; wherein compound of Formula VIb is optionally not isolated,
,
wherein R and R3 are as defined above;
OR
c2) preparing compound of Formula VIII by treating compound of Formula XII OR Formula VIb with compound of Formula VII in presence of suitable solvent; wherein compound of Formula VIII is optionally not isolated,
,
wherein A is selected from suitable leaving group, hydroxyl, alkoxy, amine or protected amine; R, R3 and R4 are as defined above; and
d) converting compound of Formula VIII to lasmiditan of Formula I or its salts thereof.

In a preferred embodiment, the group R in compound of Formula XII is selected from halogen or –NHR4.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) converting compound of Formula XII A to compound of Formula VIb in presence of suitable solvent and an aminating agent,
,
wherein X and R4 are as defined above;
b) converting compound of Formula VIb to lasmiditan of Formula I or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula VII with compound of Formula VI to give compound of Formula VIII,
,
wherein, A is suitable leaving group, R3 and R4 are as defined above; and
b) converting compound of Formula VIII to lasmiditan or pharmaceutically acceptable salt thereof.

In preferred embodiment, the present invention provides a process for the preparation of lasmiditan or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula VIIa with compound of Formula VI to give compound of Formula VIII
,
wherein, A is selected from halogen, R3 and R4 are as defined above;
b) deprotecting compound of Formula VIII in the presence of suitable acid to obtain compound of Formula IX,
;
R3 and R4 are as defined above;
c) methylating compound of Formula IX in the presence of suitable methylating agent; and
d) converting compound obtained from step c) to lasmiditan or pharmaceutically acceptable salt thereof.

In another embodiment, the said leaving group is selected from any moiety that can easily be replaced by other groups or can take part in the coupling /condensation reactions.

In another embodiment, the said suitable leaving group is selected from halogen, OR5, wherein R5 is selected from mesylate, tosylate, triflate, (un) branched, (un) saturated alkyl group or any carbon containing moiety, sulfur containing moiety and silyl containing moiety.

In a preferred embodiment, the aminating agent is selected from ammonia, ammonium hydroxide and the like.

In another embodiment, the amine protecting group is selected from any moiety that protect amine group from taking part in the reaction. The said nitrogen protecting groups are selected from any carbon containing moiety, silyl containing moiety or sulphur containing moiety. Preferably, the suitable protecting group is selected from tert butoxy carbonyl, carbazol carbonyl, benzoyl, benzyl carbonyl, benzoic acid, trifluoro methylene carbonyl, fluorenylmethyloxy carbonyl, trifluoroacetamide, allyl carbonyl, benzyloxy carbonyl, trichloroethyl carbonyl and benzyl group

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula V with compound of Formula VII in presence of suitable solvent to obtain compound of Formula X,
,
wherein A is selected from suitable leaving group, hydroxyl, alkoxy, amine or protected amine, Rx and R4 are as defined above; and
b) converting compound of Formula X to lasmiditan or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula V A with compound of Formula VII in presence of suitable solvent to obtain compound of Formula XA,
,
wherein A is selected from suitable leaving group, R and R4 are as defined above;
b) reacting compound of Formula XA or salt thereof with compound of Formula IV in presence of suitable solvent to give compound of Formula VIII,
,
wherein R, R1, R2, R3 and R4 are as defined above;
c) converting compound of Formula VIII to lasmiditan or pharmaceutically acceptable salt thereof.

In a preferred embodiment, the group R in compound of Formula X A is selected from halogen.

In another embodiment, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula XI with compound of Formula VII in presence of suitable solvent to obtain compound of Formula XB,
,
wherein A is a suitable leaving group, B and R4 are as defined above;
b) reacting compound of Formula XB or salt thereof with compound of Formula XVI in presence of suitable solvent to give compound of Formula VIII,

wherein Y is selected from halogen, protected amine, (un)substituted amine, R3, R4 & B are as defined above; and
c) converting compound of Formula VIII to lasmiditan or pharmaceutically acceptable salt thereof.

In another embodiment, the process for the preparation of lasmiditan as per the process of the present invention may be carried out in one pot without isolation of intermediates.

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

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

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

In another preferred embodiment, the suitable acid is selected from hydrochloric acid or succinic acid.

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

In another embodiment, the present invention provides novel crystalline form of lasmiditan hydrochloride salts.

In another embodiment, the present invention provide substantially pure crystalline form of lasmiditan hydrochloride salts substantially free from other crystalline polymorphic forms.

In another embodiment, the present invention provide substantially pure crystalline form of lasmiditan hydrochloride salts substatnitally free from amorphous form.

