DESC:FIELD
The present disclosure relates to a process for preparing 5-halo-2,3-diphenylpyrazine.
DEFINITION
As used in the present disclosure, the following term is generally intended to have the meaning as set forth below, except to the extent that the context in which they are used indicate otherwise.
5-halo-2,3-diphenylpyrazine refers to compounds, 5-chloro-2,3-diphenylpyrazine (I) and 5-bromo-2,3-diphenylpyrazine (V).
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
5-halo-2,3-diphenylpyrazine (A) such as 5-chloro-2,3-diphenylpyrazine [CAS No. 41270-66-0] and 5-bromo-2,3-diphenylpyrazine [CAS No. 243472-70-0] are important intermediates for synthesizing organic molecules.

(A)
These compounds are mainly used as pharmaceutical intermediates to synthesize important drug molecules. One such drug molecule is Selixpag which is a selective receptor agonist. 5-halo-2,3-diphenylpyrazine is also used for the production of pesticides.
Conventional methods for synthesizing 5-halo-2,3-diphenylpyrazine involve harsh reaction conditions. The high cost of processing, low product yield and low product purity make conventional methods ineffective.
Therefore, there is felt a need for a simple, and economical method for preparing 5-halo-2,3-diphenylpyrazine with high purity.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of 5-halo-2,3-diphenylpyrazine which is simple, and economical.
Yet another object of the present disclosure is to provide a process for the preparation of 5-halo-2,3-diphenylpyrazine with high purity.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for preparing 5-halo-2,3-diphenylpyrazine. The process comprises reacting benzil (II) with glycinamide hydrochloride (III) and a base in a first fluid medium at a temperature in the range of -5 oC to 45 oC, to obtain a first mixture. The reaction mixture is neutralized with a mineral acid to obtain a second mixture comprising 5,6-diphenylpyrazin-2-ol (IV) followed by separating 5,6-diphenylpyrazin-2-ol (IV) from the second mixture. The 5,6-diphenylpyrazin-2-ol (IV) is halogenated in a second fluid medium by using a halogenating agent in the presence of N,N-dimethyl aniline at a temperature in the range of 110 °C to 115 °C to obtain a third mixture comprising 5-halo-2,3-diphenylpyrazine (A). 5-halo-2,3-diphenylpyrazine (A) is separated from the third mixture and washed with a third fluid medium to obtain 5-halo-2,3-diphenylpyrazine (A) having a purity in the range of 95 % to 99.5%.
In an embodiment, the 5-halo-2,3-diphenylpyrazine (A) is 5-chloro-2,3-diphenylpyrazine (I), wherein the halogenating agent is phosphoryl chloride.
In an embodiment, the 5,6-diphenylpyrazin-2-ol (IV) is halogenated in the second fluid medium by using a chlorinating agent in the presence of the N,N-dimethyl aniline at a temperature in the range of 110 °C to 115 °C to obtain a mixture comprising 5-chloro-2,3-diphenylpyrazine. The 5-chloro-2,3-diphenylpyrazine (I) is separated from the mixture, and washed with the third fluid medium to obtain 5-chloro-2,3-diphenylpyrazine (I) having purity in the range of 95 % to 99.5%. The 5-chloro-2,3-diphenylpyrazine (I) is brominated with a mixture of hydrobromic acid and acetic acid, at a temperature in the range of 75°C to 85 °C to obtain a fourth mixture comprising 5-bromo-2,3-diphenylpyrazine (V). The 5-bromo-2,3-diphenylpyrazine (V) is separated from the fourth mixture and washed with a fourth fluid medium to obtain 5-bromo-2,3-diphenylpyrazine (V) having purity in the range of 95 % to 99.5%.
DETAILED DESCRIPTION
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
Pharmaceutical intermediates such as 5-halo-2,3-diphenylpyrazine are significant compounds in the synthesis of various drugs or pesticides.
However, the conventional synthesis of 5-halo-2,3-diphenylpyrazine are not only tedious and expensive, but also lead to product formation in less yield and low purity.
The present disclosure envisages a simple and economical process for preparing 5-halo-2,3-diphenylpyrazine (A) with high purity that mitigates the drawbacks mentioned herein above.

