WO2016147104A1

WO2016147104A1 - Novel process for the preparation of perampanel and its intermediates thereof

Info

Publication number: WO2016147104A1
Application number: PCT/IB2016/051438
Authority: WO
Inventors: Gobind Singh Kapkoti; Mettilda Lourdusamy; Ioan Iosif RADU; Ashesh Kamalnayan Pandya; Nitesh Dolatram Chauhan; Bipinkumar Hashmukhbhai DHOLARIYA; Vishal Keshavlal PATEL
Original assignee: Intas Pharmaceuticals Ltd.
Priority date: 2015-03-14
Filing date: 2016-03-14
Publication date: 2016-09-22

Abstract

The present invention provides novel process for preparation of 3-(2-cyanophenyl)-5-(2- pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, commonly known as perampanel having the formula I. The present invention also provides novel intermediate compound of formula VI and process for the preparation of intermediate compound of formula VI. The present invention also provides purification of perampanel.

Description

Novel process for the preparation of perampanel and its intermediates thereof

RELATED APPLICATIONS

This application is related to Indian Provisional Application 839/MUM/2015 filed 14^th March, 2015 and is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of 3-(2- cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, commonly known as perampanel.

The invention also relates to novel intermediate compounds useful in the synthesis of perampanel and process for their preparation.

BACKGROUND OF THE INVENTION

Perampanel, chemically known as 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1,2- dihydropyridin-2-one can be represented by following structural formula

Perampanel is an antiepileptic drug that acts as selective non-competitive antagonist of AMPA receptor, the major subtype of ionotropic glutamate receptors.

The pharmaceutical application of perampanel and method for its preparation is described in US 6,949,571. The process disclosed in '571 is as follows:

Above mentioned process involve expensive catalyst tetrakistriphenyl phosphine. Additionally, in stage-II of this process it is necessary to maintain anhydrous condition for chloro trimethyl silane. The final product is isolated by column chromatography. Therefore, this process is not commercially viable and also results in overall low yield. This patent also discloses an alternative process which involves eight synthetic steps, a process including eight steps is very cumbersome to be applied for commercial scale and also there is yield loss at every stage of isolation.

US 8,304,548 discloses alternative process for the preparation of perampanel by reaction of 3-bromo-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one with benzonitrile boronic acid derivative. The following reaction scheme depicts the process of '548.

This process generates N-oxide impurity of perampanel, also the yield is not satisfactory.

US 2013/0109862 discloses process for the preparation of 2-alkoxy-5-(pyridin-2- yl)pyridine, an intermediate

used in the synthesis of perampanel.

US 7,524,967 discloses process for the preparation of 5-(2'-pyridyl)-2-pyridone compound, which is summarized in the below reaction scheme:

The above described processes require many synthetic steps and provide perampanel in poor yield. Therefore, there is a need in the art to provide an efficient process, which provides perampanel in high yield and can be used in industrial scale.

Thus it is an object of the invention to provide a novel, yet efficient and simple process for synthesis of perampanel and its intermediates.

OBJECTS OF THE INVENTION

The main object of the invention is to provide a process for preparation of perampanel comprising converting a compound of formula VI

VI

to perampanel of formula I. Another object of the invention is to provide a process for preparation of perampanel comprising converting a compound of formula V

to compound of formula VI

Another object of the invention is to provide a compound of the formula V, intermediate in the synthesis of perampanel.

Another object of the invention is to provide a compound of formula VI, an intermediate in the synthesis of perampanel.

Yet another object of the invention is to provide the process of preparation of novel intermediates of formula V and VI, used in the synthesis of perampanel. SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of perampanel comprising a step of converting compound of formula VI to perampanel of formula I.

Another aspect of the invention is to provide a process of preparation of perampanel as described by following reaction scheme:

Another aspect is to provide intermediate compound of formula V

Another aspect is to provide intermediate compound of formula VI

VI

Yet another aspect of the invention provides process for preparation of intermediate of formula V

IV

wherein the process comprises step of reacting compound of formula IV with 2- (formyl phenyl) boronic acid.