In another embodiment, the present invention provides a crystalline form of lasmiditan hydrochloride salt characterized by X-Ray Powder Diffraction (XRPD) peaks (2? values) at about 9.80, 18.44, 28.71±0.2°?. In another embodiment, the present invention provides a crystalline form of lasmiditan hydrochloride salt having characteristic X-Ray Powder Diffraction (XRPD) peaks (2? values) at 9.80, 12.40, 13.45, 15.27, 18.44, 22.70, 28.71, 30.73, 31.77, 32.32, 33.05±0.2°?. In another embodiment of the present invention the substantially pure crystalline form of lasmiditan hydrochloride salt is further characterised by X-Ray Powder Diffraction (XRPD) peaks (2? values) at 9.16, 12.16, 12.79, 16.66, 20.50, 20.93, 23.29, 26.08, 27.10, 31.32, 32.61, 34.99, 38.30±0.2°?.

In specific embodiment, the present invention provides a substantially pure crystalline form of lasmiditan hydrochloride salt characterized by XRD pattern having 2? value of 9.80, 18.44, 28.71±0.2°?, and by Differential Scanning Calorimetry with onset peak at about 267.99oC and peak at about 270.98oC.
In another embodiment, the present invention provide a process for preparing pharmaceutical composition comprising crystalline form of lasmiditan hydrochloride salt along with atleast one pharmaceutical acceptable excipients.

In another embodiment, the lasmiditan or pharmaceutically acceptable salt thereof is prepared as per the Scheme 4 as mentioned below:
Scheme 4:

In an alternate embodiment, the lasmiditan or pharmaceutically acceptable salt thereof is prepared as per the Scheme 5 as mentioned below:
Scheme 5:

In an alternate embodiment, the lasmiditan or pharmaceutically acceptable salt thereof is prepared as per the Scheme 6 as mentioned below:
Scheme 6:

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

In another preferred embodiment, the lasmiditan or its salt is characterized by the particle size wherein, D90 is between 0.1µm to 200µm, preferably between 2.0 µm to 150µm and most preferably, D90 is less than about 100µm.

