Description:
FIELD OF THE INVENTION
The present invention relates to improved processes for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I and a pharmaceutically acceptable salt thereof.

The present invention further relates to a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII

Formula VII
with 2,4,6-trifluorobenzoyl chloride of Formula VIII

Formula VIII
using a suitable solvent to obtain the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I.

The present invention also relates to another process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
coupling (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-triflurobenzoic acid of Formula IX

Formula IX
using a suitable coupling agent to prepare the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I.

The present invention also relates to an improved process for preparing of an intermediate of Lasmiditan, that is (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof.

Formula VI

BACKGROUND
Lasmiditan, is a serotonin (5-HT)1F receptor agonist constituting a class of drugs, “ditans” and chemically known as 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide, is represented by the structure of Formula I.

Lasmiditan is marketed under the brand name REYVOW® in the USA and is approved for the acute treatment of migraine with or without aura in adults. REYVOW® contains 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide hemisuccinate as the active ingredient.

There are several processes known in the literature for preparation of Lasmiditan, pharmaceutically acceptable salts thereof and intermediates thereof.

US Patent Application US 20050222206 discloses a process for preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide and salt thereof, wherein one of the synthetic processes is depicted in Scheme 1.
Scheme 1:

US’206 discloses preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide by reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone with 2,4,6-triflubenzoylchloride using DCM. Further, US’206 discloses a process for preparing of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide by reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone with 2,4,6-triflubenzoylchloride using anhydrous THF to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide. Furthermore, US’206 discloses preparation of hemisuccinate salt of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide by reacting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide free base with succinic acid in acetone.

However, it is observed that, the use of DCM or THF for reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone with 2,4,6-triflubenzoylchloride has several drawbacks. We observe that, the use of DCM or THF in the reaction of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone with 2,4,6-triflubenzoylchloride results significant amount of unreacted starting materials. For example, the use of DCM results 26.59% conversion with 15.75% unreacted starting materials. Similarly, the use of THF as solvent results in 46.25% conversion with 31.89% of unreacted starting materials.

Further, US’206 discloses reaction of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone and 2,4,6-triflubenzoic acid using Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU) with collidine base to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide.

However, upon using HATU in the reaction of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone and 2,4,6-triflubenzoic acid, we observe only 1.29% conversion with 21.97% of unreacted starting materials after 3 hours of reaction and only 1.45% conversion with 21.37% of unreacted starting material after 13 hours of reaction.

US’206 also discloses preparation of the intermediate, (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone by adding n-butyllithium to 2,6-dibromopyridine to form bromolithium pyridine at the first step and then adding N,N-dimethyl-1-methylpiperidine-4-carboxamide intermediate to the bromolithium pyridine in the subsequent step to obtain (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

However, we observe that reacting n-hexyllithium with 2,6-dibromopyridine to prepare bromolithium pyridine in the first step, followed by addition of N,N-dialkyl-1-methylpiperidine-4-carboxide to the bromolithium pyridine results only 57-60% conversion of the starting materials.

US 20130072524 discloses a method for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide and salt thereof as mentioned in the scheme 2.
Scheme 2:

US’524 discloses the reaction of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride with 2,4,6-trifluorobenzoyl chloride using chlorobenzene to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hydrochloride, which is isolated before reacting with succinic acid to form 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate. US’524 also discloses a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate salt by reacting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hydrochloride and succinic acid in the presence of ethanol.

However, several drawbacks are observed in the process of reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride with 2,4,6-trifluorobenzoyl chloride using chlorobenzene, as discloses in US’524. We observe that the use of chlorobenzene in the reaction of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone or salt thereof with 2,4,6-trifluorobenzoylchloride results in 50-65% conversion with 25-28% unreacted starting material. Further, sticky mass is formed during the process, which creates difficulties during work-up procedure and isolation of the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide. Furthermore, the process as disclosed in US’524, heats and stirs the reaction mixture of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride and 2,4,6-trifluorobenzoyl chloride in chlorobenzene at a high temperature of 98-102oC to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hydrochloride.

These documents are incorporated herein by reference in entirety for all the purposes.

Hence, a need exists in the art for a high yielding, high purity and economical process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or a pharmaceutically acceptable salt thereof. There is also a need in the art to develop an improved route for preparing (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof having greater yield and purity.

Surprisingly, the inventors of the present application have unexpectedly found improved processes for the preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or a pharmaceutically acceptable salt thereof and an improved process for preparing (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof, as described below in detail.

OBJECT OF THE INVENTION
Main objective of the present invention relates to a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or a pharmaceutically acceptable salt thereof comprising the steps of:
i. reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof with the 2,4,6-trifluorobenzoyl chloride of Formula VIII using a suitable solvent to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I; and
ii. optionally, converting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I to its pharmaceutically acceptable salt.

Another objective of the present invention relates to a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or a pharmaceutically acceptable salt thereof comprising the steps of:
i. coupling (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-triflurobenzoic acid of Formula IX using a suitable coupling agent in presence of a base to prepare 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I; and
ii. optionally, converting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I to its pharmaceutically acceptable salt.

Yet another objective of the present invention also relates to a process for preparation of the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof.

