DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Lasmiditan and its pharmaceutically acceptable salts thereof. The present invention also relates to a process for the preparation of Lasmiditan intermediates.
BACKGROUND OF THE INVENTION
Lasmiditan, an agonist of 5-HT1F receptors present both in the central and peripheral nervous systems, has been approved by US Food and Drug Administration (FDA) and is marketed in the United States under the trademark of Reyvow®. The chemical name of lasmiditan is 2,4,6-Trifluoro-N-[6-(1- methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide. Its structural Formula is the following 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 below:

Scheme I
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
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 describe 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.
Considering the importance of Lasmiditan in the pharmaceutical field, there is a need remains for an improved and commercially viable process of preparing pure Lasmiditan. Use of acid addition salt of intermediates provide advantageously high purity product at expected yield.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides an improved process for preparation of Lasmiditan as mentioned in below Scheme 3.

Scheme 3
In another aspect, the present invention provides an improved process of preparation of Lasmiditan or its pharmaceutically acceptable salts, comprising of following steps:
a) reacting compound of Formula (II) with suitable chlorinating agent and NR1R2 to obtain compound of Formula (III);
b) reacting compound of Formula (III) with 2, 5-dibromo pyridine in presence of base to obtain compound of Formula (IV) and optionally converting it into organic acid addition salt using suitable organic acid;
c) reacting compound of Formula (IV) or its organic acid addition salt with ammonia in presence of catalyst to obtain compound of Formula (V) and optionally converting it into acid addition salt using suitable acid;
d) reacting compound of Formula (V) or its acid addition salt with suitable 2,4,6-trifluoro benzene derivative compound (VI) to obtain Lasmiditan of Formula (I); and
e) converting Lasmiditan of Formula (I) into its pharmaceutically acceptable salts.
In another aspect, the present invention provides acid addition salt of compound of Formula (IV) and/or compound of Formula (V); and preparation method thereof.
In further aspect, the present invention provides an improved process of preparation of Lasmiditan comprising converting acid addition salt of compound of Formula (IV) and/or compound of Formula (V) to Lasmiditan of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an improved process of preparation of Lasmiditan or its pharmaceutically acceptable salt. The present invention also provides intermediate compounds and their use in preparation of Lasmiditan.
In another embodiment, the present invention process of preparing Lasmiditan or its pharmaceutically acceptable salts, comprising of following steps:
a) reacting compound of Formula (II) with suitable chlorinating agent and NR1R2 to obtain compound of Formula (III) wherein R1 and R2 are independently selected from H, C1-4 alkyl, or R1 and R2 together form a heterocyclic ring such as morpholine, piperidine, pyrrolidine or azetidine;

b) reacting compound of Formula (III) with 2, 5-dibromo pyridine in presence of base to obtain compound of Formula (IV) and optionally converting it into organic acid addition salt using suitable organic acid;

c) reacting compound of Formula (IV) or its organic acid addition salt with ammonia in presence of catalyst to obtain compound of Formula (V) and optionally converting it into acid addition salt using suitable acid;

d) reacting compound of Formula (V) or its acid addition salt with suitable 2,4,6-trifluoro benzene derivative compound (VI) to obtain Lasmiditan of Formula (I); and
e) converting Lasmiditan of Formula (I) into its pharmaceutically acceptable salts.