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

EXAMPLES
Example 1: Preparation of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid:
Piperidine-4-carboxylic acid (10.0g 0.077mole) was dissolved in solution of dichloromethane (7 vol) and triethyl amine (0.116mole, 11.75g) and cooled the mass at 0-5°C. Slowly charged boc-anhydride (16.80g, 0.077mole) and stirred the mass for 4-5hr at room temperature. After completion of reaction, charged water (3vol) at room temperature and stirred the reaction mass and separated the aq. layer. Organic layer was washed with 0.5% citric acid solution. Isolated the dichloromethane layer and proceeded to next step as such.
Example 2: Preparation of tert-butyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate
To the 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid dichloromethane layer was added triethyl amine (0.232mole, 23.5g) and cooled the mass 0-5°C under nitrogen. Slowly charged oxalyl chloride (0.085mole, 10.78g) at 0-5°C, and maintained for 1hr at 0-5°C. Slowly charged dimethyl amine (2.0eq) at 0-5°C and stirred the mass for 4-5hr at room temp. After completion of reaction, separated the organic layer and distilled the mass to get desired product (12.0g).
Example 3: Preparation of tert-butyl 4-(6-((tert-butoxycarbonyl)amino)picolinoyl) piperidine-1-carboxylate:
To a stirred solution of tert-butyl (6-bromopyridin-2-yl) (2,4,6-trifluorobenzoyl)carbamate (15.0g 0.0348 mol) dissolved in 75.0 ml of THF was added n-butyl lithium 2.5M (13.92 ml 0.0348 mol) at -78 °C under inert atmosphere and stirred for 1.0 hrs. The N,N,1-trimethylpiperidine-4-carboxamide (5.91g 0.0348 mol) was dissolved in 20.0 ml of THF and added drop wise in to above reaction mixture. After completion of reaction, quenched the reaction mixture with sat. NH4Cl solution, acidified with conc. HCl solution and stirred for 2.0 hrs at 50 °C. The organic layer was separated and aqueous layer was then extracted with ethyl acetate. The combined organic layer were dried over sodium sulfate and evaporated to give tert-butyl 4-(6-((tert-butoxycarbonyl)amino)picolinoyl) piperidine-1-carboxylate (10.0 g)
Example 4: Preparation of tert-butyl 4-(6-(N-(tert-butoxycarbonyl)-2,4,6-trifluorobenzamido) picolinoyl) piperidine-1-carboxylate
To tert-butyl 4-(6-((tert-butoxycarbonyl)amino)picolinoyl) piperidine-1-carboxylate (10.0g 0.0246mole) dissolved in dichloromethane (10vol), was charged triethyl amine (4.99g) at room tempertaure. Cooled the reaction mass to 0-5°C under nitrogen. Slowly charged dichloromethane solution of 2,4,6-trifluorobenzoyl chloride(4.66g 1.0eq) in reaction mass at 0-5°C. Maintained the mass at 0-5°C for 3hrs. After completion of reaction, charged water (3vol) and stirred the mass at room temperature. Separated the organic layer and washed with 10% citric acid solution (92vol). Distilled the organic layer at 40°C to get the desired material (10.0g).
Example 5: Preparation of 2,4,6-trifluoro-N-(6-(piperidine-4-carbonyl)pyridin-2-yl)benzamide
To tert-butyl 4-(6-(N-(tert-butoxycarbonyl)-2,4,6-trifluorobenzamido) picolinoyl) piperidine-1-carboxylate was added aq. HCl or methanolic HCl/ether HCl at room temperture. Stirred for 1hr and distilled the aq HCl or methanolic HCl at 50-60°C under vacuum. Charged water and adjusted the pH to 10-12 with NaOH solution. Extracted the compound with dichloromethane (10vol). Distilled the organic layer under vacuum to get desired compound (6.5g).
Example 6: Preparation of tert-butyl (6-bromopyridin-2-yl)(2,4,6-trifluoro benzoyl)carbamate
To a stirred solution of tert-butyl (6-bromopyridin-2-yl)carbamate (10g, 0.0366mol) in dichloromethane (100.0 ml) at ambient temperature was added 5.54g (0.0549 mol) of triethyl amine and 7.10 g (0.0366 mol) of 2,4,6-trifluorobenzoyl chloride was added drop wise. The reaction mixture was stirred for 4.0 hrs at ambient temperature. To the reaction mixture was added 100.0 ml of DM-water and separated the layers. The combined organic layer were dried over sodium sulfate and evaporated to get tert-butyl (6-bromopyridin-2-yl)(2,4,6-trifluorobenzoyl)carbamate.
Example 7: Preparation of tert-butyl(2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide
To a stirred magnesium turning (0.837 g 0.0348 mol) in 150.0 ml of THF was added (15.0g 0.0348 mol) tert-butyl (6-bromopyridin-2-yl)(2,4,6-trifluorobenzoyl)carbamate dissolved in 15.0 ml of THF at 50oC. The 5.91g (0.0348 mol) of N,N,1-trimethylpiperidine-4-carboxamide was dissolved in 25.0 ml of THF and added into the above reaction mixture. After completion of reaction, quenched the reaction mixture with sat. NH4Cl solution, distilled out the solvent to obtain residue. The resulting residue washed with ethyl acetate (3×35.0 ml). Dried the residual solid under vacuum to get titled compound. (Purity by HPLC: 99.2%)
Example 8: Preparation of (2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide (Lasmiditan)
To tert-butyl(2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide was added aq. HCl or methanolic HCl/ether HCl at room temperture. Stirred for 1hr and distilled the aq HCl or methanolic HCl at 50-60°C under vacuum. Charged water and adjusted the pH to 10-12 with NaOH solution. Extracted the compound with dichloromethane (10vol). Distilled the organic layer under vacuum to get desired compound (Purity by HPLC: 99.92%)
Example 9: Preparation of (2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide (Lasmiditan)
To a stirred magnesium turning (0.837 g 0.0348 mol) in 150.0 ml of THF was added (15.0g 0.0348 mol) tert-butyl (6-bromopyridin-2-yl)(2,4,6-trifluorobenzoyl)carbamate dissolved in 15.0 ml of THF at 50oC. The 5.91g (0.0348 mol) of N,N,1-trimethylpiperidine-4-carboxamide was dissolved in 25.0 ml of THF and added into the above reaction mixture. After completion of reaction, quenched the reaction mixture with sat. NH4Cl solution, acidified with conc. HCl solution and stirred for 2.0 hrs at 50 °C. The organic layer was separated and aqueous layer extracted with ethyl acetate. The combined organic layer were dried over sodium sulfate and evaporated to get (2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide. (Purity by HPLC: 99.92%)