(A)
wherein ‘X’ can be at least one selected from Cl and Br.
The schematic description of the process of the present disclosure is provided below:
Step 1: Reaction of benzil (II) with glycinamide hydrochloride (III)
(II) (III) (IV)

Step 2: Chlorination of 5,6-diphenylpyrazin-2-ol (IV)

(IV) (I)
Step 3: Bromination of 5-chloro-2,3-diphenylpyrazine (I)

(I) (V)
In accordance with the present disclosure, 5-halo-2,3-diphenylpyrazine refers to derivatives 5-chloro-2,3-diphenylpyrazine (I) and 5-bromo-2,3-diphenylpyrazine (V).
The process for the preparation of 5-halo-2,3-diphenylpyrazine (A) are described in detail.
In the first step, benzil (II) is reacted with glycinamide hydrochloride (III) and a base in a first fluid medium at a temperature in the range of -5 oC to 45 oC, to obtain a first mixture. Typically, the reaction time is in the range of 1 hour to 8 hours.
The first fluid medium is selected from a group consisting of aliphatic alcohols having carbon atoms in the range of C1 to C4. In an embodiment, the first fluid medium is methanol.
The base is at least one compound selected from the group consisting of sodium hydroxide and potassium hydroxide.
In an embodiment, the base is aqueous solution of sodium hydroxide. Typically, the concentration of sodium hydroxide solution is in the range of 24% to 28%.
In an embodiment, the reaction of benzil (II) with glycinamide hydrochloride (III) and a base is performed in a stepwise manner. In an exemplary embodiment, glycinamide hydrochloride and methanol are stirred at 30 °C and cooled to 10 °C followed by the addition of aqueous sodium hydroxide solution and benzil, and stirred for 6 hours.
The first mixture is neutralized with a mineral acid to obtain a second mixture comprising 5,6-diphenylpyrazin-2-ol (IV) followed by the separation of 5,6-diphenylpyrazin-2-ol (IV) from the second mixture.
In accordance with the present disclosure, the mineral acid is selected from the group consisting of hydrochloric acid and sulfuric acid. In an embodiment, the mineral acid is hydrochloric acid.
In an embodiment, the neutralization of the reaction mixture and separation of the compound (IV) are performed in a stepwise manner. In an exemplary embodiment, the reaction mixture is neutralized by adding hydrochloric acid till pH 7, followed by stirring the neutralized mixture for 2 hours to obtain a mixture which is separated by filtration to obtain a solid residue of 5,6-diphenylpyrazin-2-ol (IV).
In an embodiment, the 5,6-diphenylpyrazin-2-ol (IV) is washed with isopropyl alcohol.
The 5,6-diphenylpyrazin-2-ol (IV) is halogenated in a second fluid medium by using a halogenating agent in the presence of N,N-dimethyl aniline at a temperature in the range of 110 °C to 115 °C, to obtain a third mixture comprising 5-halo-2,3-diphenylpyrazine (A).
Typically, the reaction time for the halogenation step is 12 hours to 16 hours. In an embodiment, the reaction time for halogenation reaction is 14 hours.
The halogenating agent is any one selected from the group consisting of chlorinating agent and brominating agent.
In an embodiment, 5-halo-2,3-diphenylpyrazine (A) is 5-chloro-2,3-diphenylpyrazine (I), wherein the halogenating agent is phosphoryl chloride.
The second fluid medium is selected from the group consisting of toluene, xylene compounds and benzene. Typically the xylene compounds comprise at least one derivative selected from the group consisting of o-xylene, m-xylene and p-xylene. In an embodiment, the second fluid medium is toluene.
5-halo-2,3-diphenylpyrazine (A) is separated from the third mixture and washed with a third fluid medium to obtain 5-halo-2,3-diphenylpyrazine (A) having a purity in the range of 95 % to 99.5%.
In an embodiment, the purity of 5-halo-2,3-diphenylpyrazine (I) is 99 %.
In an embodiment, the separation of 5-halo-2,3-diphenylpyrazine (I) from the third mixture is performed in a stepwise manner. In an exemplary embodiment, the separation is done by extraction of a biphasic mixture formed by addition of water and toluene to the third mixture.
The molar ratio of the 5,6-diphenylpyrazin-2-ol (IV) to the halogenating agent is in the range of 1:2 to 1:4. In an embodiment, the halogenating agent is a chlorinating agent, and the molar ratio of the 5,6-diphenylpyrazin-2-ol (IV) to the chlorinating agent is 1:2.3.
The molar ratio of the 5,6-diphenylpyrazin-2-ol (IV) to the N,N-dimethyl aniline is in the range of 1:0.5 to 1:2. In an embodiment, the molar ratio of the 5,6-diphenylpyrazin-2-ol (IV) to the N,N-dimethyl aniline is 1:1.
The third fluid medium is selected from a group consisting of aliphatic alcohols having carbon atoms in the range of C1 to C4. In an embodiment, the third fluid medium is isopropyl alcohol.
In an embodiment, the 5,6-diphenylpyrazin-2-ol (IV) is halogenated in the second fluid medium by using a chlorinating agent in the presence of the N,N-dimethyl aniline at a temperature in the range of 110 °C to 115 °C to obtain a mixture comprising 5-chloro-2,3-diphenylpyrazine (I). The 5-chloro-2,3-diphenylpyrazine (I) is separated from the mixture, and washed with the third fluid medium to obtain 5-chloro-2,3-diphenylpyrazine (I) having purity in the range of 95 % to 99.5%.
In an exemplary embodiment, to a mixture of 5,6-diphenylpyrazin-2-ol (IV) and toluene, phosphoryl chloride and N,N-dimethyl aniline are added and stirred at 115 °C for 14 hours.
The 5-chloro-2,3-diphenylpyrazine (I) is brominated using a mixture of hydrobromic acid and acetic acid, at a temperature in the range of 75°C to 85 °C, to obtain a fourth mixture comprising 5-bromo-2,3-diphenylpyrazine (V).
5-bromo-2,3-diphenylpyrazine (V) is separated from the fourth mixture and washed with a fourth fluid medium to obtain 5-bromo-2,3-diphenylpyrazine (V) having purity in the range of 95 % to 99.5%.
In an embodiment, the purity of 5-bromo-2,3-diphenylpyrazine (V) is 99 %.
The hydrobromic acid in acetic acid has a concentration in the range of 20% to 50%. In an embodiment, the concentration of hydrobromic acid in acetic acid is 35%.
The fourth fluid medium is selected from a group consisting of aliphatic alcohols having carbon atoms in the range of C1 to C4. In an embodiment, the fourth fluid medium is isopropyl alcohol.
In an exemplary embodiment, 5-chloro-2,3-diphenylpyrazine (I) is slowly added to a solution of 35% hydrobromic acid in acetic acid, and the resulting mixture is stirred at 80 °C for 30 hours, followed by separation to obtain 5-bromo-2,3-diphenylpyrazine (V).
The molar ratio of the 5-chloro-2,3-diphenylpyrazine (I) to the hydrobromic acid is in the range of 1:10 to 1:20.
The process of the present disclosure is simple, economical and yields 5-halo-2,3-diphenylpyrazine (A) with high purity.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following laboratory scale experiments, which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. These laboratory scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.
EXPERIMENTAL DETAILS:
Experiment 1a: Preparation of 5,6-diphenylpyrazin-2-ol
A reactor was charged with glycinamide hydrochloride (1.31 kg) and methanol (23 litres) under stirring at 30 °C. The mixture was cooled to a temperature of 10 °C, followed by the addition of 9.5 litre aqueous solution containing 2.3 kg NaOH. This was followed by addition of benzil (2.5 kg) to form a reaction mixture which was stirred at a temperature of 10 °C for 6 hours. After the reaction was completed, HCl was added till the reaction mixture was neutralized (pH=7), followed by stirring the neutralized mixture for a time period of 2 hours. After stirring, the neutralized mixture was filtered to obtain a solid residue and a filtrate. The solid residue was washed with isopropyl alcohol (1 litre) followed by drying under vacuum at 55 °C for 5 hours to obtain 5,6-diphenylpyrazin-2-ol (IV).
Yield = 2.4 kg (81%); purity = 99.0%
Experiment 1b: Preparation of 5-chloro-2,3-diphenylpyrazine

