Claims:WE CLAIM
1. A process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) or pharmaceutically acceptable salts thereof, comprising the steps of:
a) methylating isonipicotic acid of Formula G to 1-methylpiperidine-4-carboxylic acid of Formula IV or its salt in presence of suitable solvent without use of metal catalyst;
,
b) reacting 1-methylpiperidine-4-carboxylic acid of Formula IV or its salt with suitable chlorinating agent in presence of suitable solvent to give 1-methylpiperidine-4-carbonyl chloride of Formula V or its salt, wherein said compound of Formula V or its salt is optionally not isolated;
,
c) converting 1-methylpiperidine-4-carbonyl chloride of Formula V or its salt to N,N,1-trimethylpiperidine-4-carboxamide of Formula III or its salt;
, and
d) converting the compound of Formula III or its salt to lasmiditan or its pharmaceutically acceptable salt.

2. A process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) or pharmaceutically acceptable salt thereof, wherein said process comprises the steps of :
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;
,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;
, and
c) converting the 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt to lasmiditan or its pharmaceutically acceptable salt

3. The process as claimed in claim 1 or 2, wherein the said pharmaceutically acceptable salt is selected from the group comprising of hydrochloride, succinate, hemisuccinate, methane sulphonate,

4. The process as claimed in claim 3, wherein the said pharmaceutically acceptable salt is hemisuccinate.

5. The process as claimed in claim 4, wherein the said process for the preparation of lasmiditan hemisuccinate of Formula II, comprising steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;
,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;
,
c) reacting 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt with 2,4,6-trifluorobenzoyl chloride in presence suitable solvent to give lasmiditan free base of Formula I;
, and
d) converting lasmiditan free base of Formula I to lasmiditan hemisuccinate of Formula II.

6. A process for the purification of lasmiditan hemisuccinate of Formula II, wherein the said process comprising the steps of:
a) providing a solution of lasmiditan free base of Formula I in suitable solvent at suitable temperature;
b) adding suitable acid to step a) to get lasmiditan salt;
c) adding suitable base to step b) to obtain lasmiditan free base of Formula I;
d) optionally isolating lasmiditan free base of Formula I of step c);
e) optionally dissolving the lasmiditan free base of Formula I in suitable solvent to get reaction mass;
f) heating the reaction mass at a temperature in the range of ambient temperature to reflux temperature of the solvent;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

7. A process for the purification of lasmiditan hemisuccinate of Formula II, wherein the said process comprising the steps of:
a) providing a solution of crude lasmiditan hemisuccinate in water at room temperature;
b) cooling the solution of step a) to 10-15oC;
c) adjusting the pH of the solution to 9-14 by adding sodium hydroxide;
d)isolating free base of lasmiditan of Formula I;
e)dissolving the lasmiditan free base of Formula I in ketone;
f) heating the reaction mass of step e) to reflux;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

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

9. The process as claimed in claims 5 or 6, wherein said lasmiditan hemisuccinate is isolated with purity 99.0% and above.

, Description:FIELD OF THE INVENTION
The present invention provides an economic and industrially advantageous process for the preparation of 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide & pharmaceutically acceptable salt thereof. The invention further relates to a process for preparation and purification of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide hemisuccinate salt.

BACKGROUND OF THE INVENTION
2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-yl carbonyl)-pyridin-2-yl]-benzamide, as represented by compound of Formula I having proprietary name “Lasmiditan” is a 5-HT1F agonist constituting a class of drugs, “ditans”.

.

Lasmiditan is approved in the form of hemisuccinate salt having brand name REYVOW, for the treatment of migraine with or without aura in adults having chemical name 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide hemisuccinate and is represented by compound of Formula II.

US 7,423,050 B2 (US’050) discloses the process for the preparation of lasmiditan and salts thereof, specifically hydrochloride & hemisuccinate as mentioned in the Scheme 1 below:

Scheme 1:
.

US’050 also discloses a method for the preparation of hydrochloride salt and hemisuccinate salt of Lasmiditan using acetone as crystallization solvent. This patent discloses preparation of compound of Formula A using isonipicotic acid and metal catalyst.