Example 10: Preparation of tert-butyl 4-[(6-bromopyridin-2-yl)carbonyl]piperidine-1-carboxylate
Stirred magnesium turning (1.5 g 0.0635mol) at 50 °C for 1 hrs in 50.0 ml of THF. The (15.0g 0.0635 mol) 2,6-dibromopyridine was dissolved in 45.0 ml THF, added dropwise to above magnesium turnings and stirred for 2.0 hrs. The (16.27g 0.0625 mol) tert-butyl 4-(dimethylcarbamoyl)piperidine-1-carboxylate was dissolved in 25.0 ml THF and added into above reaction mixture. The reaction mixture quenched with sat. NH4Cl solution. The organic layer was separated and aqueous layer extracted with ethyl acetate. The combined organic layer were dried over sodium sulfate and evaporated to get tert-butyl 4-[(6-bromopyridin-2-yl)carbonyl]piperidine-1-carboxylate
Example 11: Preparation of tert-butyl 4-[(6-aminopyridin-2-yl)carbonyl]piperidine-1-carboxylate
To a stirred solution of tert-butyl 4-[(6-bromopyridin-2-yl)carbonyl]piperidine-1-carboxylate (10g,0.0271mol) in NMP (60.0 ml) at ambient temperature was added aq. ammonia (15.0ml) and copper(II) oxide (42.0 mg). The reaction mixture was stirred for 10-12 hrs at 110-120°C. The reaction mixture was then basified at pH 10-11 using 10% NaOH and extracted with dichloromethane×3. The combine organic layer were dried over sodium sulfate and evaporated to get tert-butyl 4-[(6-aminopyridin-2-yl)carbonyl]piperidine-1-carboxylate.
Example 12: Preparation of 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)pyridin-2-yl]benzamide
To a stirred solution of tert-butyl 4-[(6-aminopyridin-2-yl)carbonyl]piperidine-1-carboxylate (10g, 0.0327 mol) in dichloromethane (100.0 ml) at ambient temperature was added 6.78ml, (0.0491mol) of triethyl amine and 6.34 g (0.0327mol) of 2,4,6-trifluorobenzoyl chloride drop wise. The reaction mixture was stirred for 4.0 hrs at ambient temperature. To the reaction mixture was added 100.0 ml of 1 N HCl and heated to 50°C. The reaction mixtures was basified at pH 10-11 using 10% NaOH and extracted with ethyl acetate×3. The combined organic layer were dried over sodium sulfate and evaporated to get 2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)pyridin-2-yl]benzamide.
Example 13: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide (Lasmiditan)
2,4,6-trifluoro-N-(6-(piperidine-4-carbonyl)pyridin-2-yl)benzamide (6.0g 0.0165mole) was dissolved in mixture of aq. formaldehyde (37%) (5vol) and formic acid (3.80g, 0.0826mole) and refluxed for 12-15hr. After completion of reaction, distilled out the solvent to obtain residue. The resulting residue washed with ethyl acetate (3×35.0 ml). Dried the residual solid under vacuum to get desired compound. (5.6g).
Example 14: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hydrochloride salt (Lasmiditan hydrochloride)
2,4,6-trifluoro-N-(6-(piperidine-4-carbonyl)pyridin-2-yl)benzamide (6.0g 0.0165mole) was dissolved in mixture of aq. formaldehyde (37%) (5vol) and formic acid (3.80g, 0.0826mole) and refluxed for 12-15hr. After completion of reaction, distilled the aq. layer. Charged conc. HCl to reaction mass and adjusted the pH to 1-2. Added acetone (5vol) and stirred for 3hr at room temperature. Filtered the hydrochloride material and dried at 50°C under vacuum to get desired compound. (7.0g).
Example 15: Preparation of (2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide (Lasmiditan)
To a stirred magnesium turning (0.04 mol) in 150.0 ml of THF was added (0.04 mol) tert-butyl (6-(N-methoxy-N-methylaminocarbonyl)pyridin-2-yl)(2,4,6-trifluorobenzoyl)carbamate dissolved in 15.0 ml of THF at 50oC. The 0.04 mol of 4-chloro-1-methylpiperidine was dissolved in 25.0 ml of THF and added into the above reaction mixture. After completion of reaction, quenched the reaction mixture with sat. NH4Cl solution, acidified with conc. HCl solution and stirred for 2.0 hrs at 50 °C. The organic layer was separated and aqueous layer extracted with ethyl acetate. The combined organic layer were dried over sodium sulfate and evaporated to get (2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide. (Purity by HPLC: 99.9%)
Example 16: Preparation of 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide hydrochloride salts
To dissolved 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide 5.0g (01326 mol) in isopropanol (50.0ml) at ambient temperature and added a solution of 3.3 M diethyl ether/HCl (8.0ml). The reaction mixture was stirred for 30.0 minutes at refluxed. Cooled the reaction mixture up to room temperature and stirred for 2.0 hrs. Filtered the resulting white solid and washed with isopropanol 5.0 ml. Dried the residual solid under reduce pressure to give 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide hydrochloride salts.
Example 17: Preparation of Lasmidiatan hemisuccinate salt
To dissolved 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide 1.62g, 0.00429 mol in acetone (16.2 ml) at ambient temperature was added succinic acid (0.25g, .0021 mol) at ambient temperature. The reaction mixture was stirred for 30.0 minutes at refluxed. Cooled the reaction mixture up to room temperature and stirred for 2.0 hrs. Filtered the resulting white solid and washed with acetone (5.0 ml). Dried the residual solid under reduced pressure to get 2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide hemi succinate salts.
Example 18: Crystallization process for the preparation of substantially pure crystalline form of lasmiditan hydrochloride salt
Dissolved lasmiditan hydrochloride 500mg in a mixture of Methyl isobutyl ketone (MIBK) (10.0 ml) and DM water (0.5 ml) to form a clear solution at 110-115°C. Distilled out the solvent completely under vacuum at 50-60°C and degassed the material and dried for 3hrs at 60°C under vacuum to get 495 mg of the white solid (yield 99%).