Yet another objective of the present invention is to provide improved, economical and industrially advantageous processes to obtain Lasmiditan and hemisuccinate salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 provides Certification of analysis of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of Example 1.
FIG. 2(A) & 2(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of Example 2.
FIG. 3(A) & 3(B) illustrate HPLC chart and result of 2,4,6-trifluorobenzoyl chloride of Example 2.
FIG. 4(A) & 4(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of example 3.
FIG. 5(A) & 5(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of example 4.
FIG. 6(A) & 6(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of example 5.
FIG. 7(A) & 7(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of example 6.
FIG. 8(A) & 8(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of example 7.
FIG. 9(A) & 9(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate of example 8.
FIG. 10(A) & 10(B) illustrate HPLC chart and result of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of example 9.
FIG. 11(A) & 11(B) illustrate HPLC chart and result of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of example 10.
FIG. 12(A) & 12(B) illustrate HPLC chart and result of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of example 11.
FIG. 13(A) & 13(B) illustrate HPLC chart and result of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of example 12.
FIG. 14(A) & 14(B) illustrate HPLC chart and result of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of example 13.
FIG. 15(A) & 15(B) illustrate HPLC chart and result of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of example 14.
FIG. 16(A) & 16(B) illustrate HPLC chart and result of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride of example 15.
FIG. 17(A) & 17(B) illustrate HPLC chart of N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride of example 16.
FIG. 18(A) & 18(B) illustrate HPLC chart of (1-methylpiperidin-4-yl)(pyrrolidine-2-yl) methanone of example 17.

DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoylchloride of Formula VIII using a suitable solvent to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I, where the suitable solvent is IPAc.

Further, the present invention relates to a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
coupling (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof with 2,4,6-triflurobenzoic acid of Formula IX using a suitable coupling agent selected from a group consisting of MsCl and T3P.

One aspect of the present invention provides a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or hemisuccinate salt thereof comprising:
i. reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof with 2,4,6-trifluorobenzoyl chloride of Formula VIII using IPAc as solvent to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I; and
ii. optionally, reacting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of the Formula I with succinic acid to afford 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate salt.

In another aspect, the present invention provides a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or hemisuccinate salt thereof comprising:
i. preparing 2,4,6-trifluorobenzoyl chloride of Formula VIII from 2,4,6-triflurobenzoic acid of Formula IX;
ii. reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof with a 2,4,6-trifluorobenzoyl chloride of Formula VIII using IPAc as solvent to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I; and
iii. optionally, reacting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of the Formula I with succinic acid to afford 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate salt.

In another aspect, the 2,4,6-trifluorobenzoyl chloride of Formula VIII is prepared by reacting 2,4,6-triflurobenzoic acid of Formula IX with a chlorinating agent in a suitable solvent, where the solvent is selected from a group consisting of IPAc and MTBE.

In yet another aspect, the 2,4,6-trifluorobenzoyl chloride of Formula VIII is prepared in-situ from 2,4,6-triflurobenzoic acid of Formula IX.

In another aspect, the chlorinating agent is selected a group consisting of thionyl chloride, oxalyl chloride, pivaloyl chloride and phosphorous oxychloride.

In another aspect, the temperature for reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl) methanone of Formula VII with the 2,4,6-trifluorobenzoyl chloride of Formula VIII is in a range of 30 to 70°C.

In another aspect, (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof reacts with 2,4,6-trifluorobenzoyl chloride of Formula VIII in presence of a proton scavenger to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I, where the proton scavenger is selected from a group consisting of TEA and DIPEA.

In another aspect, a process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or hemisuccinate salt thereof comprising:
i. reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof with 2,4,6-trifluorobenzoic acid of Formula IX using a coupling agent in presence of a base to prepare 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I, wherein, the coupling agent is selected from a group consisting of MsCl and T3P; and
ii. optionally, reacting 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of the Formula I with succinic acid to afford 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate salt.

In another aspect, the base used during the coupling of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof and 2,4,6-trifluorobenzoic acid of Formula IX is selected from a group consisting of N-methylimidazole and N-methylmorpholine.

In another aspect, (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof is reacted with 2,4,6-trifluorobenzoic acid of Formula IX in presence of a coupling agent in a temperature range of 30 to 70°C.

In one aspect, 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate is prepared by dissolving 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I in a suitable solvent and then treating the reaction mixture with succinic acid, wherein said solvent includes, from but not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butyl alcohol, pentanol and the like. In a preferred aspect, the solvent is acetone.

In another aspect, the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of the Formula I is reacted with succinic acid in a temperature range of 40 to 60°C.

In one aspect, a process for preparing (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII or a pharmaceutically acceptable salt thereof comprising:
i. reacting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof with a suitable source of ammonia and in presence of Copper or suitable Copper salt promoter and an organic additive to afford (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII; and
ii. optionally, converting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII to its pharmaceutically acceptable salt.

In another aspect, the pharmaceutically acceptable salt of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII is (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride.

In another aspect the source of ammonia includes, but not limited to ammonia gas and aqueous ammonia.

In another aspect, the copper salt promoter includes, but not limited to Copper(I)oxide (Cu2O).

In another aspect, the organic additive includes, but not limited to ethylene glycol.

In one aspect of the present invention, a process for preparing (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof comprising:
i. reacting a compound of Formula IV or a pharmaceutically acceptable salt thereof

Formula IV
, wherein R1 and R2 independently from each other, denote C1-C4 alkyl
with 2,6-dibromopyridine of Formula V to prepare a reaction mixture;

Formula V
ii. adding a suitable organolithium compound to the reaction mixture to prepare (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI; and
iii. optionally, converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI to a pharmaceutically acceptable salt.

In one aspect, the salt form of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone is (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide.

In another aspect, the organolithium compound is selected from a group consisting of methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and n-hexyl lithium. In a preferred aspect, the organolithium compound is n-hexyl lithium.

In another aspect, the organolithium compound is added to the reaction mixture of the compounds of Formula IV and Formula V in temperature range of -20 to -40°C.

According to the present invention, purity of the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone is measured as per below HPLC method.
Column: X-Bridge C18 (4.6 x 150) mm 3.5µm; Flow rate: 1.0mL/min; Wavelength: UV at 210nm; Injection volume: 5µL; Column oven temperature: 35°C; Auto sampler temperature: 10°C; Run time: 65 minutes; Mobile phase-A: a homogeneous mixture of buffer, water HPLC grade and acetonitrile (40:55:05) v/v/v; Mobile phase-B: a homogeneous mixture of buffer, methanol and acetonitrile (40:10:50) v/v/v; Buffer: a homogeneous mixture of 0.02M (2.84 g/Lit) Di-sodium hydrogen orthophosphate anhydrous in water HPLC grade; Diluent: a homogeneous mixture of water HPLC grade and acetonitrile (80:20) v/v.