Yet another aspect of the invention provides a process for preparation of intermediate of formula VI wherein the process comprises step of reacting an aldehyde intermediate of formula V in presence of hydroxylamine or its salt and suitable solvent. Yet another aspect of the present invention is to provide use of intermediate of formula V or intermediate of formula VI in the synthesis of perampanel of formula I.

DETAILED DESCRIPTION OF THE INVENTION The main embodiment of the present invention is to provide a process for the preparation of perampanel. The novel process of the invention can be depicted by following reaction scheme:

v VI

In the above process, step (a) includes conversion of compound of formula V to compound of formula VI by reaction of 2-(6'-oxo-l'phenyl- ,6'-dihydro-[2,3- bipyridin]-5'-yl)benzaldehyde of formula V with hydroxylamine or its salt in presence of suitable solvent to give 2-(6'-oxo- -phenyl- ,6'-dihydro[2,3'- bipyridine]-5'-yl)-benzaldehyde oxime of formula VI. Generally the hydrochloride salt of hydroxylamine is used for the purpose of present invention. The reaction is carried out in presence of solvents selected from water, alkanol, ester, ether, aldehyde, ketone, hydrocarbon, halogenated hydrocarbon and the like.

Preferably the reaction is carried out in the presence of hydroxylamine hydrochloride and water or alkanol. The reaction can be carried out at a suitable temperature generally depending on the solvent and reagent used in the process. Preferably the reaction is carried out at ambient temperature (25-30°C) or higher temperature i.e. up to 150°C.

The pH of the reaction can be adjusted by any suitable base, generally inorganic base like sodium hydroxide is used.

Once the reaction is completed, the product i.e. oxime of formula VI can be separated by cooling the reaction mixture. The compound of formula VI can be isolated from the reaction mixture by known methods of filtration, the residue is washed with suitable solvent such as water, alkanol, ester, ether or like.

As an alternate the compound of formula VI can be used without isolation for the preparation of perampanel. The process of step (b) which is conversion of compound of formula VI to perampanel of formula I can be carried out in presence of suitable reagents and solvent. The suitable reagent used in step (b) can be acetic acid derivatives selected from group comprising of acetic acid anhydride, acetyl chloride or any similar compound.

Suitable solvents used in step (b) includes but not limited to alkanol, ester, aldehyde, ketone, ether, hydrocarbon.

In a preferred embodiment the process of step (b) is carried out in presence of acetic anhydride and solvent selected form water or aromatic hydrocarbon. The reaction can be carried out at any suitable temperature like from ambient temperature to about 150°C. The pH of reaction is adjusted by base such as ammonia. After completion of reaction the product i.e. perampanel is isolated by filtration and the product can be further washed by any suitable solvent and dried.

In another embodiment the present invention provides a process for preparation of intermediate of formula V.

Intermediate of formula V is prepared by reacting compound of formula IV i.e. 5'- bromo-1 'phenyl- [2,3 '-bipyridin] -6' -(l'H)-one with 2-formyl phenyl boronic acid. The process is represented by following reaction scheme:

The above reaction is carried out in presence of palladium compound, phosphi compound, base and solvent. Palladium compound is generally selected from the group comprising palladium acetate, palladium chloride, palladium hydroxide, palladium nitrate or any similar compound.

Phosphorous compound is preferably triphenylphosphine.

Base can be an inorganic base such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or the like; an alkali metal alkoxide such as sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide or the like; or an organic amine such as N-methylmorpholine, Ν,Ν-dimethylaniline, triethylamine or the like. The base is preferably cesium carbonate. Solvent is selected from group comprising alcoholic solvents, ester solvents, aldehyde solvents, ketone solvents, ether solvents, hydrocarbon solvents, halogenated hydrocarbon solvents and water, preferably aldehyde solvents like dimethylformamide . The above reaction can be carried out at room temperature or higher ranging from 25 to 150°C depending on the use of solvents. The compound of formula V can be filtered from the reaction mixture by known methods in the art and washed with suitable solvent(s). For example, compound of formula V can be washed or purified with dimethylformamide.

