WO2021240295A1

WO2021240295A1 - Process for preparation of favipiravir

Info

Publication number: WO2021240295A1
Application number: PCT/IB2021/054203
Authority: WO
Inventors: Sanjay Bhanudas BHAWSAR; Viral Bipinbhai Shah; Suresh Mahadev Kadam; Sachin Baban Gavhane; Venkata Raghavendra Charyulu Palle; Sukumar Sinha; Shailendra Nilkanth BHADANE; Uddhav Popat CHAUDHAR; Jayant Prakashrao PATIL
Original assignee: Glenmark Life Sciences Limited
Priority date: 2020-05-26
Filing date: 2021-05-17
Publication date: 2021-12-02

Abstract

The present invention relates to a process for the preparation of favipiravir and salts thereof. The present invention also relates to salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile with inorganic base, process for their preparation and conversion thereof to favipiravir. The present invention also relates to salts of 6-bromo-3-hydroxypyrazine-2-carboxamide with organic and inorganic base and their use in the preparation of favipiravir.

Description

PROCESS FOR PREPARATION OF FAVIPIRAVIR

PRIORITY

[0001] This application claims the benefit of Indian Provisional Applications 202021022001 filed on May 26, 2020 and 202021039090 filed on September 10, 2020, entitled “PROCESS FOR PREPARATION OF FAVIPIRAVIR” the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION Technical Field

[0002] The present invention relates to a process for the preparation of favipiravir and salts thereof. The present invention also relates to salts of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile with inorganic base, process for their preparation and conversion thereof to favipiravir. The present invention also relates to salts of 6-bromo-3- hydroxypyrazine-2-carboxamide with organic and inorganic base and their use in the preparation of favipiravir. Description of the Related Art

[0003] Favipiravir, also known as, 6-fluoro-3-hydroxypyrazine-2-carboxamide, is represented by the structure of formula I.

[0004] 6-Fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is one of the key intermediates in the preparation of favipiravir.

[0005] The present invention provides a process for the preparation of favipiravir via salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile. The salts of 6-fluoro-3 -hydroxy -2- pyrazinecarbonitrile with inorganic base are useful as an intermediate in the preparation of favipiravir and have advantages in that (1) can be directly subjected to hydrolysis to give favipiravir in a single step, (2) no intermediate work-up steps like extraction and removal of solvent are needed, (3) can be used on a large scale with high reactant/product w/w yield ratio, and (4) industrially feasible for preparing favipiravir. [0006] The present invention also provides salts of 6-bromo-3-hydroxypyrazine-2- carboxamide with organic and inorganic base, process for their preparation and conversion thereof to favipiravir.

SUMMARY OF THE INVENTION

[0007] The present invention provides a process for the preparation of favipiravir, a compound of formula I or salt thereof, the process comprising:

(a) reacting 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, a compound of formula III, with an inorganic base in a solvent to give salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV,

wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation;

(b) hydrolyzing the compound of formula IV with a hydrolyzing agent to give favipiravir, the compound of formula I; and

(c) optionally, reacting favipiravir, the compound of formula I with an organic or inorganic base to give a salt of favipiravir.

[0008] In one embodiment, the present invention provides a process for the preparation of salt of favipiravir, the process comprising:

(a) reacting favipiravir, a compound of formula I, with organic base or inorganic base in presence of a solvent to form a reaction mixture;

(b) obtaining the salt of favipiravir with organic base or inorganic base from the reaction mixture of step (a); and

(c) isolating the salt of favipiravir with organic base or inorganic base.

[0009] In another embodiment, the present invention provides a process for the preparation of salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation; the process comprising:

(a) reacting 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, a compound of formula III, with an inorganic base in presence of a solvent to form a reaction mixture;

(b) obtaining the salt of 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, the compound of formula IV, from the reaction mixture of step (a); and (c) isolating the salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, the compound of formula IV.

[0010] In another embodiment, the present invention provides a process for the preparation of salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VIII,

wherein X⁺ is a cation capable of forming a salt from a metal element or ammonium cation or organic base; the process comprising:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII;

with inorganic or organic base in presence of a solvent to form a reaction mixture;

(b) obtaining the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VIII, from the reaction mixture of step (a); and

(c) isolating the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VIII.

[0011] In another embodiment, the present invention provides a salt of favipiravir with an organic base or an inorganic base; wherein the salt of favipiravir with organic base is selected from the group consisting of cyclopropylamine salt of favipiravir, diisopropylamine salt of favipiravir, diisobutylamine salt of favipiravir, diethylamine salt of favipiravir and dicyclohexylamine salt of favipiravir; and wherein the salt of favipiravir with inorganic base is selected from the group consisting of potassium salt of favipiravir and lithium salt of favipiravir.

[0012] In another embodiment, the present invention provides a salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation.

[0013] In another embodiment, the present invention provides a salt of 6-bromo-3- hydroxypyrazine-2-carboxamide, the compound of formula VIII, wherein X⁺ is a cation capable of forming a salt from a metal element or ammonium cation or organic base. [0014] In another embodiment, the present invention provides a process for the preparation of favipiravir, a compound of formula I, the process comprising:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, with an inorganic base or organic base to obtain a salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, a compound of formula VIII, wherein X⁺ is a cation capable of forming a salt from a metal element, ammonium cation or an organic base;

(b) reacting the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VIII with a chlorinating agent to obtain 3,6-dichloro-2-pyrazinecarbonitrile, a compound of formula VI,

VI,

(c) reacting 3,6-dichloro-2-pyrazinecarbonitrile, the compound of formula VI with a fluorinating agent to obtain 3,6-difluoro-2-pyrazinecarbonitrile, a compound of formula V,

V,

(d) reacting 3,6-difluoro-2-pyrazinecarbonitrile, the compound of formula V with base to give 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, a compound of formula III,

(e) reacting 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, the compound of formula III with an inorganic base to give a salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation; and

(f) hydrolyzing the compound of formula IV with a hydrolyzing agent to give favipiravir, the compound of formula I.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is a characteristic XRPD of favipiravir as obtained in Example 25.

[0016] Figure 2 is a TGA thermogram of favipiravir as obtained in Example 22.

[0017] Figure 3 is a DSC thermogram of favipiravir as obtained in Example 22.