US 8,697,876 B2 (US’876) discloses a method for preparation of lasmiditan and salts thereof as mentioned in the scheme 2 below.

Scheme 2:
.

Although there are several processes known in the literature for preparation of lasmiditan and its pharmaceutically acceptable salt, there is a need to develop a process that is high yielding, reproducible, economical and provide pure compound at large scale production. Therefore, the present invention provides a process for the preparation of lasmiditan & its pharmaceutically acceptable salts with high purity wherein said process is well suited for commercial scale production.

OBJECT OF THE INVENTION
The object of the present invention is to provide a process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide hemisuccinate (lasmiditan hemisuccinate).

Another object of the present invention is to provide a process for the purification of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide hemisuccinate (lasmiditan hemisuccinate).

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of lasmiditan of Formula I or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a process for the preparation of lasmiditan hemisuccinate and purification thereof.

In another aspect, the present invention provides a process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) or pharmaceutically acceptable salts thereof, comprising the steps of:
a) methylating isonipicotic acid of Formula G to 1-methylpiperidine-4-carboxylic acid of Formula IV or its salt in presence of suitable solvent without use of metal catalyst;
,
b) reacting 1-methylpiperidine-4-carboxylic acid of Formula IV or its salt with suitable chlorinating agent in presence of suitable solvent to give 1-methylpiperidine-4-carbonyl chloride of Formula V or its salt, wherein said compound of Formula V or its salt is optionally not isolated;
,
c) converting 1-methylpiperidine-4-carbonyl chloride of Formula V or its salt to N,N,1-trimethylpiperidine-4-carboxamide of Formula III or its salt;
, and
d) converting the compound of Formula III or its salt to lasmiditan or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;
,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;
; and
c) converting the 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt to lasmiditan or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;
,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;
,
c) reacting 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt with 2,4,6-trifluorobenzoyl chloride in presence suitable solvent to give lasmiditan free base of Formula I;
, and
d) converting lasmiditan free base of Formula I to lasmiditan hemisuccinate of Formula II.

In another aspect, the present invention provides a process for the preparation of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;
,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;
, and
c) converting 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt to lasmiditan hemisuccinate of Formula II, and optionally purifying the lasmiditan hemisuccinate of Formula II.

In another aspect, the present invention provides a process for the purification of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) providing a solution of crude lasmiditan hemisuccinate in suitable solvent at suitable temperature;
b) optionally, cooling the solution of step a);
c) adjusting the pH of the solution of step a) or b) to 9-14 by adding base;
d) isolating free base of lasmiditan of Formula I;
e) dissolving lasmiditan free base of Formula I in suitable solvent;
f) heating the reaction mass of step e) at a temperature in the range of ambient temperature to reflux temperature of the solvent;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

In another aspect, the present invention provides a process for the purification of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) providing a solution of crude lasmiditan hemisuccinate in water at room temperature;
b) cooling the solution of step a) to 10-15oC;
c) adjusting the pH of the solution to 9-14 by adding sodium hydroxide;
d) isolating free base of lasmiditan of Formula I;
e) dissolving the lasmiditan free base of Formula I in ketone;
f) heating the reaction mass of step e) to reflux;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

In another aspect, the present invention provides a process for the purification of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) providing a solution of lasmiditan free base of Formula I in suitable solvent at suitable temperature;
b) adding suitable acid to step a) to get lasmiditan salt;
c) adding suitable base to step b) to obtain lasmiditan free base of Formula I;
d) optionally isolating lasmiditan free base of Formula I of step c);
e) optionally dissolving the lasmiditan free base of Formula I in suitable solvent to get reaction mass;
f) heating the reaction mass at a temperature in the range of ambient temperature to reflux temperature;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

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

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

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

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

In context of the present invention, the term “suitable solvent” or “solvent” provides solvents that are used for preparing lasmiditan and its intermediates and are selected from the group comprising of, but not limited to, C1-C6 alcohols, C1-C8 hydrocarbons, halogenated hydrocarbons, ethers, C3-C8 ketones, esters, nitriles, sulphonamides, acetamides, pyrrolidines, formamides, water and mixture thereof. For Example, some of the suitable solvents comprises of methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, pentanol, glycols, toluene, chlorobenzene, acetonitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), methyl tetrahydrofuran, dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dicholoromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, hexane, n-heptane, cyclohexane, petroleum benzine, water and mixture thereof.