In one aspect, 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide or a pharmaceutically acceptable salt thereof has a chemical purity greater than 99 percentage as determined by the HPLC method.

In another aspect, the present invention provides 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I or a pharmaceutically acceptable salt thereof, which is substantially free from impurities of Formula A-G as illustrated in Table 1.

Table 1
A.

B.

C.

D.

E.

F.

G. H.
I. J.

INFLUENCE OF SOLVENTS ON THE PREPARATION OF 2,4,6-TRIFLUORO-N-(6-(1-METHYLPIPERIDINE-4-CARBONYL)PYRIDIN-2-YL)BENZAMIDE
The inventors of present application have found that the solvents play major role in controlling formation of the impurities and quality of the product during the preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I.
During chemical development and optimization studies, the reaction of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoylchloride of Formula VIII in different solvents were investigated to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide, where the solvents under investigation were IPAc, DCM, THF, MTBE, chlorobenzene, toluene, acetonitrile and DCM followed by o-xylene. The observations from the investigation are provided in Table 2.

Table 2
Sr. No. Solvent Conversion (in %) Unreacted starting materials Yield (in %) Purity (in %) Formation of the Impurity
1 IPAc 84.76 0.39 86 99.61 Substantially Free from impurities A-G
2 DCM 26.59 15.75 Product not isolated* Product not isolated* 38.6% of impurity C observed during reaction monitoring
4 THF 46.25 31.89 50 Not determined Impurity not determined
5 MTBE 59.97 7.14
Product not isolated* Product not isolated* 18.45% of impurity C observed during reaction monitoring
6 Chlorobenzene 50.95 27.54 Product not isolated* Product not isolated* 7.79% of impurity C observed during reaction monitoring
7 Toluene 45.97 0.10
55 97.58 0.59% impurity B
8 Acetonitrile 30.39%

26.51 Product not isolated* Product not isolated* 21.80% impurity C observed during reaction monitoring
9 DCM followed by O-Xylene 86 0.29 78 99.7 7 ppm impurity B

* Due to large amount of unreacted starting material and/or large amount of impurity, the product was not isolated.

Surprisingly, the inventors have found against expectation that reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoylchloride of Formula VIII in IPAc results in the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I in pharmaceutical grade, which is substantially free from impurities of Formula A-G as illustrated in Table 1. Further, the present inventors have found that, reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoylchloride of Formula VIII in IPAc results in 80-85% conversion and 0.3-0.8% unreacted starting material, while the product yield is 80-90% and purity is 99.50-99.95%. Furthermore, there is no sticky mass formation during the preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I in the present invention.

INFLUENCE OF SEQUENCE OF ADDITION OF REACTANTS ON THE PREPARATION OF (6-BROMOPYRIDIN-2-YL)(1-METHYLPIPERIDIN-4-YL)METHANONE OF FORMULA VI
The inventors of present application have found that sequence of adding reactants play major role in controlling formation of the impurities and quality of the product during the preparation of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof.

During chemical development and optimization studies, the following four sequences were investigated for preparing (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof.
1st sequence: Addition of n-hexyllithium to 2,6-dibromopyridine, followed by subsequent addition of N,N-dialkyl-1-methylpiperidine-4-carboxide;
2nd sequence: Addition of 2,6-dibromopyridine to n-hexyllithium, followed by subsequent addition of N,N-dialkyl-1-methylpiperidine-4-carboxide;
3rd sequence: Addition of n-hexyllithium to N,N-dialkyl-1-methylpiperidine-4-carboxide, followed by subsequent addition of 2,6-dibromopyridine.
4th sequence (Present invention): 2,6-dibromopyridine and N,N-dialkyl-1-methylpiperidine-4-carboxide mixture taken in one pot, followed by addition of n-hexyllithium.

The observations from the investigation are provided in Table 3.
Table 3
Sr. No. Sequence No. Conversion (in %) Unreacted starting materials (in %) Yield (in %) Purity (in %)
1 1st 57.14 0.12 50% 91.13%
2 2nd No product formation observed 25.87 Not determined Not determined
3 3rd 0.23 78.25 Not determined Not determined
4 4th 69.13 0.19 90% 99.32%

Surprisingly, the inventors have found against expectation that the 4th sequence of addition have resulted in 69.13% conversion, 90% product yield and 99.32% purity, which is significantly higher than 1st, 2nd and 3rd sequences.
In context with the stated above, particularly preferred subject matter of the present invention is provided by the following consecutively numbered and inter-related embodiments:
1. A process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with the 2,4,6-trifluorobenzoyl chloride of Formula VIII using IPAc as a solvent to obtain the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I.
2. The process according to embodiment 1, wherein the 2,4,6-trifluorobenzoyl chloride of Formula VIII is obtainable by reacting 2,4,6-triflurobenzoic acid of Formula IX with a chlorinating agent.
3. The process according to embodiment 2, wherein the chlorinating agent is selected from a group consisting of thionyl chloride, oxalyl chloride, pivaloyl chloride and phosphorous oxychloride.
4. A process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoic acid of Formula IX using a coupling agent in presence of a base to obtain the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of the Formula I, wherein, the coupling agent is selected from a group consisting of MsCl and T3P.
5. The process according to embodiment 4, wherein the base is selected from a group consisting of N-methylimidazole and N-methyl morpholine.
6. A process for preparing (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof comprising:
i. reacting a compound of Formula IV or a pharmaceutically acceptable salt thereof

Formula IV
, wherein R1 and R2 independently from each other, denote C1-C4 alkyl
with 2,6-dibromopyridine of Formula V to prepare a reaction mixture;
ii. adding an organolithium compound to the reaction mixture to prepare the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI; and
iii. optionally, converting (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI to the pharmaceutically acceptable salt.
7. The process according to embodiment 6, wherein the organolithium compound is selected from a group consisting of methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and n-hexyl lithium.
8. Use (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI prepared according to embodiment 6 to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I.