A reactor was charged with toluene (12 litres) and 5,6-diphenylpyrazine2-ol (IV) (2.4 kg) under stirring at a temperature of 30 °C to obtain a mixture. To the mixture was added, phosphoryl chloride (POCl3) (3.5 kg) and N,N-dimethyl aniline (1.2 kg), followed by stirring at 115 °C for 14 hours to obtain a heated mixture. The heated mixture was cooled to a temperature of 20 °C and 17 litres of water was added under stirring to obtain a biphasic mixture. The biphasic mixture was allowed to stand to separate toluene layer and an aqueous layer. The toluene layer was separated from the aqueous layer. The toluene layer after separation was mixed with 5 litres of toluene and 200 g of carbon, followed by filtration to obtain a product mixture. Toluene was removed from the product mixture by distillation under vacuum to obtain a solid. The solid was washed with isopropyl alcohol followed by drying at 55 °C to obtain 5-chloro-2,3-diphenylpyrazine (I).
Yield = 1.95 kg (74%); Purity (HPLC) = 99.0%

Experiment 2: Preparation of 5-bromo-2,3-diphenylpyrazine
A reactor was charged with 23 litres of 35% HBr in acetic acid. 5-Chloro-2,3-diphenylpyrazine (1.95 kg) was added with stirring over 30 minutes to obtain a mixture. The temperature of the reactor was increased to 80 °C and the mixture was stirred for 30 hours, followed by cooling to room temperature to obtain a cooled mixture. 12 litre of toluene was mixed with the cooled mixture under stirring for 1 hour at 25 °C to form a product mixture. 20 kg of ice and 20 kg of water was taken in another reactor. The product mixture was added to the mixture of ice and water. The toluene layer was separated and mixed with 250 g sodium chloride, followed by filtration to obtain a filtrate. Toluene was removed from the filtrate under vacuum to obtain a solid. The solid was washed with isopropyl alcohol and dried to obtain 5-bromo-2,3-diphenylpyrazine.