[0018] Figure 4 is a characteristic XRPD of favipiravir potassium salt as obtained in Example 2. [0019] Figure 5 is a TGA thermogram of favipiravir potassium salt as obtained in Example 2. [0020] Figure 6 is a characteristic XRPD of favipiravir lithium salt as obtained in Example 3. [0021] Figure 7 is a TGA thermogram of favipiravir lithium salt as obtained in Example 3. [0022] Figure 8 is a DSC thermogram of favipiravir lithium salt as obtained in Example 3. [0023] Figure 9 is a characteristic XRPD of favipiravir dicyclohexylamine salt as obtained in Example 4.

[0024] Figure 10 is a TGA thermogram of favipiravir dicyclohexylamine salt as obtained in Example 4. [0025] Figure 11 is a characteristic XRPD of favipiravir diisopropylamine salt as obtained in Example 5.

[0026] Figure 12 is a TGA thermogram of favipiravir diisopropylamine salt as obtained in Example 5.

[0027] Figure 13 is a characteristic XRPD of favipiravir diethylamine salt as obtained in Example 6.

[0028] Figure 14 is a TGA thermogram of favipiravir diethylamine salt as obtained in Example 6.

[0029] Figure 15 is a characteristic XRPD of favipiravir diisobutylamine salt as obtained in Example 7. [0030] Figure 16 is a TGA thermogram of favipiravir diisobutylamine salt as obtained in

Example 7.

[0031] Figure 17 is a characteristic XRPD of favipiravir cyclopropylamine salt as obtained in Example 8.

[0032] Figure 18 is a TGA thermogram of favipiravir cyclopropylamine salt as obtained in Example 8.

[0033] Figure 19 is characteristic XRPD of sodium salt of 3-hydroxy-6-fluoro-2- pyrazinecarbonitrile as obtained in Example 12.

[0034] Figure 20 is a TGA thermogram sodium salt of 3-hydroxy-6-fluoro-2- pyrazinecarbonitrile as obtained in Example 12. [0035] Figure 21 is a DSC thermogram of sodium salt of 3-hydroxy-6-fluoro-2- pyrazinecarbonitrile as obtained in Example 12.

[0036] Figure 22 is characteristic XRPD of potassium salt of 3-hydroxy-6-fluoro-2- pyrazinecarbonitrile as obtained in Example 13.

[0037] Figure 23 is a TGA thermogram potassium salt of 3-hydroxy-6-fluoro-2- pyrazinecarbonitrile as obtained in Example 13.

[0038] Figure 24 is a DSC thermogram of potassium salt of 3-hydroxy-6-fluoro-2- pyrazinecarbonitrile as obtained in Example 13. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention provides a process for the preparation of favipiravir, a compound of formula I or salt thereof, the process comprising:

(a) reacting 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, a compound of formula III, with an inorganic base in a solvent to give salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation;

[0040] In one embodiment, the metal element is selected from alkali metal, alkaline earth metal and transition metal.

[0041] In one embodiment, alkali metal includes but is not limited to sodium, potassium, lithium, and the like; alkaline earth metal includes but is not limited to calcium, magnesium and the like; transition metal includes but is not limited to cobalt, copper, iron, nickel, zinc, manganese and the like.

[0042] In one embodiment, the inorganic base in step (a) is selected from the group consisting of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali and alkaline earth metal bicarbonates, transition metal hydroxides and transition metal carbonates, ammonia, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate.

[0043] In one embodiment, alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal hydroxide is selected from calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate and the like; alkaline earth metal carbonate is selected from calcium carbonate, magnesium carbonate and the like; alkali metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; alkaline earth metal bicarbonate is selected from calcium bicarbonate, magnesium bicarbonate and the like; transition metal hydroxide is selected from cobalt hydroxide, copper hydroxide, iron hydroxide, nickel hydroxide, zinc hydroxide, manganese hydroxide and the like; transition metal carbonate is selected from cobalt carbonate, copper carbonate, iron carbonate, nickel carbonate, zinc carbonate, manganese carbonate and the like.

[0044] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is reacted with an inorganic base selected from the group consisting of sodium hydroxide, sodium carbonate and sodium bicarbonate to give sodium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile.

[0045] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is reacted with an inorganic base selected from the group consisting of potassium hydroxide, potassium carbonate and potassium bicarbonate to give potassium salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile.

[0046] In one embodiment, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.

[0047] In one embodiment, the solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0048] In one embodiment, in step (b) of the process for preparation of favipiravir, the compound of formula IV obtained in step (a) is hydrolyzed with hydrolyzing agent to give favipiravir, a compound of formula I.

[0049] In one embodiment, in step (b), the hydrolyzing agent is selected from hydrogen peroxide, organic or inorganic acid, organic or inorganic base.

[0050] In one embodiment, hydrolyzing agent is hydrogen peroxide or inorganic acids for example sulfuric acid, hydrochloric acid, hydrogen bromide, polyphosphoric acid, boron trifluoride, and the like or inorganic bases for example sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous ammonia and the like. [0051] In one embodiment, the reaction may be carried out at a temperature of about 0°C to about 100°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.

[0052] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile includes the tautomer 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile, a compound of formula II,

II.

[0053] In one embodiment, the present invention provides a process for the preparation of salt of favipiravir, the process comprising:

(c) isolating the salt of favipiravir with organic base or inorganic base.

[0054] In one embodiment, the organic base in step (a) is organic amine selected from the group consisting of dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, dibenzylamine, N-benzylmethylamine, dicyclohexylamine, cyclopropylamine, methylamine, ethylamine, propylamine, butylamine, benzylamine, aniline, pyridine, trimethylamine, triethylamine, tripropylamine, tributylamine, trioctylamine, tribenzylamine, N,N- dimethylcyclohexylamine, diisopropylethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, piperazine, picoline, quinolone, N-methyl-di- isopropylamine, l,4-diazabicyclo(2.2.2)octane (DABCO), l,5-diazabicyclo(4.3.0)non-5- ene (DBN), l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N-methylpyrrolidine, N- methylpiperidine, N- methylmorpholine, N,N-dimethylpiperazine, pentamethyl guanidine, 2,6-lutidine, 2,4,6-collidine.

