DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Trametinib and its intermediate of Formula (II).

BACKGROUND OF THE INVENTION
Trametinib (I) is chemically known as N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3- d]pyrimidin -1-l]-phenyl}acetamide. Dimethyl sulfoxide solvate of Trametinib (I) is a kinase inhibitor and is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Trametinib is administered orally as Trametinib dimethylsulfoxide under the trade name Mekinist® marketed by Novartis.

US 7,378.423 (hereinafter referred to as the US '423) discloses Trametinib or its physiologically acceptable salts or solvates thereof. US '423 discloses the preparation of Trametinib dimethyl sulfoxide is schematically represented as below.
Scheme 1
In the above Scheme 1, the conversion from compound of formula VIII to compound of formula IX using p-toluenesulfonyl chloride involves the use of triethyl amine as a base. However, the reaction using triethyl amine as a base results in a very low yield and purity.
Considering the importance of Trametinib in the pharmaceutical field, there is a need to develop an improved process for its preparation that provides a higher yield of the end product with better purity.

SUMMARY OF THE INVENTION
The main aspect of the invention relates to an improved process for the preparation of Trametinib or its solvate, comprising the steps of:
i) reacting a compound of Formula (III),

with p-toluene sulfonyl chloride in the presence of a metal hydride in a suitable solvent(s) to obtain a compound of Formula (II);

ii) optionally purifying the compound of Formula (II); and
iii) converting the compound of Formula (II) to Trametinib or its solvate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of trametinib of Formula (I) or its solvate thereof.
In an embodiment of the present invention provides an improved process for the preparation of Trametinib or its solvate, comprising the steps of:
a) reacting a compound of Formula (III),

with p-toluene sulfonyl chloride in the presence of a metal hydride in a suitable solvent(s) to obtain a compound of Formula (II);

b) optionally purifying the compound of Formula (II); and
c) converting the compound of Formula (II) to Trametinib or its solvate.
In another embodiment of the present invention, the suitable solvent used in step (a) is selected from group consisting of, but not limited to,, alcohols, amides, esters, ethers, halogenated solvents, hydrocarbon solvents, ketone, nitriles; wherein alcohols are selected from the methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol, isobutanol, tertiary butanol, benzyl alcohol, ethylene glycol, propylene glycol; amides are selected from formamide, dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidone; esters are selected from ethyl acetate, methyl acetate, ethyl acetoacetate, propyl acetate, butyl acetate, isobutyl acetate; ethers are selected from diisopropyl ether, di-tert-butyl ether, methyl tert-butyl ether,diethyl ether, tetrahydrofuran, 1,4-dioxane; halogenated solvents are selected from dichloromethane, dichloroethane, chloroform, chlorobenzene; aliphatic hydrocarbon solvents are selected from heptane, hexane, aromatic hydrocarbon solvents are selected form toluene, cycloheptane, cyclohexane, cyclohexene, cyclooctane, cyclopentane; ketones are selected from acetone, butanone, ethyl isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; nitriles are selected from acetonitrile, proprionitrile, or benzonitrile.
In another embodiment of the present invention, the reaction of step (a) may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, at a temperature in the range of 0°C to 100°C; more preferably at a temperature in the range of 5°C to 35°C.
In another embodiment of the present invention, the reaction of step (a) carried out by addition of metal hydride such as sodium hydride. The metal hydride may be added either lot wise or directly.
In one embodiment, the compound of Formula (II) may be isolated by conventional work-up and optionally purified by any technique known in the art, or the compound may be subjected to next reaction without isolation and/or purification.
In another embodiment of the present invention, compound of Formula (II) is isolated and optionally subjected to purification methods, including but not limited to crystallization, recrystallization and stirring in a solvent.
In another embodiment of the present invention, compound of formula (II) is converted to trametinib by following procedures as known in the art. In another embodiment, the trametinib obtained is converted into its solvate, such as DMSO solvate, acetic acid solvate, DMAc solvate, NMP solvate and the like of formula (I), which is further converted into its unsolvated form.
Another aspect of the present invention relates to an improved process for the preparation of trametinib of Formula (I) or its solvate thereof, comprising converting formula (III) to trametinib of Formula (I) or its solvate thereof as represented schematically in scheme 3 as shown below.