The starting material used in the above reaction, i.e. 5 '-bromo-1 '-phenyl- [2,3'- bipyridin]-6'-(l'H)-one of formula IV can be prepared as exemplified in examples. In another embodiment of the invention, the present invention provides intermediate compound of thereof

In yet another embodiment of the invention, the present invention provides intermediate compound of formula VI or salt thereof

VI

In another embodiment of the invention, the present invention provides use of these compounds of formula V or VI in the preparation of perampanel. In another embodiment, the present invention provides a process for the purification of perampanel. Purification of perampanel can be carried out in presence of solvent or mixture of solvents including but not limited to alcohols, esters, ethers, hydrocarbon solvents, halogenated hydrocarbon solvents or ketones. Purification of perampanel can also be carried out by solvent/anti-solvent process.

In a preferred embodiment of the invention, Perampanel can be washed with alcoholic solvent such as methanol, halogenated hydrocarbon solvent such as dichloromethane and hydrocarbon solvent such as n-heptane. The process of present invention to prepare perampenel can be summarized by following reaction scheme:

Perampanel obtained from the process of present invention is in crystalline form. The PXRD values of crystalline form of perampanel are as summarized in below Table 1 :

Table 1

20.491 4.33 6.1

23.238 3.82 21.1

24.303 3.65 38.3

27.453 3.24 13.9

Identification of solid obtained by the present invention can be made by methods known in the art, such as X-Ray diffraction. It should be understood that operator, instrument and other similar changes may result in some margin of error with respect to analytical characterization of the solid.

The XRD method used for the identification and characterization of crystalline form of Perampanel is described below: a) XRPD method:

Analytical characterization of Perampanel was carried out by using X-ray powder diffraction using AD-429 D8 advance of Bruker make. The details of experimental parameters are given in below Table 2.

Table 2

Scan step size 0.02°

Antiscattering Slit Fixed

Rotation On

Voltage 40 KV

The following examples are intended to illustrate the present invention. It should be understood that the invention is not limited to those specific examples. Numerous changes and modifications may be made to the embodiments of the invention without departing from actual scope of the invention.

EXAMPLE 1: Preparation of l'-phenyl-[2,3'-bipyridin]-6'-(l'H)-one (III)

90 ml of dimethyl formamide was added to a RBF, to this 10 gm of 5-(2-pyridyl)- l,2-dihydropyridine-2-one, 12.4 gm of phenyl boronic acid, 1.042 gm of copper (II) acetate monohydrate and 9.18 gm of pyridine were added. Reaction mixture was stirred at 20-30°C and the reaction was monitored by HPLC. After completion of reaction the reaction mixture was added to 400 ml of ammonia solution [(Aq. Ammonia (40 ml) mixed in purified water (360 ml)], followed by addition of 1.3 ml of dimethyl formamide. Reaction mixture was stirred for 15-25 minutes at 25-35°C, filtered and the residue was washed with purified water (50.0 ml). The solid thus obtained was dried under vacuum at below 70°C for 24 hrs to give 11.5 gm of title compound. EXAMPLE 2: Preparation of 5'-bromo-l'-phenyl-[2,3'-bipyridin]-6'-(l'H)-one ( IV)

50 ml of dimethyl formamide and 10.0 gm of -phenyl-[2,3'-bipyridin]-6'-(l'H)- one were charged in a RBF, to this N-Bromosuccinimide solution [(N- bromosuccinimide (8.6 gm) in dimethyl formamide (25.0 ml)] was added drop wise at 25-45°. After completion of addition reaction mixture was stirred for 3 hours. The reaction mixture was added to water (400 ml) and the resulting mixture was stirred for 60 to 90 minutes at 25-30°C. Reaction mixture was filtered and washed with purified water (100 ml) to give 12.4 gm of title compound.

EXAMPLE 3: Preparation of 2-(6'-oxo-l'-phenyl-l',6'-dihydro[2,3'-bipyridin]- 5'-yl)-benzaldehyde (V) 240 ml of dimethyl formamide 10.0 gm of 5'-bromo- -phenyl-[2,3'-bipyridin]- 6'-(l'H)-one, 9.165 gm of 2-formyl phenyl boronic acid and 19.9 gm of cesium carbonate were charged in to a RBF. To the resulting reaction mixture Palladium (II) Acetate (0.171 gm) and triphenyl phosphine (0.8 gm) were added, reaction mixture was heated to 110 to 120°C. After completion of reaction, the reaction mixture was filtered and the filtrate was cooled to precipitate the solid. The solid was dried under vacuum at below 70°C for 12 hrs to give 8.0 gm of title compound.