[0055] In one embodiment, the inorganic base in step (a) is selected from the group consisting of potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate, lithium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate and lithium bicarbonate.

[0056] In one embodiment, the solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0057] In one embodiment, the reaction may be carried out at a temperature of about 25°C to about 100°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.

[0058] In one embodiment, in step (b), the salt of favipiravir is obtained from the reaction mixture of step (a), the process comprising:

(i) optionally cooling, and stirring the mixture obtained in (a); or

(ii) removing the solvent from the mixture obtained in (a); or

(iii) treating the mixture of step (a) with an anti-solvent, optionally cooling and stirring the obtained mixture.

[0059] In one embodiment, the salt of favipiravir is obtained by optionally cooling and stirring the mixture of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.

[0060] In one embodiment, the salt of favipiravir is obtained by removing the solvent from the mixture obtained in step (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent; or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.

[0061] In one embodiment, the salt of favipiravir is obtained by adding an anti-solvent to the mixture obtained in step (a) to form a mixture and optionally cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.

[0062] In one embodiment, the anti-solvent is selected such that the salt of favipiravir is precipitated out from the solution. [0063] In one embodiment, the anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, «-propyl acetate, isopropyl acetate, /er/-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl /er/-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, «-propyl alcohol, isopropyl alcohol, «-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert- butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0064] In one embodiments, in step (c) of the process for the preparation of the salt of favipiravir, salt of favipiravir is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0065] In one embodiment, the isolated salt of favipiravir may be further dried. The drying may be carried out at temperature from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 25 hours, or longer.

[0066] In one embodiment, the salt of favipiravir with organic or inorganic base is converted to favipiravir, a compound of formula I, by subjecting the salt of favipiravir with an acid.

[0067] In one embodiment, the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrogen bromide.

[0068] In one embodiment, the present invention provides a process for the purification of favipiravir, the process comprising:

(a) reacting favipiravir with an organic base or an inorganic base to obtain a salt of favipiravir; and

(b) reacting the salt of favipiravir with an acid to give favipiravir.

[0069] The organic and inorganic base of step (a) and the acid of step (b) are as discussed supra. [0070] In another embodiment, the present invention provides a process for the preparation of salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation; the process comprising:

(b) obtaining the salt of 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, the compound of formula IV, from the reaction mixture of step (a); and

(c) isolating the salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, the compound of formula IV.

[0071] In one embodiment, the inorganic base in step (a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, ammonium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate and lithium bicarbonate.

[0072] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is reacted with an inorganic base selected from the group consisting of sodium hydroxide, sodium carbonate and sodium bicarbonate to give sodium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile.

[0073] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is reacted with an inorganic base selected from the group consisting of potassium hydroxide, potassium carbonate and potassium bicarbonate to give potassium salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile.

[0074] In one embodiment, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.

[0075] In one embodiment, the solvent includes but not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0076] In one embodiment, the reaction may be carried out at a temperature of about 0°C to about 100°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.

[0077] In one embodiment, in step (b), the salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile is obtained from the reaction mixture of step (a), the process comprising:

(i) optionally cooling, and stirring the mixture obtained in (a); or

(ii) removing the solvent from the mixture obtained in (a); or

[0078] In one embodiment, the salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, is obtained by optionally cooling and stirring the mixture of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.

[0079] In one embodiment, the salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, is obtained by removing the solvent from the mixture obtained in step (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent; or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.

[0080] In one embodiment, the salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, is obtained by adding an anti-solvent to the mixture obtained in step (a) to form a mixture and optionally cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.

[0081] In one embodiment, the anti-solvent is selected such that the salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, is precipitated out from the solution. [0082] In one embodiment, the anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, «-propyl acetate, isopropyl acetate, /er/-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl /er/-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, «-propyl alcohol, isopropyl alcohol, «-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert- butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0083] In another embodiment, the present invention provides a process for the preparation of salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VIII, wherein X⁺ is a cation capable of forming a salt from a metal element or ammonium cation or organic base; the process comprising: (a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, with inorganic or organic base in presence of a solvent to form a reaction mixture;

[0084] In one embodiment, alkali metal is selected from sodium, potassium, lithium, and the like; alkaline earth metal is selected from calcium, magnesium and the like; and transition metal is selected from cobalt, copper, iron, nickel, zinc, manganese and the like. [0085] In one embodiment, the inorganic base in step (a) is selected from the group consisting of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali and alkaline earth metal bicarbonates, transition metal hydroxides, transition metal carbonates, ammonium hydroxide, ammonium carbonate and ammonium bicarbonate.

[0086] In one embodiment, alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal hydroxide is selected from calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate and the like; alkaline earth metal carbonate is selected from calcium carbonate, magnesium carbonate and the like; alkali metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; alkaline earth metal bicarbonate is selected from calcium bicarbonate, magnesium bicarbonate and the like; transition metal hydroxides is selected from cobalt hydroxide, copper hydroxide, iron hydroxide, nickel hydroxide, zinc hydroxide, manganese hydroxide and the like; transition metal carbonate is selected from cobalt carbonate, copper carbonate, iron carbonate, nickel carbonate, zinc carbonate, manganese carbonate and the like.

[0087] In one embodiment, the organic base in step (a) is a formula of NR1R2R3; wherein Rl, R2, R3 may be independently selected from the group consisting of H, C1-C6 alkyl, C3- C6 cycloalkyl, C6-C18 aryl, optionally substituted with -OH, or Rl may be H and R2 and R3 together with the nitrogen atom to which they are attached forms a 4-8 membered heterocyclic ring which may be optionally substituted.

[0088] In one embodiment, organic base with a formula NR1R2R3 is selected from the group consisting of dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, dibenzylamine, N-benzylmethylamine, dicyclohexylamine, cyclopropylamine, methylamine, ethylamine, propylamine, butylamine, benzylamine, aniline, pyridine, trimethylamine, triethylamine, tripropylamine, tributylamine, tribenzylamine, N,N-dimethylcyclohexylamine, diisopropylethylamine, meglumine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, piperazine, picoline, quinolone, N-methyl-di -isopropylamine, 1,4- diazabicyclo(2.2.2)octane (DABCO), l,5-diazabicyclo(4.3.0)non-5-ene(DBN), 1,8- diazabicyclo(5.4.0)undec-7-ene(DBU), N-methylpyrrolidine, N-methylpiperidine, N- methylmorpholine, N,N-dimethylpiperazine, pentamethyl guanidine, 2,6-lutidine, 2,4,6- collidine and the like.