Yield = 1.85 kg (81%); Purity (HPLC) = 99.0%
It is evident from the above reaction steps that the process of the present disclosure employs mild reaction conditions, and employs readily available reagents that are economical. Also, the process of the present disclosure produce 5-halo-2,3-diphenylpyrazine with high purity.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for the preparation of 5-halo-2,3-diphenylpyrazine:
- that is simple and economical; and
- yields products having high purity.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation

,CLAIMS:WE CLAIM:

1. A process for preparing 5-halo-2,3-diphenylpyrazine (A), said process comprising the following steps:
(i) reacting benzil (II) with glycinamide hydrochloride (III) and a base in a first fluid medium at a temperature in the range of -5 oC to 45 oC, to obtain a first mixture;
(ii) neutralizing said first mixture with a mineral acid to obtain a second mixture comprising 5,6-diphenylpyrazin-2-ol (IV);
(iii) separating 5,6-diphenylpyrazin-2-ol (IV) from said second mixture;
(iv) halogenating said 5,6-diphenylpyrazin-2-ol (IV) in a second fluid medium by using a halogenating agent in the presence of N,N-dimethyl aniline at a temperature in the range of 110 °C to 115 °C to obtain a third mixture comprising 5-halo-2,3-diphenylpyrazine (A); and
(v) separating 5-halo-2,3-diphenylpyrazine (A) from said third mixture, and washing with a third fluid medium to obtain 5-halo-2,3-diphenylpyrazine (A) having purity in the range of 95 % to 99.5%.
2. The process as claimed in claim 1, wherein 5-halo-2,3-diphenylpyrazine (A) is 5-chloro-2,3-diphenylpyrazine (I), wherein the halogenating agent is phosphoryl chloride.
3. The process as claimed in claim 1, further comprising the following steps:
(iv) halogenating said 5,6-diphenylpyrazin-2-ol (IV) in said second fluid medium by using a chlorinating agent in the presence of said N,N-dimethyl aniline at a temperature in the range of 110 °C to 115 °C to obtain a mixture comprising 5-chloro-2,3-diphenylpyrazine (I);
(v) separating 5-chloro-2,3-diphenylpyrazine (I) from said mixture, and washing with said third fluid medium to obtain 5-chloro-2,3-diphenylpyrazine (I) having purity in the range of 95 % to 99.5%;
(vi) brominating said 5-chloro-2,3-diphenylpyrazine (I) with a mixture of hydrobromic acid and acetic acid, at a temperature in the range of 75°C to 85 °C to obtain a fourth mixture comprising 5-bromo-2,3-diphenylpyrazine (V); and
(vii) separating 5-bromo-2,3-diphenylpyrazine (V) from said fourth mixture and washing with a fourth fluid medium to obtain 5-bromo-2,3-diphenylpyrazine (V) having purity in the range of 95 % to 99.5%.
4. The process as claimed in claim 3, wherein said hydrobromic acid has a concentration in the range of 20% to 50%.
5. The process as claimed in claim 3, wherein the molar ratio of said 5-chloro-2,3-diphenylpyrazine (I) to said hydrobromic acid is in the range of 1:10 to 1:20.
6. The process as claimed in claim 1, wherein said base used in step (i) is selected from the group consisting of sodium hydroxide and potassium hydroxide.

7. The process as claimed in claim 1, wherein said mineral acid used in step (ii) is selected from the group consisting of hydrochloric acid and sulfuric acid.

8. The process as claimed in claim 1, wherein said first fluid medium, said third fluid medium and said fourth fluid medium are independently selected from the group consisting of aliphatic alcohols having carbon atoms in the range of C1 to C4.

9. The process as claimed in claim 1, wherein said first fluid medium is methanol and wherein said third fluid medium and said fourth fluid medium is isopropyl alcohol.

10. The process as claimed in claim 1, wherein said second fluid medium is at least one selected from the group consisting of toluene, xylene compounds and benzene.

11. The process as claimed in claim 1, wherein the molar ratio of said 5,6-diphenylpyrazin-2-ol (IV) to said halogenating agent is in the range of 1:2 to 1:4.

12. The process as claimed in claim 1, wherein the molar ratio of said 5,6-diphenylpyrazin-2-ol (IV) to said N,N-dimethyl aniline is in the range of 1:0.5 to 1:2.