DESC:AN IMPROVED PROCESS FOR THE PREPARATION OF SELEXIPAG INTERMEDIATES

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-halo-5,6-diphenyl-1,4-pyrazine, an intermediate of Selexipag.
BACKGROUND OF THE INVENTION
Selexipag is chemically described as, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N(methylsulfonyl) acetamide and is structurally represented by compound of Formula I:

Formula I
is used for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.
According to prior art, 2-halo-5,6-diphenyl-1,4-pyrazine compound of formula II is prepared from 2-hyrdoxy-5,6-diphenyl-1,4-pyrazine compound of formula III using thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus oxybromide, dibromo sulfoxide, oxalyl bromide or phosphorus tribromide.

wherein, X is chloro, bromo or iodo. However, traditional preparation methods involve complex process, high cost, low yields and less product purity.
Therefore, there is still a need in the art for an improved low-cost process for the preparation of purified 2-halo-5,6-diphenyl-1,4-pyrazine, compound of formula II, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.
The process of the present invention has advantages of simple, easy handling and increased productivity which afford a significantly greater yield. The process is also industrially scalable; cost effective which makes it highly suitable for industrial scale.
SUMMARY OF THE INVENTION
In the first embodiment, the present application provides a process for the preparation of 2-halo-5,6-diphenyl-1,4-pyrazine, compound of formula II, comprising:
reacting 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with a halogenation reagent selected from the group consisting of tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium bromide (TBAB) and tetra-n-butylammonium iodide (TBAI), in the presence of phosphorus pentoxide (P2O5) or triphenylphosphine (PPh3).

wherein, X is a halogen selected from the group consisting of chloro, bromo and iodo.
In the second embodiment, the present application provides a process for the preparation of 2-bromo-5,6-diphenyl-1,4-pyrazine, compound of formula IV, comprising:
reacting 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with tetra-n-butylammonium bromide (TBAB), in the presence of phosphorus pentoxide (P2O5).

DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the preparation of 2-halo-5,6-diphenyl-1,4-pyrazine, compound of formula II, comprising:
reacting a 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with a halogenation reagent selected from the group consisting of tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium bromide (TBAB) and tetra-n-butylammonium iodide (TBAI), in the presence of phosphorus pentoxide(P2O5) or triphenylphosphine (PPh3),

wherein, X is as defined above.
The reaction of 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with halogenation reagent may be performed in a suitable solvent. The solvents includes but not limited to water, dimethyl sulfoxide, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the solvent may be toluene.
The reaction of 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with halogenation reagent may be carried out for about 30 minutes to about 36 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 1 hour to about 24 hours at about 60 °C to about room temperature. The resulting 2-halo-5,6-diphenyl-1,4-pyrazine, compound of formula II may be isolated from the reaction mass by any method known in the art.
In the aspects of the second embodiment, the present application provides a process for the preparation of 2-bromo-5,6-diphenyl-1,4-pyrazine, compound of formula IV, comprising:
reacting 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with tetra-n-butylammonium bromide (TBAB) in the presence of phosphorus pentoxide (P2O5).

The reaction of 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with tetra-n-butylammonium bromide (TBAB) may be performed in a suitable solvent. The solvents includes but not limited to water, dimethyl sulfoxide, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the solvent may be toluene.
The reaction of 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with tetra-n-butylammonium bromide (TBAB) may be carried out for about 30 minutes to about 36 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 1 hour to about 24 hours at about 60 °C to about room temperature. The resulting compound, 2-bromo-5,6-diphenyl-1,4-pyrazine, compound of formula IV, may be isolated from the reaction mass by any method known in the art.
The 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III used as starting material may be prepared by any of the methods known in the literature.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.
The isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10°C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of 2-bromo-5,6-diphenyl-1,4-pyrazine
A round bottom flask was charged with toluene (500 ml), 2-hydroxy-5,6-diphenyl-1,4-pyrazine (50 gm), tetra-n-butylammonium bromide (81 gm) and phosphorous pentoxide (71 gm) at room temperature and stirred for 10 minutes. The temperature of the reaction mass was raised to 110 oC and maintained for 4-5 hours. Then the reaction mass was cooled to room temperature, dichloromethane (200 ml) was charged and stirred well. Water (300 ml) was charged into another round bottom flask and the above reaction mass was quenched. The layers were separated and aqueous layer was extracted twice with dichloromethane (100 ml). Now total organic layers were combined and washed twice with 1N sodium hydroxide (100 ml) and water (150 ml). Again the organic layer was washed with 10% sodium chloride (100 ml) solution. The solvent was completely distilled out and washed with ethylacetate (50 ml) dried to give titled compound.
Yield: 44 gm

Example 2: Preparation of 2-bromo-5,6-diphenyl-1,4-pyrazine
A round bottom flask was charged with toluene (600 ml), 2-hydroxy-5,6-diphenyl-1,4-pyrazine (100 gm), tetra-n-butylammonium bromide (162 gm) and phosphorous pentoxide (140 gm) at room temperature and stirred for 10 minutes. The temperature of the reaction mass was raised to 110 oC and maintained for 10-11 hours. Then the reaction mass was cooled to room temperature, dichloromethane (1000 ml) was charged and stirred well. Water (500 ml) was charged into another round bottom flask and the above reaction mass was quenched. The layers were separated and aqueous layer was extracted twice with dichloromethane (200 ml). Now total organic layers were combined and washed twice with 1N sodium hydroxide (200 ml) and water (300 ml). Again the organic layer was washed with 10% sodium chloride (200 ml) solution. The solvent was completely distilled out and washed with ethylacetate (100 ml) dried to give titled compound.
Yield: 100 gm ,CLAIMS:We Claim:
1) A process for the preparation of 2-halo-5,6-diphenyl-1,4-pyrazine, compound of formula II, comprising:
reacting 2-hydroxy-5,6-diphenyl-1,4-pyrazine, compound of formula III with tetra n-butylammonium halide, in the presence of phosphorus pentoxide (P2O5) or triphenylphosphine (PPh3).

wherein, X is a halogen selected from the group consisting of chloro, bromo and iodo.
2) The process according to claim 1, where in tetra n-butylammonium halide is selected from the group consisting of tetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium bromide (TBAB) and tetra-n-butylammonium iodide (TBAI).
3) A process for the preparation of 2-bromo-5,6-diphenyl-1,4-pyrazine of formula IV, comprising:
reacting 2-hydroxy-5,6-diphenyl-1,4-pyrazine compound of formula III with tetra-n-butylammonium bromide (TBAB), in the presence of phosphorus pentoxide (P2O5).