[0089] In one embodiment, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.

[0090] In one embodiment, the solvent includes but not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0091] In one embodiment, in step (b), the salt of 6-bromo-3-hydroxypyrazine-2- carboxamide is obtained from the reaction mixture of step (a), the process comprising:

(i) optionally cooling, and stirring the mixture obtained in (a); or

(ii) removing the solvent from the mixture obtained in (a); or

[0092] In one embodiment, the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide is obtained by optionally cooling and stirring the mixture of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.

[0093] In one embodiment, the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide is obtained by removing the solvent from the mixture obtained in step (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent; or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.

[0094] In one embodiment, the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide is obtained by adding an anti-solvent to the mixture obtained in step (a) to form a mixture and optionally cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 30°C.

[0095] In one embodiment, the anti-solvent is selected such that the salt of 6-bromo-3- hydroxypyrazine-2-carboxamide is precipitated out from the solution.

[0096] In one embodiment, the anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, «-propyl acetate, isopropyl acetate, /er/-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl /er/-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, «-propyl alcohol, isopropyl alcohol, «-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert- butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0097] In one embodiment, the present invention provides a salt of favipiravir with an organic base or an inorganic base.

[0098] In one embodiment, the salt of favipiravir with organic base is organic amine salt of favipiravir.

[0099] In one embodiment, the salt of favipiravir with organic base is selected from the group consisting of cyclopropylamine salt of favipiravir, diisopropylamine salt of favipiravir, diisobutylamine salt of favipiravir, diethylamine salt of favipiravir and dicyclohexylamine salt of favipiravir; and wherein the salt of favipiravir with inorganic base is selected from the group consisting of potassium salt of favipiravir and lithium salt of favipiravir.

[0100] In one embodiment, the present invention provides the organic amine salts of favipiravir.

[0101] In one embodiment, the present invention provides dicyclohexylamine salt of favipiravir.

[0102] In one embodiment, the present invention provides diisopropylamine salt of favipiravir. [0103] In one embodiment, the present invention provides diethylamine salt of favipiravir.

[0104] In one embodiment, the present invention provides diisobutylamine salt of favipiravir. [0105] In one embodiment, the present invention provides cyclopropylamine salt of favipiravir.

[0106] In one embodiment, the present invention provides organic amine salt of favipiravir in crystalline form.

[0107] In one embodiment, the present invention provides the organic amine salts of favipiravir in crystalline form, wherein the organic amine is selected from the group consisting of dicyclohexylamine, diisopropylamine, diethylamine, diisobutylamine and cy cl opropy 1 amine . [0108] In one embodiment, the present invention provides a dicyclohexylamine salt of favipiravir characterized by a proton NMR spectrum having peaks at d 10.51 (brs, 1H), 8.51 (brs, 1H), 7.94-7.92 (d, 1H), 7.27 (brs, 1H), 3.04 (m, 2H), 1.97 (m, 4H), 1.74-1.72 (m, 4H), 1.61-1.58 (d, 2H), 1.32-1.21 (m, 8H), 1.09-1.06 (m, 2H).

[0109] In one embodiment, the present invention provides a diisopropylamine salt of favipiravir characterized by a proton NMR spectrum having peaks at d 10.36 (brs, 1H), 7.99-7.97 (d, 1H), 7.37 (brs, 1H), 3.39-3.33 (m, 2H), 1.22-1.21 (d, 12H).

[0110] In one embodiment, the present invention provides a diethylamine salt of favipiravir characterized by a proton NMR spectrum having peaks at d 10.50 (brs, 1H), 8.87 (brs, 1H), 7.95-7.93 (d, 1H), 7.30 (brs, 1H), 2.96-2.91 (m, 4H), 1.18-1.15 (t, 6H). [0111] In one embodiment, the present invention provides a diisobutylamine salt of favipiravir-characterized by a proton NMR spectrum having peaks at d 10.24 (brs, 1H), 8.52-8.50 (brs, 1H), 8.04-8.02 (d, 1H), 7.47 (brs, 1H), 2.68-2.67 (d, 4H), 1.95-1.88 (m, 2H), 0.92-0.91 (s, 12H).

[0112] In one embodiment, the present invention provides a cyclopropylamine salt of favipiravir-characterized by a proton NMR spectrum having peaks at d 10.24 (brs, 1H), 8.36 (brs, 2H), 8.02-8.00 (d, 1H), 7.52 (brs, 1H), 2.58-2.50 (m, 1H), 0.72-0.62 (m, 4H).

[0113] In one embodiment, the salts of favipiravir with inorganic base include salts of alkali metals such as potassium, lithium and the like; salts of alkali earth metals such as calcium, magnesium, and the like; ammonium salts.

[0114] In one embodiment, the present invention provides sodium salt of favipiravir. [0115] In one embodiment, the present invention provides potassium salt of favipiravir. [0116] In one embodiment, the present invention provides potassium salt of favipiravir in crystalline form.

[0117] In one embodiment, the present invention provides a potassium salt of favipiravir characterized by a proton NMR spectrum having peaks at d 10.90 (brs, 1H), 7.83-7.81 (d, 1H), 6.98 (brs, 1H).

[0118] In one embodiment, the present invention provides a lithium salt of favipiravir. [0119] In one embodiment, the present invention provides a lithium salt of favipiravir in crystalline form. [0120] In one embodiment, the present invention provides a lithium salt of favipiravir characterized by a proton NMR spectrum having peaks at d 9.89 (brs, 1H), 7.92-7.90 (d, 1H), 7.13 (brs, 1H).

[0121] In one embodiment, the present invention provides a salt of 6-fluoro-3 -hydroxy -

2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation.

[0122] In one embodiment, the metal element is selected from alkali metal, alkaline earth metal or transition metal.

[0123] In one embodiment, alkali metal is selected from sodium, potassium, lithium and the like; alkaline earth metal is selected from calcium, magnesium and the like; transition metal is selected from cobalt, copper, iron, cobalt, nickel, manganese, zinc and the like. [0124] In one embodiment, the present invention provides sodium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile.