EXAMPLE 4: Preparation of 2-(6'-oxo-l'-phenyl-l',6'-dihydro[2,3'-bipyridin]- 5'-yl)-benzaldehyde oxime (VI)

30 ml of methanol, 30 ml of purified water, 10 gm of 2-(6'-oxo-l'-phenyl- ,6'- dihydro[2,3'-bipyridin]-5'-yl)-benzaldehyde and 2.9 gm of hydroxyl amine hydrochloride were added in a RBF. The resulting reaction mixture was heated to 50 to 55°C while stirring for 3 hours. After completion of reaction, the reaction mixture was cooled to 25 to 35 °C. Sodium hydroxide solution (NaOH (2.272 gm+225 ml water) was added to the reaction mixture, the solid thus separated was filtered, and washed with purified water (100 ml), the product thus obtained was dried under vacuum to give 7.82 gm of title compound.

EXAMPLE 5: Preparation of 2-(6'-oxo-l'-phenyl-l',6'-dihydro[2,3'-bipyridin]- 5'-yl)-benzonitrile [perampanel (I)]

40 ml of acetic anhydride, 10 gm of 2-(6'-oxo- -phenyl- ,6'-dihydro[2,3'- bipyridin]-5'-yl)-benzaldehyde oxime and 0.108 gm of NaOH were charged in to a RBF. The resulting reaction mixture was heated to 100 to 140°C for 2 hours. Reaction mass was cooled to 90 to 95°C, to the cooled reaction mixture 50 ml of toluene was added. Toluene was distilled off and the residue thus obtained was cooled to 25 to 35°C. Purified water (100 ml) was slowly added to the residue at 25 to 35°C with continuous stirring, followed by addition of 100 ml of methylene chloride, the reaction mixture was cooled to 15 to 25°C. pH of the reaction mixture was adjusted to 8 to 9 by using ammonia solution. Aqueous layer thus formed was separated and charged in to the RBF. To the organic layer a methylene chloride (50 ml) and sodium chloride solution [(sodium chloride (10 gm) in purified water (50 ml)] were added, layers separated and organic layer was washed with water. Methanol (100 ml) was added to the organic layer at 50-60°C and the reaction mixture was stirred for 3 to 4 hrs at the same temperature. Product was precipitated by cooling the reaction mixture at 25-30°C. The reaction mixture was filtered and solid was washed with methanol (20 ml) to get wet cake. Methylene chloride (50 ml) was added to wet cake, and the reaction mixture was stirred for 20-30 minutes at 30-35°C. Reaction mixture was filtered and the solid was taken in 120 ml of n-heptane, filtered and the solid was dried to get 7.5 gm of perampanel.

Claims

We claim:

1. A process for the preparation of perampanel comprising a step of converting compo I

V^l

to perampanel of formula I

I

A process as claimed in claim 1, wherein the conversion of compound of formula VI to compound of formula I is carried out using a reagent selected from a group comprising of acetic acid derivative.

A process for the preparation of perampanel of formula I comprising a step of converting a compound of formula V

to a compound of formula VI

4. A process as claimed in claim 3, wherein the conversion of compound of formula V to compound of formula VI is carried out in presence of hydroxylamine or its salt.

5. A compound of formula V

6. A process to prepare compound of formula V comprising a step of reacting comp

with 2-formyl phenyl boronic acid of following structural formula

H

7. A compound of formula VI

8. Use of compound of formula V in synthesis of perampanel. 9. Use of compound of formula VI in synthesis of perampanel.

10. A process for the preparation of perampanel of formula I comprising steps of: a) Reacting compound of formula IV with 2-formyl phenyl boronic acid to give co

b) Conversion of compound of formula V to compound of formula VI;

c) Conversion of compound of formula VI to perampanel of formula I.

VI