DEFINITION(S)
The general chemical terms used throughout have their usual meanings. For example, the term alkyl refers to a branched or unbranched saturated hydrocarbon group. The term n-alkyl refers to an unbranched alkyl group. The term Cx-Cy refers to an alkyl group having between x and y carbon atoms, inclusively, in the branched or unbranched hydrocarbon group. By way of illustration, but without limitation, the term “C1-C4 alkyl” refers to a straight chain or branched hydrocarbon moiety having from 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, and n-butyl.

The term ‘alkoxy’ and ‘aryloxy’ refer to an alkyl group or aryl group, each optionally substituted, that is bonded through an oxygen atom.

The term ‘halogen’ or ‘halo’ refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro and bromo.

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

‘Pharmaceutical’ or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to a recipient.

“Pharmaceutically acceptable salt” or “salt” 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, phydroxybenzoic 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 salt including alkali metal or alkaline earth metal salt for example sodium, potassium, magnesium, calcium or zinc salt, ammonium salt; and the like.

The terms “pharmaceutical grade” in view of the API Lasmiditan or salt thereof characterizes any active or inactive drug, biologic, reagent, etc., manufactured under Good Manufacturing Practices (GMP) which is approved, conditionally approved, or indexed by the Food and Drug Administration (FDA) or for which a chemical purity standard has been written or established by a recognized compendia (e.g., United States Pharmacopeia-National Formulary (USP/NF) or British Pharmacopeia (BP)).

ABBREVIATION(S)
Throughout the specification the following abbreviations apply:
“DCM” denotes dichloromethane
“TEA” denotes triethylamine
“IPAc” denotes Isopropyl acetate
“IPA” denotes Isopropyl alcohol
“MTBE” denotes Methyl tert-butyl ether, also known as methyl tertiary butyl ether
“DMF” denotes dimethylformamide.
“ACN” denotes acetonitrile.
“THF” denotes tetrahydrofuran.
“DIPEA” denotes diisopropylethylamine
“HPLC” denotes High Performance Liquid Chromatography
“HATU” denotes Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium
“MsCl” denotes Mesyl chloride or Methanesulfonyl chloride
“T3P” denotes Propanephosphonic acid anhydride
“HBr” denotes hydrobromic acid or hydrogen bromide
“HCl” denotes hydrochloric acid or hydrogen chloride
Present invention is further illustrated with the following non-limiting examples.

EXAMPLES:
Example 1: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate in IPAc.
Synthesis of 2,4,6-trifluorobenzoyl chloride: 2,4,6-trifluorobenzoic acid (1.85 kg) was charged into a reactor, followed by addition of IPAc (15 L) and DMF (7 g.). Then oxalyl chloride (1.6 kg) was charged into the reactor. The reaction mixture was stirred for about 3 hours at 20 to 30°C under nitrogen. The organic solvent was removed from reaction mixture by distillation. Then IPAc (20 L) was charged to the reactor to obtain a reaction mixture containing 2,4,6-trifluorobenzoyl chloride.
A suspension was prepared by adding (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (2.5 kg) and IPAc (25 L) and water (7.5 L) in another reactor. The suspension was treated with a 20 weight% aqueous solution of sodium hydroxide (1.0 L). Then, the suspension was stirred for ~20 minutes and then allowed to settle for ~15 minutes and separating organic layer from aqueous layer. The aqueous layer was back extracted with IPAc (7.5 L). The organic layers were combined, washed with 10% brine solution and then concentrated under vacuum to obtain (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone free base. Further, N,N-diisopropylethylamine (2.0 kg) and IPAc (5 L) were charged into the reactor to prepare a reaction mixture containing the free base of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

Further, the reaction mixture containing the free base of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone was added to the reaction mixture containing 2,4,6-trifluorobenzoyl chloride at 20 to 60°C under nitrogen atmosphere, which was then undergo stirring for about 3.0 hours. The reaction progress was monitored by HPLC. After completion of reaction, water (10 L) was charged into the reactor and pH of more than 12 was adjusted using 20% aqueous sodium hydroxide solution ~2 volume. Then, the reaction mixture allowed to settle for ~15 minutes and separating organic layer from aqueous layer. The organic phase was washed with 10% brine solution (7.5 L) and dried under vacuum to get 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide free base.

Acetone (10 L) was added to 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide free base and then activated carbon (75 g.) was added to it and stirred for ~15 minutes. The reaction mixture was filtered and charged with succinic acid (0.6 kg). The reaction mixture was heated at 50 to 55°C and stirred for approximately 30 minutes at 50 to 55°C. The reaction mixture was cooled to room temperature and stirred for 2 hours. The reaction mixture was further cooled at 5 to 10°C. The resulting solid were collected by filtration and washed with acetone (5 L). The solid were dried under vacuum at 50oC to obtain crude 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate with 86% yield and 99.61% purity.

Example 2: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate in MTBE and IPAc.
Synthesis of 2,4,6-trifluorobenzoyl chloride: In another reactor, 2,4,6-trifluorobenzoic acid (29.03 g., 1.21 mole) was taken, followed by addition of MTBE (200 ml.) and DMF (0.28 g.) into the reactor. Further, oxalyl chloride (25.5 g., 1.47 mole equivalent) was charged into the reactor and the reaction mixture was stirred for about 2 hours at 20 to 30°C under nitrogen atmosphere. Then, the reaction mixture was partially distilled, and then charged with IPAc (320 ml.) to obtain a reaction mixture containing 2,4,6-trifluorobenzoyl chloride.