[0125] In one embodiment, the present invention provides potassium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile

[0126] In one embodiment, the present invention provides a sodium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile characterized by a proton NMR spectrum having peaks at d 8.00-7.98 (d, 1H).

[0127] In one embodiment, the present invention provides a potassium salt of 6-fluoro-

3-hydroxy-2-pyrazinecarbonitrile characterized by a proton NMR spectrum having peaks at d 7.99-7.97 (d, 1H).

[0128] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is reacted with an inorganic base selected from the group consisting of sodium hydroxide, sodium carbonate and sodium bicarbonate to give sodium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile.

[0129] In one embodiment, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is reacted with an inorganic base selected from the group consisting of potassium hydroxide, potassium carbonate and potassium bicarbonate to give potassium salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile.

[0130] In one embodiment, the present invention provides a salt of 6-bromo-3- hydroxypyrazine-2-carboxamide, the compound of formula VIII, wherein X⁺ is a cation capable of forming a salt from a metal element or ammonium cation or organic base. [0131] In one embodiment, the metal element is selected from alkali metal, alkaline earth metal or transition metal.

[0132] In one embodiment, alkali metal is selected from sodium, potassium, lithium, and the like; alkaline earth metal is selected from calcium, magnesium and the like; and transition metal is selected from cobalt, copper, iron, nickel, zinc, manganese and the like. [0133] In one embodiment, the present invention provides sodium salt of 6-bromo-3- hydroxypyrazine-2-carboxamide.

[0134] In one embodiment, the present invention provides potassium salt of 6-bromo-3- hydroxypyrazine-2-carboxamide.

[0135] In one embodiment, the present invention provides a sodium salt of 6-bromo-3- hydroxypyrazine-2-carboxamide characterized by a proton NMR spectrum having peaks d 10.49 (brs, 1H), 7.89 (s, 1H), 7.15 (brs, 1H).

[0136] In one embodiment, the present invention provides a potassium salt of 6-bromo- 3-hydroxypyrazine-2-carboxamide characterized by a proton NMR spectrum having peaks d 10.58 (brs, 1H), 7.86 (s, 1H), 7.05 (brs, 1H).

[0137] In one embodiment, 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, is reacted with an inorganic base selected from the group consisting of sodium hydroxide, sodium carbonate and sodium bicarbonate to give sodium salt of 6- bromo-3-hydroxypyrazine-2-carboxamide.

[0138] In one embodiment, 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, is reacted with an inorganic base selected from the group consisting of potassium hydroxide, potassium carbonate and potassium bicarbonate to give potassium salt of 6-bromo-3-hydroxypyrazine-2-carboxamide.

[0139] In one embodiment, the organic base is a formula of NR1R2R3; wherein Rl, R2, R3 may be independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C18 aryl, optionally substituted with -OH, or Rl may be H and R2 and R3 together with the nitrogen atom to which they are attached forms a 4-8 membered heterocyclic ring which may be optionally substituted.

[0140] In one embodiment, organic base with a formula NR1R2R3 is selected from the group consisting of dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, dibenzylamine, N-benzylmethylamine, dicyclohexylamine, cyclopropylamine, methylamine, ethylamine, propylamine, butylamine, benzylamine, aniline, pyridine, trimethylamine, triethylamine, tripropylamine, tributylamine, tribenzylamine, N,N-dimethylcyclohexylamine, diisopropylethylamine, meglumine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, piperazine, picoline, quinolone, N-methyl-di -isopropylamine, 1,4- diazabicyclo(2.2.2)octane (DABCO), l,5-diazabicyclo(4.3.0)non-5-ene(DBN), 1,8- diazabicyclo(5.4.0)undec-7-ene(DBU), N-methylpyrrolidine, N-methylpiperidine, N- methylmorpholine, N,N-dimethylpiperazine, pentamethyl guanidine, 2,6-lutidine, 2,4,6- collidine and the like.

[0141] In one embodiment, the present invention provides diisopropylethylamine salt of 6- bromo-3-hydroxypyrazine-2-carboxamide.

[0142] In one embodiment, the present invention provides triethylamine salt of 6-bromo- 3-hydroxypyrazine-2-carboxamide.

[0143] In one embodiment, 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, is reacted with diisopropylethylamine to give diisopropylamine salt of 6- bromo-3-hydroxypyrazine-2-carboxamide.

[0144] In one embodiment, 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, is reacted with triethylamine to give triethylamine salt of 6-bromo-3- hydroxypyrazine-2-carboxamide.

[0145] In one embodiment, the present invention provides a triethylamine salt of 6- bromo-3-hydroxypyrazine-2-carboxamide characterized by a proton NMR spectrum having peaks d 10.59 (brs, 1H), 10.09 (brs, 1H), 8.05 (s, 1H), 7.50 (brs, 1H), 3.13-3.076 (m, 6H), 1.19-1.15 (t, 9H).

[0146] In one embodiment, the present invention provides a process for the preparation of salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VIII, the process comprising reacting 3-hydroxypyrazine-2-carboxamide with a brominating agent to give 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VII and reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VII with an inorganic base or organic base to obtain the salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, the compound of formula VIII.

[0147] In one embodiment, the 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII obtained may be present in the reaction mixture and used for reaction with inorganic base or organic base to obtain the salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, the compound of formula VIII without isolating 6-bromo-3-hydroxypyrazine-

2-carboxamide from the reaction mixture.

[0148] In one embodiment, the 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII obtained and present in the reaction mixture, may be isolated in a solid form or as a residue and then reacted with the inorganic or organic base to obtain the salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VIII. [0149] In one embodiment, the present invention provides a process for the preparation of 3,6-dichloro-2-pyrazinecarbonitrile, the process comprising reacting salt of 6-bromo-

3-hydroxypyrazine-2-carboxamide, the compound of formula VIII with a chlorinating agent to give 3,6-dichloro-2-pyrazinecarbonitrile.

[0150] In one embodiment, the sodium salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, a compound of formula VIII, is reacted with a chlorinating agent to obtain

3,6-dichloro-2-pyrazinecarbonitrile.