Scheme-3
The prior art process involves the use of TEA as a base and ACN as a solvent wherein the reaction does not go to completion and results in a lower yield below 50%. The merit of the process according to the present invention resides using reaction condition providing better conversion and resulting higher yield as shown in examples below.
In another embodiment, a small amount of an antioxidant such as, but not limited to, citric acid, ascorbic acid, triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol (BHT), butylated hydroxyanisole, a mixture of 2-tert-butylhydroxy anisole and 3-tert-butylhydroxy anisole (BHA), ethyl gallate (EtG) and propyl gallate (PrG) may be added to the clear solution of trametinib before isolation.
In yet another embodiment, Trametinib prepared according to the present invention may be packed under stringent packaging condition to avoid moisture and oxygen entry, optionally in presence of oxygen absorbent and / or desiccant.
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 EDTA, 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 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate [Formula II]
To a stirred reaction mixture of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethylpyrido[2,3-d] pyrimidine-2,4,7(1H,3H,8H)-trione (100 g) in THF (700ml) at 10°C, p-toluene sulfonyl chloride (78.93 gm) was added at 10°C followed by lot-wise addition of sodium hydride (10 gm). The reaction mixture stirred at room temperature until completion of reaction. After completion of reaction, methanol was added to reaction mixture, stirred, and filtered to obtain wet cake. The obtained wet cake was stirred in water, filtered and dried to obtain formula II (Yield: 83.33%)

Example 2: Preparation of N-(3-((3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d] pyrimidin-5-yl) amino) phenyl)acetamide
To a stirred reaction mixture of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d] pyrimidin-5-yl-4-methyl benzene-sulfonate (100 g), 2, 6-Lutidine (50.47 g) in N, N-dimethylacetamide (350 ml); N-3-amino phenyl acetamide (47.16 g) was added and stirred at reflux temperature until completion of reaction. After completion of reaction, methanol was added to reaction mixture, stirred and filtered to obtain Trametinib stage-IA.

Example 3: Preparation of Trametinib [Formula-I]
To a stirred reaction mixture of N-(3-((3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo1,2,3,4,7,8-hexahydropyrido[2,3-d] pyrimidin-5-yl) amino) phenyl) acetamide (100g) in THF (200ml); sodium methoxide solution in methanol was added at room temperature and stirred until completion of reaction. After completion of reaction, acetic acid (500 ml) was added to reaction mixture followed by water. The reaction mixture was stirred, filtered and dried to obtain solid. The obtained solid was stirred in DMSO at 82°C followed by cooling at room temperature to obtain Trametinib DMSO solvate. Trametinib DMSO solvate was dissolved in mixture of MDC and methanol at room temperature. The reaction mixture was subjected to charcoal treatment, filtered and the filtrate was concentrated to obtain residue. To obtained residue acetonitrile was added at hot temperature, stirred cooled to room temperature, filtered and washed with acetonitrile to obtain wet cake solid. The wet cake as obtained was stirred with water at reflux temperature, cooled to room temperature, filtered, washed with water and dried to obtain Trametinib. (Yield: 65.71%)

Dated this: 19th day of March, 2025 Dr. S. Ganesan

,CLAIMS:WE CLAIM:
1. A process for the preparation of Trametinib or its solvate, comprising the steps of:
a) reacting a compound of Formula (III),

with p-toluene sulfonyl chloride in the presence of a metal hydride in a suitable solvent(s) to obtain a compound of Formula (II);

b) optionally purifying the compound of Formula (II); and
c) converting the compound of Formula (II) to Trametinib or its solvate.
2. The process as claimed in claim 1, wherein metal hydride is sodium hydride.
3. The process as claimed in claim 1, wherein suitable solvent used in step (a) is selected from alcohols, amides, esters, ether, halogenated, hydrocarbon, ketones, and nitriles.
4. The process as claimed in claim 3, wherein suitable solvent is selected from an ether solvent.
5. The process as claimed in claim 4, wherein the ether solvents are selected from tetrahydrofuran, diisopropyl ether, di-tert-butyl ether, diethyl ether, methyl tert-butyl ether, and 1,4-dioxane.
6. The process as claimed in claim 1, wherein reaction of step (a) is carried out at 0°C to 100°C temperature.
7. The process as claimed in claim 6, wherein reaction of step (a) is carried out at 5°C to 35°C.

Dated this: 19th day of March, 2025 Dr. S. Ganesan