A suspension of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (40 g.,0.136 mole) and IPAc (400 ml.) and water (120 ml.) was prepared in a reactor. The suspension was then treated with 20 weight% aqueous solution of sodium hydroxide (80 ml.). Then, the suspension were stirred for 20-30 minutes and then allowed to settle for 5 minutes and separating organic layer from aqueous layer. The aqueous layer was back extracted with IPAc (120 ml.). Organic layers were combined and then concentrated under vacuum to obtain (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone free base.

Meanwhile, a solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl) methanone (free base) N,N-diisopropylethylamine (32.7 g., 1.85 mol.), IPAc (80 ml.) and acetonitrile (20 ml.) was prepared in a separate reactor and the solution was charged into the reaction mixture containing 2,4,6-trifluorobenzoyl chloride at 20 to 40°C under nitrogen atmosphere. The mixture was heated at 50 to 60°C and stirred for about 3.0 hours. The reaction progress was monitored by HPLC. After completion of reaction, water (160 ml.) was charged into the reactor and pH more than 12 was adjusted using 20% aqueous sodium hydroxide solution (150 ml.). Then, the reaction mixture was allowed to settle for ~15 minutes and separating organic layer from aqueous layer. The organic phase was dried under vacuum to get 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide free base. Further, acetone (160 ml.) was charged into the free base reaction mixture, followed by addition of succinic acid (9.6g., 0.6 mol.) to it. The reaction mixture was heated at 50-55°C and stirred for 1 hour. Then the reaction mixture was cooled at 0 to 10°C and stirred for approximately 1 hour. The resulting solid was collected by filtration and washed with acetone (80 ml.). The solid was dried under vacuum at 50oC to obtain 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (48 g.) with 99.90% purity. Upon reaction completion, 83.09% conversion and 0.79% unreacted starting material was determined.

Example 3: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate in chlorobenzene.
A suspension of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (15 g., 0.051 mol.), IPAc (150 ml.) and water (45 ml.) was treated with a 20% W/V aqueous solution of sodium hydroxide (32 ml.) under stirring. Then, the suspension was stirred for ~15 minutes and separating organic layer from aqueous layer. The aqueous layer was back extracted with IPAc (45 ml.). Organic layers were combined and concentrated under vacuum to obtain (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone free base.

2,4,6-trifluorobenzoic acid (11.0 g., 1.21 mol.), chlorobenzene (150 ml.) and DMF (0.1 g.) were charged into another reactor and then thionyl chloride (8.92 g.) was added into it. The reaction mixture was heated at 50-60°C and stirred for about 2-3 hours at 50 to 60°C to obtain 2,4,6-trifluorobenzoyl chloride.

A solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone, N,N-diisopropylethylamine (12.2g., 1.85 mol.) and chlorobenzene was prepared and charged to the 2,4,6-trifluorobenzoyl chloride at 50 to 60°C. The reaction mixture was further heated at 60 to 80°C and stirred for about 4 hours. Sticky reaction mass formation was observed in the reaction mixture. The reaction mixture was cooled to room temperature and water (60 ml.) was added. pH more than 12 was adjusted using by using 20% aqueous sodium hydroxide solution (30ml.). The reaction mixture was stirred for 20 minutes and subsequently settled to separate organic layer from aqueous layer. Aqueous layer back extracted with IPAc (60 ml.) The combined organic phases were combined and dried under vacuum to obtain free base of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide.

Further, acetone (90 ml.) was added to the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide free base, followed by addition of succinic acid (3.6g., 0.6 mol.). The reaction mixture was heated at 50-55°C and stirred for 1 hour. Then, the reaction mixture was cooled at 0 to 10°C. The resulting solid was collected by filtration and dried under vacuum at 50oC to afford the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (9.5 g.) with 78.82% purity.

Example 4: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate in toluene.
A suspension of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (4.5 g., 0.015 mol.) in Methyl tert-butyl ether (75 ml.) and water (50 ml.) was prepared in a reactor. The suspension was treated with 20% W/V aqueous sodium hydroxide solution (13 ml.) under stirring. Then, the suspension were stirred 10 minutes and separating organic layer from aqueous layer. Aqueous layer back extracted with Methyl tert-butyl ether (15 ml.). Organic layers were combined and washed with 10% brine solution (15 ml.) and then concentrated under vacuum to obtain (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

Into another reactor, 2,4,6-trifluorobenzoic acid (3 g.) was charged followed by toluene (30 ml.) and catalytic amount of DMF (0.1 g.). Then, oxalyl chloride (2.89 g., 1.35 mole equivalent) was added to the reactor and the reaction mixture was stirred for 2 hours at 20 to 30°C. The reaction mixture was further heated at 60 to 75°C for 3-4 hours to prepare 2,4,6-trifluorobenzoyl chloride.

A solution of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone, N,N-diisopropylethylamine (3.2 g., 1.5 mol.) and toluene (15 ml.) was prepared in a separate reactor and then the solution was added to 2,4,6-trifluorobenzoyl chloride. The reaction mixture was stirred for 5-6 hours at 70 to 75°C. After completion of reaction, the reaction mixture was cooled at 20 to 30°C and then water (30 ml.) and 10% sodium hydroxide solution (10 ml.) were added to the reaction mixture. The reaction mixture was stirred and organic layer was separated from aqueous layer. The aqueous layer was back extracted aqueous layer with toluene (20 ml.). Organic layers were combined and then dried under vacuum to obtain free base of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide.

The free base of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide was subsequently charged with acetone (25 ml.), and then with succinic acid (0.7 g., 0.4 mole equivalent). The reaction mass was heated at 50 to 55°C and stirred for 30 minutes. Then, the reaction mixture was cooled at 20 to 30°C. Then, the reaction mass was filtered and dried under vacuum at 50oC to obtain the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (3.75 g.) with 97.58% purity.