[0151] In one embodiment, the potassium salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, a compound of formula VIII is reacted with a chlorinating agent to obtain

3,6-dichloro-2-pyrazinecarbonitrile.

[0152] In one embodiment, the organic amine salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, a compound of formula VIII is reacted with a chlorinating agent to obtain

3,6-dichloro-2-pyrazinecarbonitrile.

[0153] In one embodiment, the chlorinating agent includes but is not limited to chlorine, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, or mixtures thereof. [0154] In one embodiment, the reaction is carried out in presence or absence of solvent. [0155] In one embodiment, the reaction is carried out in presence of a base. The base may be selected from an organic or an inorganic base.

[0156] In one embodiment, the base selected is triethylamine, diisopropylethylamine. [0157] In one embodiment, the chlorination is carried out with a chlorinating agent in presence of a base and absence of solvent.

[0158] In one embodiment, the present invention provides a process for the preparation of favipiravir, a compound of formula I; the process comprising:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII with a chlorinating agent to obtain 3,6-dichloro-2-pyrazinecarbonitrile, a compound of formula VI; (b) reacting 3,6-dichloro-2-pyrazinecarbonitrile, the compound of formula VI with a fluorinating agent to obtain 3,6-difluoro-2-pyrazinecarbonitrile, a compound of formula V; and

(c) converting 3,6-difluoro-2-pyrazinecarbonitrile, the compound of formula V to favipiravir, the compound of formula I.

[0159] In one embodiment, the chlorinating agent includes but is not limited to chlorine, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, or mixtures thereof. [0160] In one embodiment, the chlorinating agent in step (a) is phosphorus oxychloride. [0161] In one embodiment, in step (a), the reaction is carried out in presence or absence of solvent.

[0162] In one embodiment, the solvent includes but is not limited to ethers such as dimethyl ether, diethyl ether, diisopropyl ether, /er/-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, «-propyl acetate, /cvv-butyl acetate and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, dichloromethane, dichloroethane, chloroform and the like; aromatic hydrocarbons such as toluene, benzene; xylene and the like; or mixtures thereof.

[0163] In one embodiment, in step (a), the reaction is carried out in presence of a base. The base may be selected from an organic or an inorganic base.

[0164] In one embodiment, the base selected is triethylamine.

[0165] In one embodiment, the base selected is diisopropylethylamine.

[0166] In one embodiment, in step (a), the chlorination is carried out with a chlorinating agent in presence of a base and absence of solvent.

[0167] In one embodiment, the 3,6-dichloro-2-pyrazinecarbonitrile obtained in step (a) is not isolated and carried forward for further reaction.

[0168] In one embodiment, the fluorinating agent includes but is not limited to fluorine gas, potassium fluoride, tetrabutyl ammonium fluoride, trifluoromethyl hypofluorite, acetyl hypofluorite, difluoroxenon, perchloryl fluoride, cesium sulfate fluorite, N- fluoropyridinium triflate, N-fluoro-N-alkylallenesulfonamide, N-fluorosaccharin sultam, N-fluorobis(trifluoromethanesulfone)-imide, N-fluorobis-(benzenesulfone)-imide and N- fluoro-O-benzenedisulfonimide, or mixtures thereof.

[0169] In one embodiment, in step (b), the fluorinating agent is potassium fluoride. [0170] In one embodiment, the reaction in step (b) is carried out in presence of a solvent. [0171] In one embodiment, the solvent includes but is not limited to ethers such as dimethyl ether, diethyl ether, diisopropyl ether, /er/-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, «-propyl acetate, /cvv-butyl acetate and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, dichloromethane, dichloroethane, chloroform and the like; aromatic hydrocarbons such as toluene, benzene; xylene and the like; or mixtures thereof.

[0172] In one embodiment, the step (b) is carried out without using any additional additive.

[0173] In one embodiment, the 3,6-difluoro-2-pyrazinecarbonitrile obtained in step (b) is not isolated and carried forward for further reaction.

[0174] In one embodiment, the 3,6-difluoro-2-pyrazinecarbonitrile is converted to favipiravir by a process comprising treating 3,6-difluoro-2-pyrazinecarbonitrile with base to obtain 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and optionally forming a salt and further reacting the 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile or salt thereof with peroxide.

[0175] In one embodiment, the base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, dipotassium hydrogenphosphate, tripotassium phosphate, diisopropylethylamine, triethylamine; quaternary ammonium hydroxide; potassium formate, sodium formate, formic acid-triethylamine, benzoic acid- triethylamine, acetic acid-triethylamine, potassium acetate, sodium acetate, sodium propionate, sodium hexanoate, sodium benzoate, and mixtures thereof.

[0176] In one embodiment, the reaction may be carried out in presence of water.

[0177] In one embodiment, the reaction may be carried out in presence of organic solvent. [0178] In one embodiment, the reaction may be carried out in absence of water. [0179] In one embodiment, the reaction may be carried out in presence of organic solvent and absence of water.

[0180] The product obtained may include the tautomer 6-fluoro-3-oxo-3,4-dihydro-2- pyrazinecarbonitrile.

[0181] In one embodiment, the product obtained after treatment with base is subjected to workup.

[0182] The workup may comprise treating with base like ammonia with optional use of water and charcoalization followed by filtration.

[0183] In one embodiment, as a part of workup, a base like potassium acetate or sodium acetate may be added to the filtered product and the pH of the reaction mass may be adjusted in the range of 9-10 by use of ammonia or acetic acid.

[0184] In one embodiment, the product obtained in the reaction mass may be treated with an inorganic base or organic base to obtain the salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile compound of formula III.

[0185] In one embodiment, the product obtained in the reaction mass may be treated with an organic amine base to obtain the organic amine salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile. The organic amine may be secondary amine like dicyclohexyl amine, dipropyl amine, dibutylamine, dibenzylamine, N-benzylmethylamine and the like. [0186] In one embodiment, the 3,6-difluoro-2-pyrazinecarbonitrile, a compound of formula V is converted to favipiravir by a process comprising treating 3,6-difluoro-2- pyrazinecarbonitrile with peracid to obtain 3,6-difluoro-2-pyrazinecarboxamide and further reacting the 3,6-difluoro-2-pyrazinecarboxamide with base.