In one embodiment of the present invention, step (a) is carried out by first converting compound of Formula (II) to in to its acid chloride using chlorinating agent. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (ACN), 1,4-Dioxane, acetic acid, isopropyl alcohol (IPA), dimethyl formamide (DMF) and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, the reaction step (a) acid chloride formation may be carried out at reflux temperature.
Further, obtained acid chloride in-situ reacts with NR1R2 to form compound of Formula (III); wherein R1 and R2 are independently selected from hydrogen, C1-4 alkyl, or R1 and R2, together form a heterocyclic ring such as morpholine, piperidine, pyrrolidine or azetidine. Preferably, NR1R2 is pyrrolidine. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, the amide formation may be carried out at 0 °C to 30 °C temperature.
In one embodiment, compound of Formula (III) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of the present invention, step (b) may be carried out by reacting compound of Formula (III) with 2, 5-dibromo pyridine to obtain compound of Formula (IV). The reaction may be performed using Grignard reagent or butyl lithium selected from ethyl magnesium bromide, tert-butyl magnesium bromide, methyl magnesium bromide, n-butyl lithium, tert-butyl lithium and Lithium bis(trimethylsilyl)amide. The reaction may be carried out in the presence of an inert organic solvent including but not limited to hydrocarbon solvents or ether solvents such as toluene, hexane, heptane, pentane, mixture of alkanes, tetrahydrofuran (THF), 2-methyl THF, MTBE, diethylether, dimethoxyethane (glyme), diglyme, cyclopentyl methyl ether and mixtures thereof. The reaction may be carried out at a temperature of about -78 °C to about room temperature. Preferably, the coupling reaction step (b) may be carried out at -55 °C to -65 °C.
In one embodiment, compound of Formula (IV) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment, compound of Formula (IV) may be isolated as its organic acid addition salt. Organic acids commonly employed to form such salts include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, benzene sulfonic acid, maleic acid, formic acid, fumaric acid, salicylic acid, tartaric acid and the like. Preferable acid to form salt of compound of Formula (IV) is succinic acid or succinate salt.
In another embodiment of the present invention, the process step involves reacting compound of Formula (IV) with succinic acid to form succinate salt. The reaction may be carried out in the presence of an inert organic solvent including but not limited to alcoholic solvent such as ethanol methanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, MTBE, acetone, toluene and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used.
Obtained acid addition salt can be used directly in next reaction or neutralized with the base such as NaOH, cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, triethylamine, diisopropylethylamine , 2,6-lutidine, DBU or dimethylaniline to obtain compound of Formula (IV).
In another embodiment of the present invention, step (c) may be carried out by reacting compound of Formula (IV) or its organic acid addition salt with ammonia to obtain compound of Formula (V). The reaction may be carried out in the presence of catalyst such copper oxide, copper chloride, copper iodide, copper sulfide, copper bromide, copper sulfate and copper hydroxide. The reaction may be carried out in the presence of an organic solvent comprising ethanol methanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, ethylene glycol, propylene glycol or water and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. The reaction may be carried out under pressure of 1.0 to 10.0 Kg/cm2.
In one embodiment, compound of Formula (V) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment, compound of Formula (V) may be isolated as its acid addition salt. Inorganic acids commonly employed to form such salts include hydrochloric acid, carbonic acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid hydrofluoric acid and the like. Organic acids commonly employed to form such salts include include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, benzene sulfonic acid, maleic acid, formic acid, fumaric acid, salicylic acid, tartaric acid and the like. Preferable acid to form salt of compound of Formula (V) is succinic acid or succinate salt.
In another embodiment of the present invention, the process step involves reacting compound of Formula (V) with succinic acid to form succinate salt or hydrochloric acid to form HCl salt. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as alcohol such as ethanol methanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used.
Obtained acid addition salt can be used directly in next reaction or neutralized with the base such as NaOH, cesium carbonate, potassium carbonate, sodium carbonate, trimethylamine or diisopropylethylamine to obtain compound of Formula (V).
In another embodiment of the present invention, in step (d) may be carried out by reacting compound of Formula (V) with 2,4,6- trifluorobenzene derivative compound of formula (VI) preferably selected from 2,4,6- trifluorobenzoyl chloride to obtain compound of Formula (I). The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as toluene, tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (ACN), 1,4-Dioxane, dimethyl formamide (DMF) and mixtures thereof. The reaction may be carried out in presence of organic base such as triethyl amine, diisopropyl ethyl amine, tributyl amine and n-butyl amine; or inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. More preferable organic base is diisopropyl ethyl amine. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used.
The 2,4,6- trifluorobenzene derivative compound of formula (VI) used in above step is as below:

In one embodiment, the present invention more particularly provides a process for the preparation of compound of Formula (I) schematically represented below.

Scheme 3
In another embodiment, compound of formula (I) can be converted into its hemisuccinate salt by employing conventional methods known in the art.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.

Examples:
Example-1: Preparation of 1-methyl-4(pyrrolidin-1-yl-carbonyl)-piperidine.
To a solution of MDC (600 mL) and N,N-Dimethylformamide (1 mL), was added 1-methyl-4-carboxy piperidine HCl (100 g, 0.5566 moles) followed by oxalyl chloride (77.0 g, 1.1 eq. mole) at room temperature. The resulting reaction mixture was stirred for at 30±5 °C till completion of reaction. After completion, the reaction mass was distilled out. The resulting residue was dissolved in MDC (600 mL) and cooled to 0±5°C then pyrrolidine (145.0 g, 3.66 eq. mole) was added in to the reaction mass. The resulting reaction mass was stirred for 2-3 hours at 25±5 °C. Then after an aqueous solution of sodium carbonate (80g) and sodium hydroxide (2g) in water (540 mL) was added. organic layer was separated and the aqueous layer was extracted with MDC. organic layers were combined and distilled out. The resulting residue was purified/crystallized in n-Heptane and dried at 40-45°C under vacuum to get of 1-Methyl-4(pyrrolidin-1-yl-carbonyl)-piperidine (87 gm) Yield 79%.