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

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

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

In another embodiment, the present invention provides a process for the preparation of lasmiditan hemisuccinate.

Another embodiment of the present invention is to provide a process for the purification of lasmiditan hemisuccinate

In another embodiment, the present invention provides a process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) or pharmaceutically acceptable salts thereof, comprising the steps of:
a) methylating isonipicotic acid of Formula G to 1-methylpiperidine-4-carboxylic acid of Formula IV or its salt in presence of suitable solvent without use of metal catalyst;
,
b) reacting 1-methylpiperidine-4-carboxylic acid of Formula IV or its salt with suitable chlorinating agent in presence of suitable solvent to give 1-methylpiperidine-4-carbonyl chloride of Formula V or its salt, wherein said compound of Formula V or its salt is optionally not isolated;
,
c) converting 1-methylpiperidine-4-carbonyl chloride of Formula V or its salt to N,N,1-trimethylpiperidine-4-carboxamide of Formula III or its salt;
, and
d) converting the compound of Formula III or its salt to lasmiditan or its pharmaceutically acceptable salt.
In another embodiment, the suitable chlorinating agent used for chlorinating compound of Formula IV is selected from, but not limited to, thionyl chloride, oxalyl chloride, p-toluoyl chloride, and phosgene.

In another embodiment, the present invention provides a process for the preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl]benzamide (lasmiditan) or pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;

,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;

, and
c) converting the 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt to lasmiditan or its pharmaceutically acceptable salt

In another embodiment, the suitable amine source used for aminating compound of Formula VI is selected from, but not limited to, aqueous ammonia, anhydrous liquid ammonia or ammonia gas.

In preferred embodiment, the amination of compound of Formula VI is carried out in presence of suitable solvent and amine source. In another embodiment, the amination of compound of Formula VI is carried out without solvent in presence of amine source.

In another embodiment, the present invention provides a process for the preparation of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;

,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;

,
c) reacting 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt with 2,4,6-trifluorobenzoyl chloride in presence suitable solvent to give lasmiditan free base of Formula I;

, and
d) converting lasmiditan free base of Formula I to lasmiditan hemisuccinate of Formula II.

In another embodiment, the present invention provides a process for the preparation of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) reacting N,N,1-trimethylpiperidine-4-carboxamide of Formula III with 2,6-dibromopyridine in presence of suitable solvent to give (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt, wherein said compound of Formula VI or its salt is optionally not isolated;
,
b) converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or its salt to (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt in presence of suitable amine source, wherein said compound of Formula VIII or its salt is optionally not isolated;

, and
c) converting 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII or its salt to lasmiditan hemisuccinate of Formula II, and optionally purifying the lasmiditan hemisuccinate of Formula II.

In another embodiment, the present invention provides a process for the purification of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) providing a solution of crude lasmiditan hemisuccinate in suitable solvent at suitable temperature;
b) optionally, cooling the solution of step a);
c) adjusting the pH of the solution of step a) or b) to 9-14 by adding base;
d) isolating free base of lasmiditan of Formula I;
e) dissolving lasmiditan free base of Formula I in suitable solvent;
f) heating the reaction mass of step e) at a temperature in the range of ambient temperature to reflux temperature of the solvent;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

In another embodiment, the present invention provides a process for the purification of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) providing a solution of crude lasmiditan hemisuccinate in water at room temperature;
b) cooling the solution of step a) to 10-15oC;
c) adjusting the pH of the solution to 9-14 by adding sodium hydroxide;
d)isolating free base of lasmiditan of Formula I;
e)dissolving the lasmiditan free base of Formula I in ketone;
f) heating the reaction mass of step e) to reflux;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

In another embodiment, the present invention provides a process for the purification of lasmiditan hemisuccinate of Formula II, comprising the steps of:
a) providing a solution of lasmiditan free base of Formula I in suitable solvent at suitable temperature;
b) adding suitable acid to step a) to get lasmiditan salt;
c) adding suitable base to step b) to obtain lasmiditan free base of Formula I;
d) optionally isolating lasmiditan free base of Formula I of step c);
e) optionally dissolving the lasmiditan free base of Formula I in suitable solvent to get reaction mass;
f) heating the reaction mass at a temperature in the range of ambient temperature to reflux temperature;
g) adding succinic acid to the reaction mass of step f); and
h) isolating the pure lasmiditan hemisuccinate of Formula II.