[0187] In one embodiment, the reaction with peracid may be carried out in presence of base selected from alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates. The peracid may be selected from hydrogen peroxide and the like [0188] In one embodiment, the present invention provides a process for the preparation of favipiravir, the process comprising:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide with a chlorinating agent to obtain 6-bromo-3-chloro-2-pyrazinecarbonitrile,

(b) reacting the 6-bromo-3-chloro-2-pyrazinecarbonitrile with a fluorinating agent to obtain 3,6-difluoro-2-pyrazinecarbonitrile; and

(c) converting the 3,6-difluoro-2-pyrazinecarbonitrile to favipiravir. [0189] In one embodiment, in step (a) the conversion is carried out by using chlorinating agent for example phosphorus oxychloride for a limited time of about 1-2 hours.

[0190] In one embodiment, in step (b) the conversion is carried out by using fluorinating agent for example potassium fluoride.

[0191] In one embodiment, the step (c) is carried out as discussed supra.

[0192] In one embodiment, the present invention provides a process for the preparation of 6-bromo-3-hydroxypyrazine-2-carboxamide, the process comprising:

(a) reacting dialkyl malonate with sodium nitrite in the presence of an acid to give dialkyl (hydroxyimino)malonate;

(b) reducing dialkyl (hydroxyimino)malonate to give dialkyl aminomalonate or salt thereof;

(c) reacting dialkyl aminomalonate or salt thereof with a source of ammonia to give aminomalonamide;

(d) reacting aminomalonamide with glyoxal and a base to give 3-hydroxypyrazine-2- carboxamide; and

(e) reacting 3-hydroxypyrazine-2-carboxamide with a brominating agent to give 6- bromo-3-hydroxypyrazine-2-carboxamide.

[0193] In one embodiment, in step (a) of the process for the preparation of 6-bromo-3- hydroxypyrazine-2-carboxamide, dialkyl malonate is reacted with sodium nitrite in the presence of an acid to give dialkyl (hydroxyimino)malonate.

[0194] In one embodiment, the acid includes but is not limited to hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, or mixtures thereof.

[0195] In one embodiment, the reaction may be carried out in the presence of a solvent. [0196] In one embodiment, the solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, /tvV-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, «-propyl acetate, /er/-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.

[0197] In one embodiment, diethyl malonate is reacted with sodium nitrite in the presence of an acetic acid to give diethyl (hydroxyimino)malonate.

[0198] In one embodiment, in step (b) of the process for the preparation of 6-bromo-3- hydroxypyrazine-2-carboxamide, dialkyl (hydroxyimino)malonate is reduced to give dialkyl aminomalonate or salt thereof.

[0199] In one embodiment, the reduction reaction was carried out by hydrogenation of dialkyl (hydroxyimino) malonate in the presence of a catalyst.

[0200] In one embodiment, the reduction reaction was carried out using hydrides such as sodium borohydride, lithium borohydride and the like.

[0201] In one embodiment, the catalyst is selected from the group consisting of palladium, platinum, Raney nickel, and mixtures thereof.

[0202] In one embodiment, diethyl (hydroxyimino) malonate is reduced to give diethyl aminomalonate or salt thereof.

[0203] In one embodiment, diethyl (hydroxyimino) malonate is reduced by hydrogenation in the presence of palladium catalyst to give diethyl aminomalonate or salt thereof.

[0204] In one embodiment, in step (c) of the process for the preparation of 6-bromo-3- hydroxypyrazine-2-carboxamide, dialkyl aminomalonate or salt thereof is reacted with a source of ammonia to give aminomalonamide.

[0205] In one embodiment, the source of ammonia includes but is not limited to ammonia gas, ammonium hydroxide solution, or mixtures thereof.

[0206] In one embodiment, diethyl aminomalonate or salt thereof is reacted with a source of ammonia to give aminomalonamide.

[0207] In one embodiment, in step (d) of the process for the preparation of 6-bromo-3- hydroxypyrazine-2-carboxamide, aminomalonamide is reacted with glyoxal and a base to give 3-hydroxypyrazine-2-carboxamide.

[0208] In one embodiment, the base includes but is not limited to sodium hydroxide, potassium hydroxide, trisodium phosphate and tripotassium phosphate.

[0209] In one embodiment, aminomalonamide is reacted with glyoxal and sodium hydroxide to give 3-hydroxypyrazine-2-carboxamide. [0210] In one embodiment, in step (e) of the process for the preparation of 6-bromo-3- hydroxypyrazine-2-carboxamide, 3-hydroxypyrazine-2-carboxamide is reacted with a brominating agent to give 6-bromo-3-hydroxypyrazine-2-carboxamide.

[0211] In one embodiment, the brominating agent includes but is not limited to bromine, N-bromo succinimide, or mixtures thereof.

[0212] In one embodiment, the intermediates of steps (a), (b), (c) or (d) are not isolated. [0213] In one embodiment, the present invention provides a process for the preparation of favipiravir, a compound of formula I; the process comprising:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII, with an inorganic base or organic base to obtain salt of 6-bromo-3-hydroxypyrazine-2 carboxamide, a compound of formula VIII, wherein X⁺ is a cation capable of forming a salt from a metal element, ammonium cation or an organic base;

(e) reacting 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, the compound of formula III with an inorganic base to give salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV, wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation;

[0214] In one embodiment, the steps (a) to (f) are carried out as discussed supra.

[0215] In one embodiment, the present invention provides a process for the preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile or salt thereof, the process comprising:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide or salt thereof with a chlorinating agent to obtain 3,6-dichloro-2-pyrazinecarbonitrile; (b) reacting 3,6-dichloro-2-pyrazinecarbonitrile with a fluorinating agent to obtain 3,6- difluoro-2-pyrazinecarbonitrile;

(c) reacting 3,6-difluoro-2-pyrazinecarbonitrile with a base to give 6-fluoro-3 -hydroxy - 2-pyrazinecarbonitrile; and

(d) optionally, reacting 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile with a base to give a salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile.

[0216] In one embodiment, in step (a), the chlorinating agent is as discussed supra.

[0217] In one embodiment, step (a) is carried out in absence of solvent.

[0218] In one embodiment, in step (b), the fluorinating agent is as discussed supra.

[0219] In one embodiment, step (b) is carried out in absence of additive.