Example-2: Preparation of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone succinic acid salt
To toluene (500 mL) was added 2,6-dibromopyridine (150.84, 1.25 eq. mole) followed by 2.5M n-butyl lithium solution in hexane (285.54 mL, 1.40 eq. moles) at -55 to -65°C and stirring was continued for 30 minutes. Then after a solution of 1-methyl-4(pyrrolidin-1-yl-carbonyl)-piperidine (100.0 g; 0.5094 moles) in toluene (500 mL) was added to the reaction mixture at -55 to -65°C and stirring was continued till completion. After completion of reaction it was quenched by addition of aqueous ammonium acetate solution (500 mL). Organic layer was separated out and distilled under vacuum. The obtained residue was treated with succinic acid (63.16 g, 1.05 eq. mole) in isopropyl alcohol (500 mL) at 60-70°C for 1 hour and the obtain reaction mass was cooled to room temperature. The obtained solid was filtered and dried at 55-60°C under vacuum to get (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone succinic acid salt (133 gm). Yield 70%. 1H NMR: (500 MHz, DMSO d-6), ? 11.861 (bs, 2H), 7.97 (m, 2H), 7.94 (m, 1H), 3.67 (dt, 1H), 3.00 (d, 2H), 2.375-2.315 (m, 9H), 1.86 (d, 2H), 1.675-1.603 (m, 2H).Mass (M+H) 283.0 and Succinic acid content 30.7%.

Example-3: Preparation of 6-(1-methylpiperidine-4-carbonyl)pyridin-2-amine dihydrochloride
To a solution of (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl)methanone succinic acid salt (100.0 g, 0.2679 moles) in aq. ammonia ( mL) was added cuprous oxide (1.91 g, 0.05 eq. mole) in autoclave followed by ammonia gas (pressure 3.0 to 5.0 Kg/cm2 at 75-85°C) and maintained till completion. After completion of reaction, reaction mixture was cooled to 25-35°C followed by adding a solution of NaOH (32.15 g) in water (150 mL) and product was extracted with MTBE. NaCl (20 g) was added to aqueous layer and again the product was extracted with MTBE. All the organic layers were combined and concentrated. The resulting residue dissolved in IPA (450 mL). IPA was partially distilled out upto 150 mL followed by adding IPA.HCl (150 mL). The resulting reaction mixture was stirred for 30-60 min. at 50-to 60°C, cooled to 30±5 °C for 4-5 hours. The obtained solid was filtered, dried (55 g, yield 70%) and was further crystallized in a 1:1 mixture of IPA and MeOH (300 ML) to get 45 gms of 6-(1-methylpiperidine-4-carbonyl)pyridin-2-amine dihydrochloride.

Example-4: Preparation of 2,4,6-trifluoro benzoyl chloride:
To a solution of MDC (700 mL) and DMF (1 mL) was added 2,4,6-trifluorobenzoic acid (100 g, 0.568 moles) followed by oxalyl chloride (101.0 g, 1.40 eq. mole) at room temperature and was stirred till completion of reaction. After completion of reaction, reaction mass was distilled out by using high vacuum (vapor temperature 46-72°C at 12 to 40 torr), to get 2,4,6-trifluoro benzoyl chloride (100g) Yield 93%.

Example-5: Preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl] benzamide (Lasmiditan free base):
To a slurred solution of dihydrochloride salt of 6-(1-methylpiperidine-4-carbonyl)pyridin-2-amine (100.0 g, 0.342 moles) in MTBE (500 mL) was added a solution of sodium hydroxide (54.74 g) in water (547 mL). The reaction mass was stirred for 30 min. at 30-35°C. MTBE layer was separated and aqueous layer was extracted with MTBE. organic layers were combined and solvent was distilled out. The resulting residue was dissolved in toluene (300 mL) and toluene was distilled out. Toluene (300 mL), tetrahydrofuran (500 mL) and N,N-diisopropylethylamine (106.13 g, 2.4 eq. mole) were added to the residue. A solution of 2,4, 6-triflurobenzoyl chloride (79.87 g1.20 eq. mole) in toluene (200 mL) was added at 50-80°C and the resulting reaction mixture was stirred till completion. After completion of the reaction, methanol (150. mL) was added in to the reaction mixture at 30-35°C. The obtained reaction mass was washed with 5% aqueous sodium bicarbonate followed by water wash. The organic layer was partially distilled out up to volume (400-450 mL), followed by addition of n-heptane (200 mL) at 60-70°C and stirred for 30-50 min, cooled to 30-35°C and stirred for 5-6 hours. The obtained solid was filtered and dried in vacuum 50-55°C to get Lasmiditan free base (90 gm) Yield 70%.

Example-6: Preparation of Lasmiditan Hemi Succinate:
To a stirring solution of Lasmiditan free base (100.0 g, 0.265 moles) in acetone (400 mL) was added a solution of succinic acid (16.58 g) in methanol (400 mL) at 50-55 °C. The reaction mass was stirred for 30 min, cooled to 0-10°C and stirred for 4-5 hours. The obtained solid was filtered and dried at 50°C under vacuum to get title compound (90gm) Yield 82%.