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

In another embodiment, purification of lasmiditan hemisuccinate in the context of present invention can be performed multiple times depending upon the purity of final product.

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

In another embodiment, the present invention provides substantially pure lasmiditan free base or salt thereof, substantially free from impurities of Formula A-K, wherein each impurity is less than about 0.3% w/w,
, ,
, ,
, , ,
, , and
.
In another embodiment, the present invention provides substantially pure lasmiditan free base or salt thereof, wherein the total purity of lasmiditan and its salts is about 99.0% and more.

In another embodiment, the present invention provides substantially pure lasmiditan hemisuccinate, wherein the total purity of lasmiditan hemisuccinate is about 99.0% and more.

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

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

In another embodiment, the lasmiditan or its pharmaceutically acceptable salts are prepared as per the scheme 3 as mentioned below:
Scheme 3:

In another embodiment, the lasmiditan hemisuccinate is prepared as per the scheme 4 as mentioned below:
Scheme 4:

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 embodiment, cooling temperature in the context of present invention is from room temperature to 0oC depending upon the requirement of the reaction step.

In preferred embodiment, cooling temperature in the context of present invention is from room temperature to 10oC.

In another embodiment, the process of preparation of lasmiditan or its pharmaceutically acceptable salt of Formula I is performed in situ without isolation of intermediates.

In preferred embodiment, the process of preparation of lasmiditan hemisuccinate of Formula II is performed in situ without isolation of intermediates.

In another embodiment, the present invention provides a process of preparing compound of VI comprising steps of :
a) reacting compound of Formula III with 2,6-dibromopyridine in presence of suitable solvent and suitable alkyl magnesium halide or N-alkyl lithium to give compound of Formula VI;
; and
b) optionally purifying compound of formula VI obtained in step a) .

In preferred embodiment, alkyl magnesium halide used for the reaction between compound of formula III and 2,6-dibromopyridine is selected from the group comprising of , but not limited to, methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium chloride, propyl magnesium bromide, propyl magnesium chloride or isopropyl magnesium chloride/LiCl.

In another preferred embodiment, N-alkyl lithium used for the reaction between compound of formula III and 2,6-dibromopyridine is selected from the group comprising of, but not limited to, N-methyllithium, N-ethyl lithium,N-butyllithium, isopropyllithium, tert-butyllithium preferably N-butyllithium.

In another embodiment, the present invention provides a process of preparing the lasmiditan hemisuccinate of Formula II comprising:
a) reacting 6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VIII with 2,4,6-trifluorobenzoyl chloride in presence of suitable solvent to give lasmiditan free base of Formula I wherein, lasmiditan free base of Formula I is optionally not isolated;
,
b) providing a solution of lasmidiatan free base of Formula I in suitable solvent;
c) stirring the reaction mass of step b) at suitable heating temperature;
d) distilling the reaction mass of step c) and adding suitable solvent;
e) heating the reaction mass of step d) at a temperature in the range of ambient temperature to reflux temperature of the solvent;
f) adding succinic acid to reaction mass of step e); and
g) cooling the reaction mass of step f) to obtain lasmiditan hemisuccinate of Formula II.

In another preferred embodiment, the lasmiditan or its pharmaceutically acceptable salt prepared as per the process of the present invention is characterized by the particle size distribution wherein, d90 is between 0.1µm to 200µm.

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

EXAMPLES
EXAMPLE 1: Preparation of 4-Methyl-isonipecotic acid hydrochloride:
Charged 210 ml of formic acid and 135 ml of formaldehyde to piperidine-4-carboxylic acid (100 g) at room temperature. Raised the temperature to 60-100°C. After completion of reaction, distilled out the reaction mass completely. Charged 100 ml of conc. HCl followed by cooling the reaction mass at room temperature and charged 300 ml of acetone at room temperature. Stirred and filtered the product and washed with acetone. Dried the product under vacuum at 50-55oC for 7-10 hours to get desired compound.