Example 5: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate in DCM.
A suspension of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (30 g.) in MTBE (300 ml.) and water (90 ml.) was treated with 20% w/v aqueous sodium hydroxide solution (65ml.) and was stirred at room temperature. The phases were allowed to settle and then separated. Aqueous layer back extracted with MTBE (90 ml.). Organic layers were combined and then distilled out under vacuum to obtain (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. In separate reactor, 2,4,6-trifluorobenzoic acid (11.1 g.) was charged followed by DCM (100 ml.) and catalytic amount of DMF (0.1 g.). Then, oxalyl chloride (9.6 g.) was added to reaction mixture and stirred at 20 to 30°C for 2 hours to obtain a reaction mass. The reaction mass was distilled to obtain a 2,4,6-trifluorobenzoyl chloride. Then, the (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone was charged to the reactor containing 2,4,6-trifluorobenzoyl chloride reaction mass in the presence of N,N-diisopropylethylamine (12.2 g.) at 20 to 30°C under nitrogen atmosphere. The reaction mixture was heated at 40°C and Stirred for 2 hours. The reaction progress was monitored by HPLC. The titled product, 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide was not isolated.

Example 6: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate in THF.
(6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (13.5 g., 0.046 mol.),IPAc (135 ml.) and water (41 ml.) were charged to a reactor, followed by 20%W/V aqueous sodium hydroxide solution (27 ml.). The reaction mixture was stirred and layers were separated. Aqueous layer was back extracted with IPAc (41ml.). Organic layers were combined and concentrated under vacuum to obtain (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone.

2,4,6-triflurobenzoic acid (10 g.) was charged to a reactor followed by MTBE (68 ml ) and catalytic amount of DMF (0.1 g.) and then oxalyl chloride (1.0 mole eq. or 1.5 mole equivalent) was added to reactor under nitrogen atmosphere. The reaction mixture was stirred for 3 hours at 20 to 30°C to obtain a reaction mass of 2,4,6-trifluorobenzoyl chloride. Further, the reaction mass was distilled atmospherically completely, then THF (81 ml.) was added. Then (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone and TEA (8.6 g.) were added to the 2,4,6- trifluorobenzoyl chloride at 20 to 35°C under nitrogen atmosphere and heat the reaction mixture for 1-3 hours at 50 to 60°C After completion of reaction, water (54 ml.) was charged into the reactor. Then the organic layer was separated from the aqueous layer. The organic layer was treated with 10% brine solution and then concentrated. The concentrated organic mass was charged with acetone (68 ml.) followed by succinic acid (3.3 g.) at 20 to 30°C. The reaction mixture was stirred for 2 to 4 hours, subsequently filtered and dried under vacuum at 50oC to afford the title compound 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (10 g.).

Example 7: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate using MsCl as coupling agent.
2,4,6-triflurobenzoic acid (7.2 g.) was charged into a reactor. Then, acetonitrile (15 ml.) and N-methylimidazole (10 g.) were charged into the reactor under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes and then charged with MsCl (5.9 gram) under nitrogen atmosphere to obtain a reaction mass. The reaction mass was stirred for 60 minutes at 0 to 10°C. (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (7.5 gram) in dilution with acetonitrile (15ml.) was added to the reaction mass, heated at 55 to 60°C and stirred for 8 hours. Further, the reaction mixture was cooled at 20 to 30°C.Then, water (21 ml.) and IPAc (75 ml.) followed by 20% sodium hydroxide solution (15ml.) The reaction mixture was stirred for ~30 minutes and subsequently settled to separate organic layer from aqueous layer, Aqueous layer back extracted with IPAc (22.5 ml.), then combined organic layer wash with 10% aqueous sodium chloride solution (22ml.). Organic layers concentrated under vacuum, then acetone (38 ml.) and succinic acid (1.5 g.) were charged. The reaction mixture was heated at 50 to 60°C and stirred for 60 minutes. Further, the reaction mixture was cooled at 0 to 10°C, then filtered and dried under vacuum at 50°C to afford the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (6 g.) with 99.71% purity.

Example 8: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate using T3P as coupling agent.
2,4,6-triflurobenzoic acid (9.6 g.) was charged into a reactor. Then, acetonitrile (100 ml.) and N-methylimidazole (14.9 g.) was charged into the reactor, followed by (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl) methanone (10 g.). Then, T3P (58 ml.) was charged into the reactor. The reaction mass heated at 55 to 60°C and stirred for 38-40 hours and stirred at 80 to 85°C for 15-16 hours. After completion of reaction, the reaction mass was concentrated under vacuum at 45°C and charged with water (100ml.) and IPAc (100ml.) stirred and separated organic layer, the organic layer was concentrated under vacuum at 45°C and charged with Acetone(50 ml.) followed by succinic acid (2.1 g.) at 20 to 30°C and then stirred for 1 hours. The reaction mixture was subsequently filtered and dried under vacuum at 45oC to afford the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide hemisuccinate (8.2 g.) with purity of 99.93%.

Example 9: Preparation of 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide succinate using HATU as coupling agent.
HATU (10.6 g., 1.0 mol.) and TEA (2.8 g., 1.01 equivalent) were charged into the reaction mass of 2,4,6-triflurobenzoic acid (5 g., 1.0 mol.) and N,N-dimethylformamide (25 ml.). Reaction mixture was cooled at 0 to 10°C, followed by addition of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (4.13 g., 0.5 equivalent). The reaction mixture stirred for ~26 hours at 10 to 30°C and the reaction progress was monitored by HPLC. After 3 hours of reaction, 21.97% unreacted starting material with 1.29% conversion was observed. After 13 hours of reaction, 21.37% unreacted starting material with 1.45% conversion was observed.