Example-7: Preparation of 6-(1-methylpiperidine-4-carbonyl)pyridin-2-amine succinic acid salt.
To a stirring solution of 6-(1-methylpiperidine-4-carbonyl)pyridin-2-amine (60 g, 0.27 moles) in IPA (360 ml) was added succinic acid (35.6g, 0.3 moles) at 50-60°C. The resulting reaction mass was stirred for 30 min. Then gradually was cooled to 25-35°C and continued stirring till completion of the reaction. The obtained solid was filtered and dried in vacuum at 55-60°C to get title compound (73.4 gm) Yield 83.29%. 1H NMR: (500 MHz, DMSO d-6), ? 10.76 (bs, 2H), 7.53 (dd, 1H), 7.07 (d, 1H), 76.67 (d, 1H), 6.21(s, 2H) 3.71 (m, 1H), 3.00 (dt, 2H), 2.30 (m, 9H), 1.82 (dt, 2H), 1.61 (m, 2H). Mass (M+H) 220.5 and Succinic acid content 35.2%.

Example-8: Preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl) pyridine-2-yl]benzamide (Lasmiditan free base):
To a solution of toluene (45 mL) and tetrahydrofuran (75 mL) was added 6-(1-methylpiperidine-4-carbonyl)pyridin-2-amine succinic acid salt (15 g, 0.044 moles), followed by N,N-diisopropylethylamine (13.8 g, 2.4 eq. mole 0.107). A solution of 2, 4, 6-trifluro acid chloride (10.37g, 1.2 eq. 0.053 mole) in toluene (30 mL) was added at 60-80°C to the reaction mixture and was stirred at 60-80°C till completion. After completion of reaction, methanol (22.5. mL) was added followed by addition of 5% aqueous sodium bicarbonate solution. The organic layer was separated and followed by water washing. The organic layer was partially distilled out to remain (60 mL) followed by addition of n-Heptane (30 mL) and reaction mixture was stirred at 30-35°C for 4-5 hours. The obtained solid was filtered and dried in vacuum at 50-55°C to get Lasmiditan free base (7 gm) Yield 42.5%.

Dated this: Feb 10th, 2023 Dr. S. Ganesan
Alembic Pharmaceutical Ltd.
,CLAIMS:1. Acid addition salt of compound of Formula (IV).

wherein acid is selected from p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid, benzene sulfonic acid, maleic acid, formic acid, fumaric acid, salicylic acid and tartaric acid.

2. Succinic acid salt of compound of formula (IV).

3. Acid addition salt of compound of Formula (V).

wherein acid is selected from p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, succinic acid, citric acid, benzoic acid, acetic acid, benzene sulfonic acid, maleic acid, formic acid, fumaric acid, salicylic acid, tartaric acid..

4. Succinic acid salt of compound of formula (V).

5. A process of preparing Lasmiditan of formula (I) comprising of following steps:

a) reacting compound of Formula (II) with suitable chlorinating agent and NR1R2 to obtain compound of Formula (III) wherein R1 and R2 are independently selected from hydrogen, C1-4 alkyl or R1 and R2 together form a heterocyclic ring such as morpholine, piperidine, pyrrolidine or azetidine;

b) reacting compound of Formula (III) with 2, 5-dibromo pyridine in presence of base to obtain compound of Formula (IV) and optionally converting it into organic acid addition salt using suitable organic acid;

c) reacting compound of Formula (IV) or its organic acid addition salt with ammonia in presence of catalyst to obtain compound of Formula (V) and optionally converting it into acid addition salt using suitable acid;

d) reacting compound of Formula (V) or its acid addition salt with suitable 2,4,6-trifluoro benzene derivative compound (VI) to obtain Lasmiditan of Formula (I).

6. The process as claimed in step (a) of claim 1, wherein suitable chlorinating agent is selected from oxalyl chloride, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, triphosgene and phosphorous oxychloride.

7. The process as claimed in step (b) of claim 1, wherein suitable base is selected from ethyl magnesium bromide, tert-butyl magnesium bromide, methyl magnesium bromide, n-butyl lithium, tert-butyl lithium and Lithium bis(trimethylsilyl)amide.

8. The process as claimed in step (c) of claim 1, wherein suitable catalyst is selected from copper oxide, copper chloride, copper iodide, copper sulfide, copper bromide, copper sulfate and copper hydroxide.

9. The process as claimed in step (d) of claim 1, wherein suitable 2,4,6-trifluoro benzene derivative compound is selected from compound of formula (VI).

10. The process as claimed in claim 1 further comprising of converting Lasmiditan of Formula (I) into its pharmaceutically acceptable salts.