CLAIMS:WE CLAIM

1. A process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) converting compound of Formula III or salt thereof to compound of Formula IV in presence of suitable solvent,
,
wherein R1 and R2 are independently selected from straight or branched chain alkyl, or R1, R2 together form (un)substituted cyclic ring optionally comprising one or more heteroatoms and R3 independently selected C1-C6 alkyl or R4; R4 is independently selected from hydrogen, nitrogen protecting group selected from carbon containing moieties, silyl containing moieties and sulfur containing moieties; wherein when R3 is alkyl then R4 is not hydrogen;
b) reacting compound of Formula IV or salt thereof with compound of Formula V B in presence of suitable solvent to give compound of Formula XII,
,
wherein X is selected from halogen, R is selected from suitable leaving group, hydroxyl, alkoxy, (un)substituted amine, protected amine and R1, R2 and R3 are as defined above;
c1) converting compound of Formula XII to compound of Formula VIb in presence of suitable solvent; wherein compound of Formula VIb is optionally not isolated,
,
wherein R and R3 are as defined above;
OR
c2) preparing compound of Formula VIII by treating compound of Formula XII OR Formula VIb with compound of Formula VII in presence of suitable solvent; wherein compound of Formula VIII is optionally not isolated,
,
wherein A is selected from suitable leaving group, hydroxyl, alkoxy, amine or protected amine; R3 and R4 are as defined above; and
d) converting compound of Formula VIII to lasmiditan of Formula I or pharmaceutically acceptable salt thereof.

2. The process as claimed in claim 1, wherein the group R is selected from halogen or –NHR4.

3. A process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting compound of Formula V with compound of Formula VII in presence of suitable solvent to obtain compound of Formula X,
,
wherein A is selected from suitable leaving group, hydroxyl, alkoxy, amine or protected amine; Rx is R or -CORx1 and wherein R is selected from suitable leaving group, hydroxyl, alkoxy, (un)substituted amine, protected amine; Rx1 is selected from hydroxyl, halogen, alkoxy, protected amine, (un) substituted amine, (un) substituted alkyl, (un) substituted cyclic ring optionally substituted with one or more heteroatom and R4 is as defined above; and
b) converting compound of Formula X to lasmiditan or pharmaceutically acceptable salt thereof.

4. The process as claimed in claim 3, wherein the group Rx is selected from halogen or -CORx1

5. The process as claimed in claim 3, wherein said process comprising the steps of:
a) reacting compound of Formula XI with compound of Formula VII in presence of suitable solvent to obtain compound of Formula XB,
,
wherein A is suitable leaving group, wherein B is selected from hydroxyl, halogen, C1-C6 alkoxy, protected amine, (un)substituted amine optionally independently substituted with C1-C6 alkyl, C1-C6 alkoxy, R4 is as defined above;
b) reacting compound of Formula XB or salt thereof with compound of Formula XVI in presence of suitable solvent to give compound of Formula VIII,

wherein X, R3, R4 & B are as defined above, and
c) converting compound of Formula VIII to lasmiditan or pharmaceutically acceptable salt thereof.

6. Compounds or salt thereof are represented by Formulae:
, , and ,
wherein Rx, R3 R4 & Q are as defined above.

7. The compounds as claimed in claim 6, wherein said compounds are represented by Formulae:
, , , , , , and
wherein R, R1, R2, R3 R4, X, & B are as defined above.

8. A process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salt thereof, comprising conversion of compound of formula VIII to lasmiditan of Formula I or pharmaceutically acceptable salt thereof in the presence of solvent

9. The compounds as claimed in claims 6 and 7, wherein said compounds are used for the preparation of lasmiditan or pharmaceutically acceptable salt thereof.

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