EXAMPLE 2: Preparation of N,N,1-trimethylpiperidine-4-carboxamide:
Charged 100g of 4-Methyl-isonipecotic acid hydrochloride to 800 ml of dichloromethane at room temperature. Cooled the reaction mass to 5-10oC. Added catalytic amount of DMF followed by slow addition of 89.39 g (54.51 ml) of thionyl chloride (drop wise) at 5-10°C. Raised the temperature up to 40°C for 1-2 hours. After completion of reaction, cooled the reaction mass at 20-35°C. Distilled out dichloromethane under vacuum at 25-35°C. Toluene (200 ml) was charged and distilled out completely. Charged 800 ml of tetrahydrofuran at 20-25°C. Cooled to 0-10°C. Added a mixture of dimethylamine and THF solution and maintained the reaction mass at 1-2 hours. After reaction completion added 144 ml of 30% NaOH solution drop wise at 5-10°C. Added 160 ml of DM water to dissolve solid part in reaction mass at 20°C. Settled and separated the layer at 20-30°C. Extracted the aqueous layer with dichloromethane. Combined all organic layers, and distilled out completely under vacuum at 50°C. Charged Methyl tertiary butyl ether in distilled mass and passed the reaction mass to hyflow bed and again distilled out the organic solvent completely to get the desired compound.

EXAMPLE 3: Preparation of 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine:
In a clean and dry RBF, charged Methyl tert-butyl ether 200 ml and cooled to -70 to -80oC. Slowly added n-Butyl Lithium (2.5 M in hexane) 186 ml at -70 to -80°C. Stirred for 45-60 minutes. Slowly added 2,6-dibromopyridine (100 g solution in 1000 ml methyl tert-butyl ether ) at -50 to -80°C. Maintained the reaction mass at this temperature for 1-2 hours. Added N,N’-Dimethyl-N-methylisonipecotamide in methyl tert-butyl ether drop wise in reaction mass at -65 to -80°C under nitrogen. After completion of reaction slowly raised the temperature up to room temperature and added saturated ammonium chloride solution. Adjusted the pH to 1-2 with conc. HCl solution at 20-30°C. Separated out the layer. Basified the aqueous layer with 30% NaOH solution and adjusted the pH 9-10 at RT. Extracted the reaction mass with ethyl acetate at RT and separated the organic layer. Distilled the organic layer under vacuum at 40-45°C.

EXAMPLE 4: Preparation of 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine:
Charged 21.6g of 2,6-dibromopyridine followed by addition of tetrahydrofuran 100 ml as a solvent at room temperature. Slowly added iPrMgCl/LiCl 58.5 ml & maintained the reaction mass for one hour. Added 13 g N,N’-Dimethyl-N-methylisonipecotamide dropwise by dissolving in 300ml tetrahydrofuran at room temperature . Maintained the reaction mass at room temperature till the completion of reaction. Reaction mass was quenched using 80 ml ammonium chloride solution. Adjusted the pH 7.6-7.7 with concentrated HCL and stirred for 15-20 minute. Reaction mass was settled to separate out organic layer. Extracted the aqueous layer with tetrahydrofuran.Combined all the organic layer added 80 ml water followed by 6.5 ml of heptane and adjusted the pH 1 to 1.5 with HCL and stirred for 15-20 minute to separate out the organic layer .Extracted the organic layer with 40 ml HCL .Combined all the acidic aqueous layer and charge 80 ml butanol. Basified the aqueous layer with NaOH to adjust the pH 9-10 with 20% NaOH solution and stirred for 15-20 minute and settled to separate out the aqueous layer. Extracted the aqueous layer with 40 ml butanol followed by complete distillation under vacuum to get the product. Yield 15.8g.