Example 10: Preparation of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone following 1st sequence of addition.
2,6-dibromopyridine (10 g.) was charged into round bottom flask followed by toluene (100 ml.) at room temperature. Further, the reaction mass was cooled at -35°C and subsequently charged with n-hexyl lithium 33% solution (18 ml.). The reaction mass was stirred for 15 minutes under nitrogen atmosphere and then charged with N,N-dialkyl-1-methylpiperidine-4-carboxide (8.4 g.) in toluene (50 ml.) at -35 to -20°C. The reaction mixture was further stirred for 2.5 hours. After completion of reaction, water (50 ml.) was charged into the reactor and the compound was extracted with toluene. The reaction mixture was stirred, and allowed to settle to separate organic layer from aqueous layer. Further, the organic layer was concentrated under vacuum to obtain free base of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone. Then aqueous HBr solution (10 ml.) was added to the free base. The reaction mixture was stirred for 2 hours and then filtered and dried under vacuum at 50°C to afford the (6-bromopyridin-2-yl)(1-methyl piperidin-4-yl)methanone hydrobromide (7.7 g.) with purity of 91.13%.

Example 11: Preparation of 6-(bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone following 2nd sequence of addition.
MTBE (20 ml.) was charged into round bottom flask at room temperature. Then, the reaction mass was cooled to -70°C under nitrogen atmosphere. Then, n-hexyl lithium solution (4 ml.) was charged into the flask and stirred for about 2 hours under nitrogen atmosphere. Then, N, N-dialkyl-1-methylpiperidine-4-carboxide (1.69 g.) being diluted with MTBE (30 ml.) was added to the reaction mass at -70 to -60°C and the reaction progress was monitored. A significant amount (25.87%) of the 2,6-dibromopyridine (starting material) was remained unreacted.

Example 12: Preparation of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone following 3rd sequence of addition.
Toluene (100 ml.) was charged into a round bottom flask. Then, N, N-dialkyl-1-methylpiperidine-4-carboxide (9.2 g.) was charged into round bottom flask at room temperature and subsequently reaction mass was cooled at -40°C under nitrogen atmosphere. 33% solution of n-hexyl lithium (4.23 ml.) was added to the reaction mass and stirred for 10-20 minutes. Then, solution of toluene (50 ml.) and 2,6-dibromopyridine (10 g.) was charged slowly into the reaction mixture under nitrogen atmosphere at -20 to -40°C. The reaction mixture was stirred for 2 hours and reaction progress was monitored by HPLC.

Example 13: Preparation of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide following 4th sequence of addition and using Toluene as solvent.
A mixture of 2,6-dibromopyridine (60 g.) (1.0 mole equivalent) and N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride (52.7 g.) (1.0 to 1.2 mole equivalent) and toluene (900 ml.) was charged to a reactor at room temperature and cooled at -40°C. To the cooled suspension, 33% solution of n-hexyl lithium in hexane (108 ml.) was charged over a period of 30 minutes. The mixture was aged while maintaining temperature at -40 to -20°C. After aging, water (5 volume) was added to the reaction mixture and phases were allowed to settle. The phases were separated, and the organic layer was concentrated vacuum to obtain (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone free base. Then, acetone was added to the free base to obtain a clear solution. Then aqueous HBr solution (60 ml.) was added to the clear solution and was stirred for 2 hours and subsequently filtered and dried under vacuum at 50°C to afford the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide (83 g.) with 99.32% purity.

Example 14: Preparation of (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide following 4th sequence of addition and using a solvent mixture of toluene and THF.
2,6-dibromopyridine (15 g.) (1.0 mole equivalent) and (1-methylpiperidin-4-yl)(pyrrolidine-2-yl) methanone (15 g.) (1.0 to 1.2 mole equivalent) were charged into a reactor followed by addition of toluene (210 ml.) and THF (15 ml.) at room temperature. The reaction mixture was cooled at -40 to -20°C. Then, 33% solution of n-hexyl lithium (30 ml.) was added to the cooled reaction mixture at -40°C. The reaction mixture was undergo aging at -40 to -20°C. After aging, water (75 ml.) was charged into the reactor and the compound was extracted with toluene (45 ml.). The phases were allowed to settle and then organic layer was separate from aqueous layer. Further, the organic layer was concentrated under vacuum at 40 to 50°C. Then acetone was added to the organic layer to obtain a solution. Further, 48% aqueous HBr solution (15 ml.) was added into reaction mixture at 20 to 30°C. The reaction mass was stirred for about 3 hours and subsequently filtered and dried under vacuum at 50°C to afford the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide (18.6 g.) with 99.57% purity.

Example 15: Preparation of (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride.
A pressure reactor was charged with Ethylene glycol (380 ml.), (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrobromide (95 g.). Copper (I) oxide (1.9 g.) as a catalyst was charged into the reactor. The reaction mixture was stirred for about 2 hours at 20 to 60oC under ammonia pressure (4 to 6 kg). Further, the reaction mixture was heated at 70-80oC and maintained at the same temperature for about 8 hours under ammonia pressure (4 to 6 kg). The reaction mixture was then cooled at 20 to 30oC followed by addition of water (665 ml.) and sodium chloride (166 g.) to obtain a reaction mass and charge 10% sodium hydroxide solution (475ml.) and IPAc (665ml.).Stirred the reaction mixture for 15 minutes at 20 to 30°C and the reaction mass was filtered and followed, and the phases were allowed to settle and subsequently, organic layer was separated from aqueous layer. The aqueous layer was back extracted with IPAc (3Times x 285 ml.). Combined organic layer was washed with water (475ml.) for 30 minutes at 20 to 30°C. The organic layer went through distillation and charged methanol (380ml.) and IPA (190 ml.) was added to it. The mixture was cooled to 0 to 10oC. Then, 4M IPA.HCl (119 ml.) was added to the cooled reaction mixture. The mixture was stirred for 3-4 hours, The slurry was filtered at 0 to 5oC and spray washed with IPA (190 ml.) dried under vacuum at 45 to 50oC to afford the (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone dihydrochloride (42 g.) with purity of 99.83%.