EXAMPLE 5: Preparation of 2-Amino-6-(1-methylpiperidin-4ylcarbonyl)-pyridine:
In an autoclave, charged 100 g of 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine followed by addition of 20 ml methanol. Charge 1.0 L aqueous ammonia and 2.5 g copper (I) oxide at 20-30°C. Raised the temperature up to 90-100°C. Maintained the reaction mass for 4-6 hours after completion of reaction, cooled the mass at 20-30°C. Extracted the reaction mass with MDC. Combined all the organic layers and distilled out under vacuum at 40-45°C completely. Added 120 ml of isopropanol to 60 g freebase oil at 20-30°C. Slowly added 120 ml of isopropanol HCl (15-20%) at 20-30°C.Raised the temperature at 80°C under reflux for 30 minutes. Cooled to 20-30°C, filtered the product and washed with isopropanol. Isolated compound was taken in RBF and added DM water at room temperature. Adjusted the pH to 11-12 with 30% NaOH solution. Extracted the aqueous layer with Methyl tert-butyl ether at 20-30°C. Treated the organic layer with charcoal and distilled out the organic layer completely under vacuum at 45-50°C.

Example 6: Synthesis of 2,4,6-Triflorobenzoyl chloride: In a clean and dry RBF charged 100 g of 2,4,6-Trifluorobenzoic acid followed by 1.0 L of dichloromethane at room temperature. Added catalytic amount of DMF. Slowly added 97.28 g of oxalyl chloride at room temperature. Raised the temperature at 30-35°C. Maintained for 1-2 hour. Distilled the MDC completely under vacuum at 40°C to obtain the product.

EXAMPLE 7: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (Lasmiditan hemisuccinate) of Formula II:
In a clean and dry RBF charged 100g of 2-Amino-6-(1-methylpiperidin-4ylcarbonyl)-pyridine followed by 1.0 L of anhydrous tetrahydrofuran and 110.8 g of triethyl amine at 10-15oC under nitrogen atmosphere. Slowly added 133 g of 2,4,6-Triflorobenzoyl chloride at 10-15°C. Stirred for 1-2 hours under nitrogen at 10-15°C. After completion of reaction, added 250 ml of 30% NaOH solution and 150 ml of DM water at RT. Stirred for 2-4 hours. Extracted aqueous layer with 100 ml of methyl tert-butyl ether. Combine all the organic layer and distilled the organic layer under vacuum at 50oC. To the distillate added acetone and heated to reflux temperature. Added succinic acid solution in acetone droop wise and stir for 1 hour. Slowly cooled to room temperature to precipitate out the product. Filtered washed with acetone.

EXAMPLE 8: Purification of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (Lasmiditan hemisuccinate) of Formula II
In a clean and dry RBF charged 100 gm of crude lasmiditan hemisuccinate followed by addition of 700 ml of purified water at room temperature. Cooled the reaction mass at 10-15oC followed by addition of 30% NaOH solution and extracted the reaction mass with Methyl tert-butyl ether to separate the organic layer. Organic layer was distilled completely to obtain lasmiditan free base. Charged 200 ml of acetone on distilled mass and heated to reflux. Added 15.64 gm of succinic acid in acetone drop wise to the refluxed mass and stirred for 1 hour. Slowly cooled the reaction mass to room temperature. Filtered the product and washed with acetone and dried under vacuum to get pure Lasmiditan hemisuccinate having HPLC purity 99.09%.

EXAMPLE 9: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (Lasmiditan hemisuccinate) of Formula II:
Charged 210 ml of formic acid and 135 ml of formaldehyde to piperidine-4-carboxylic acid (100 g) at room temperature. Raised the temperature to 60-100°C. After completion of reaction, distilled out the reaction mass completely. Charged 100 ml of conc. HCl followed by cooling the reaction mass at room temperature and charged 300 ml of acetone at room temperature and sucked dried. Added 800 ml of dichloromethane at room temperature .Cool the reaction mass to 5-10oC. Added catalytic amount of DMF followed by slow addition of 89.39 g (54.51 ml) of thionyl chloride (drop wise) at 5-10°C. Raised the temperature up to 40°C for 1-2 hours. After completion of reaction, cooled the reaction mass at 20-35°C. Distilled out dichloromethane under vacuum at 25-35°C.Toluene 200 ml was charged and distilled out completely. Charged 800 ml of tetrahydrofuran at 20-25°C. Cooled to 0-10°C. Added a mixture of dimethylamine and THF solution and maintained the reaction mass at 1-2 hours. After reaction completion added 144 ml of 30% NaOH solution drop wise at 5-10°C. Added 160 ml of DM water to dissolve solid part in reaction mass at 20°C. Settled and separated the layer at 20-30°C. Extracted the aqueous layer with dichloromethane. Combined all organic layers, and distilled out completely under vacuum at 50°C. Charged Methyl tertiary butyl ether in distilled mass and passed the reaction mass to hyflow bed and again distilled out the organic solvent completely .Charged Methyl tert-butyl ether 200 ml and cooled to -70 to -80oC. Slowly added n-Butyl Lithium (2.5 M in hexane) 186 ml at -70 to -80°C. Stirred for 45-60 minutes. Slowly added 2,6-dibromopyridine (100 g solution in 1000 ml methyl tert-butyl ether ) at -50 to -80°C. Maintained the reaction mass at this temperature for 1-2 hours. Added N,N’-Dimethyl-N-methylisonipecotamide in Methyl tert-butyl ether drop wise in reaction mass at -65 to -80°C under nitrogen. After completion of reaction slowly raised the temperature up to room temperature and added saturated ammonium chloride solution. Adjusted the pH to 1-2 with conc. HCl solution at 20-30°C. Separated out the layer. Basified the aqueous layer with 30% NaOH solution and adjusted the pH 9-10 at RT. Extracted the reaction mass with ethyl acetate at RT and separated the organic layer. Distilled the organic layer under vacuum at 40-45°C. Added methanol, aqueous ammonia and 2.5 g copper (I) Oxide at 20-30°C. Raised the temperature up to 90-100°C. Maintained the reaction mass for 4-6 hours After completion of reaction, cooled the mass at 20-30°C. Extracted the reaction mass with MDC. Combined all the organic layers and distilled out under vacuum at 40-45°C completely. Added 120 ml of isopropanol to 60 g freebase oil at 20-30°C. Slowly added 120 ml of isopropanol HCl (15-20%) at 20-30°C.Raised the temperature at 80°C under reflux for 30 minutes. Cooled to 20-30°C, filtered the product and washed with isopropanol. Isolated compound was taken in RBF and added DM water at room temperature. Adjusted the pH to 11-12 with 30% NaOH solution. Extracted the aqueous layer with Methyl tert-butyl ether at 20-30°C. Distilled out the organic layer completely under vacuum at 45-50°C.Added 1.0 L of anhydrous tetrahydrofuran and 110.8 g of triethyl amine at 10-15oC under nitrogen atmosphere. Slowly added 133 g of 2,4,6-Triflorobenzoyl chloride at 10-15°C. Stirred for 1-2 hours under nitrogen at 10-15°C. After completion of reaction, added 250 ml of 30% NaOH solution and 150 ml of DM water at RT. Stirred for 2-4 hours. Extracted aqueous layer with 100 ml of methyl tert-butyl ether. Combine all the organic layer and distilled the organic layer under vacuum at 50oC.To the distillate added acetone and heated to reflux temperature. Added succinic acid solution in acetone droop wise and stir for 1 hour. Slowly cooled to room temperature to precipitate out the product. Filtered washed with acetone and dried the product.
EXAMPLE 10: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide (Lasmiditan) of Formula I:
In a clean and dry RBF charged 100g of 2-Amino-6-(1-methylpiperidin-4ylcarbonyl)-pyridine followed by 1.0 L of anhydrous tetrahydrofuran and 110.8 g of triethyl amine at 10-15oC under nitrogen atmosphere. Slowly added 133 g of 2,4,6-Triflorobenzoyl chloride at 10-15°C. Stirred for 1-2 hours under nitrogen at 10-15°C. After completion of reaction, added 250 ml of 30% NaOH solution and 150 ml of DM water at RT. Stirred for 2-4 hours. Extracted aqueous layer with 100 ml of methyl tert-butyl ether. Combine all the organic layer and distilled the organic layer completely under vacuum at 50oC to get the product having HPLC purity 99.9% by HPLC.