Example 16: Preparation of N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride.
DCM (1200 ml.) was taken in a reaction vessel. 1-methylpiperidine-4-carboxylic acid hydrochloride (150 g.) was charged to the vessel under nitrogen atmosphere. Then, DMF (1.5 g.) was added into the reaction vessel. Further, oxalyl chloride (127.3 g.) was added to the vessel under nitrogen atmosphere at 20 to 30oC to form a reaction mass, which was stirred for 65 minutes at 20 to 35oC. The solvent was then eliminated by means of vacuum distillation at 50°C atmospherically. The reaction mass was then cooled to 0 to 10oC. DCM (1050 ml.) was added to the cooled reaction mass under nitrogen atmosphere.

In another reaction vessel, a solution of Diethylamine (91.6 g.) and TEA (42.24g.) was prepared under nitrogen atmosphere, which was added to the cooled reaction mass to obtain a reaction mixture. The reaction mixture was stirred for 120 minutes under nitrogen atmosphere. Then, water (450 ml.) into reaction mass and pH of the reaction mixture was adjusted to more than 12 by adding 20% aqueous sodium hydroxide solution (475 ml.) with stirring for 30 minutes at 20 to 30oC. Then the phases were allowed to settle to separate organic layer and aqueous layer. MTBE (2 L) was charged to the aqueous layer in a separate reaction vessel. The solution was allowed to settle after stirring for 30 minutes and organic layer was separated from aqueous layer. Combined organic layers were treated with 10% aqueous sodium chloride solution (450 ml.) and stirred for 30 minutes to separate the organic layer. The organic layer was concentrated under vacuum till 1 to 2 volumes of the reaction mass left behind. The concentrated reaction mixture was charged with MTBE (1200ml.) under stirring and cooled at 0 to 20oC. Further, IPA.HCl (225 ml.) was added to the reaction mixture and stirred under nitrogen atmosphere for ~15 hours. The slurry was filtered to obtain a solid mass, which was then washed with MTBE (300 ml.) and dried under vacuum at 45 to 50oC to afford the N,N-diethyl-1-methylpiperidine-4-carboxamide hydrochloride (166 g.) with purity of 99.48%.

Example 17: Preparation of (1-methylpiperidin-4-yl)(pyrrolidine-2-yl) methanone.
DCM (70 ml.) was charged to a first reaction vessel. Then, 1-methylpiperidine-4-carboxylic acid hydrochloride (100 g.) was charged to the vessel under nitrogen atmosphere. Then, DMF (0.5 g.) was charged to the reactor and flushed with DCM (100 ml.). Oxalyl chloride (83.7 g.) was then added to the vessel under nitrogen atmosphere at 20 to 30oC to form a reaction mass, which was stirred for 120-240 minutes at 20 to 35oC. The solvent was then eliminated by means of vacuum distillation at 25 to 55oC atmospherically till 3 to 4 volumes of the reaction mass left behind. The reaction mass was cooled to 0 to 10oC. DCM (700 ml.) was added to the cooled reaction mass under nitrogen atmosphere. In another reaction vessel, a solution of pyrrolidine (58.7 g.) and TEA (27.8 g.) was prepared under nitrogen atmosphere, which was subsequently added to the cooled reaction mass to obtain a reaction mixture. The reaction mixture was stirred for 120 minutes under nitrogen atmosphere. pH of the reaction mixture was adjusted to more than 12 by adding 20% aqueous sodium hydroxide solution (320 ml.) with stirring for 30 minutes at 20 to 30oC and then the reaction mixture was allowed to settle to separate organic layer from aqueous layer. DCM (2 L) was charged to the aqueous layer in a separate reaction vessel and stirred for 30 minutes to separate organic layer. The organic layers were combined to which, 10% aqueous sodium chloride solution (300 ml.) was charged followed by stirring for 30 minutes to further separate organic layer. The organic layer was concentrated under vacuum till 1 to 2 volumes of the reaction mass left behind. Then, n-heptane (300 ml.) was added to the concentrated organic mass and stirred for 2 hours at 0 to 20°C. The slurry was filtered to obtain a solid mass, which was then washed with n-heptane (200 ml.) and dried under vacuum at 40 to 45°C to afford the (1-methylpiperidin-4-yl)(pyrrolidine-2-yl) methanone (82 g.) with purity of 93.79%.
, Claims:1. A process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoyl chloride of Formula VIII using IPAc as a solvent to obtain the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I.

2. The process according to claim 1, wherein the 2,4,6-trifluorobenzoyl chloride of Formula VIII is obtainable by reacting 2,4,6-triflurobenzoic acid of Formula IX with a chlorinating agent.

3. The process according to claim 2, wherein the chlorinating agent is selected from a group consisting of thionyl chloride, oxalyl chloride, pivaloyl chloride and phosphorous oxychloride.

4. A process for preparing 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of Formula I comprising:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VII with 2,4,6-trifluorobenzoic acid of Formula IX using a coupling agent in presence of a base to obtain the 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide of the Formula I, wherein, the coupling agent is selected from a group consisting of MsCl and T3P.

5. The process according to claim 4, wherein the base is selected from a group consisting of N-methylimidazole and N-methylmorpholine.

6. A process for preparing (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI or a pharmaceutically acceptable salt thereof comprising:
i. reacting a compound of Formula IV or a pharmaceutically acceptable salt thereof

Formula IV
, wherein R1 and R2 independently from each other, denote C1-C4 alkyl
with 2,6-dibromopyridine of Formula V to prepare a reaction mixture;
ii. adding an organolithium compound to the reaction mixture to prepare the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI; and
iii. optionally, converting the (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone of Formula VI to the pharmaceutically acceptable salt.

7. The process according to claim 6, wherein the organolithium compound selected from a group consisting of methyl lithium, n-butyl lithium, secondary-butyl lithium, tertiary-butyl lithium and n-hexyl lithium.