[0220] In one embodiment, steps (a), (b) and (c) are carried out in-situ.

[0221] The term “in-situ” means the intermediates formed in the steps referred to are not isolated.

[0222] In one embodiment, the term “not isolated” means the intermediates referred to are not separated as a solid.

[0223] In one embodiment, the present invention provides a process for the preparation of favipiravir, the process comprising:

(a) reacting 3-hydroxypyrazine-2-carboxamide with a nitrating agent to give 3 -hydroxy - 6-nitropyrazine-2-carboxamide;

(b) reacting 3-hydroxy-6-nitropyraxine-2-carboxamide with a chlorinating agent to give 3,6-dichloropyrazine-2-carbonitrile;

(c) reacting 3,6-dichloropyrazine-2-carbonitrile with a fluorinating agent to give 3,6- difluoropyrazine-2-carbonitrile;

(d) reacting 3,6-difluoropyrazine-2-carbonitrile with a hydrolyzing agent to give 3,6- difluoropyrazine-2-carboxamide and

(e) reacting 3,6-difluoropyrazine-2-carboxamide with a base to give favipiravir.

[0224] In one embodiment, the nitrating agent includes but not limited to mixed acid consisting of nitric acid and sulphuric acid.

[0225] In one embodiment, the present invention provides a process for the preparation of favipiravir, the process comprising:

(a) reacting 3-amino-6-bromopyrazine-2-carboxylic acid with an acid in a solvent to give methyl-3-amino-6-bromopyrazine-2-carboxylate; (b) reacting methyl-3 -amino-6-bromopyrazine-2-carboxylate with an acid and metal nitrite to give methyl-6-bromo-3-hydroxypyrazine-2-carboxylate;

(c) reacting methyl-6-bromo-3-hydroxypyrazine-2-carboxylate with a benzylating agent to give methyl-3-(benzyloxy)-6-bromopyrazine-2-carboxylate; (d) reacting methyl-3 -(benzyloxy)-6-bromopyrazine-2-carboxylate with a fluorinating agent to give methyl-3-(benzyloxy)-6-fluoropyrazine-2-carboxylate;

(e) deprotection of methyl-3 -(benzyloxy)-6-fluoropyrazine-2-carboxylate to give methyl-6-fluoro-3-hydroxypyrazine-2-carboxylate;

(f) reacting methyl-6-fluoro-3-hydroxypyrazine-2-carboxylate with a base to give favipiravir.

[0226] In one embodiment, in step (c), benzylating agent includes but not limited to benzyl halide.

[0227] In one embodiment, in step (e), deprotection is carried out by hydrogenation using catalyst for example Pd/C. [0228] In one embodiment, the present invention provides crystalline favipiravir.

[0229] In one embodiment, the favipiravir is obtained in a purity of >99.0%.

[0230] In one embodiment, the favipiravir is obtained in a purity of >99.0% and wherein the level of 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VII, is less than 0.15%. [0231] In one embodiment, the level of compound of formula VII in favipiravir is less than 0.05%.

[0232] In one embodiment, the favipiravir is obtained in a purity of >99.0% and wherein the level of dicyclohexylamine salt of 6-fluoro-3-hydroxypyrazine-2-carbonitrile is less than 0.15%. [0233] In one embodiment, the level of compound of formula IVa in favipiravir is less than 0.05%.

[0234] In one embodiment, the favipiravir is obtained in a purity of >99.0% and wherein the level of 6-chloro-3-hydroxypyrazine-2-carboxamide, a compound of formula X, is less than 0.15%.

[0235] In one embodiment, the level of compound of formula X in favipiravir is less than 0.05%.

[0236] In one embodiment, the favipiravir is obtained in a purity of >99.9%.

[0237] In one embodiment, the present invention provides pharmaceutical compositions comprising favipiravir obtained by the processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.

[0238] In one embodiment, the present invention provides pharmaceutical compositions comprising favipiravir obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state favipiravir into any of the foregoing desired particle size range.

[0239] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

[0240] EXAMPLE 1: Preparation of favipiravir sodium salt

A suspension of favipiravir (5g) and sodium bicarbonate (2.8g) in water (35mL) and 2- propanol (35mL) was heated to about 75-80°C. After 2-propanol (70mL) was added dropwise at about 40-45°C, the mixture was cooled to about 5°C and stirred at the same temperature for about one hour. The solid obtained was filtered and dried at about 50°C. Yield: 5.2g (90.7%); HPLC Purity: 99.91%; Water Content: 6.89%; DSC (°C): Endo 193.77, Exo 237.32 & 317.64; TGA (%): 0-50°C = 0.00965, 50-100°C = 0.294, 100- 150°C = 1.983; XRD:

[0241] EXAMPLE 2: Preparation of favipiravir potassium salt

A suspension of favipiravir (5g) and potassium bicarbonate (3.34g) in water (35mL) and 2-propanol (35mL) was stirred at about room temperature. After 2-propanol (70mL) was added dropwise at room temperature, the mixture was stirred at about the same temperature for about one hour. The solid obtained was filtered and dried at about 50°C. Yield: 5.6g (89.7%); HPLC Purity: 99.97%; Water Content: 0.18%; TGA (%): 0-50°C = 0.0138, 50-100°C = 0.0216, 100-150°C = 0.034; XRD:

[0242] EXAMPLE 3: Preparation of favipiravir lithium salt

The salt was obtained in same way as in Example 2 using lithium hydroxide monohydrate (1.4g). Yield: 3.3g (63.2%); HPLC Purity: 99.99%; Water Content: 9.48%; XRD:

[0243] EXAMPLE 4: Preparation of favipiravir dicyclohexylamine salt

To a suspension of favipiravir (5g) and acetone (50mL), was added dicyclohexylamine (6.34g) at about room temperature dropwise. The mixture was stirred at about the same temperature for about one hour. The solid obtained was filtered and dried at about 50°C. Yield: lOg (92.8%); HPLC Purity: 99.96%; Water Content: 0.45%; DSC (°C): Endo 184.63, Exo213.23; TGA (%):

0-50°C = 0.0908, 50-100°C = 0.780, 100-150°C = 11.15

EXAMPLE 5: Preparation of favipiravir diisopropylamine salt

The salt was obtained in same way as in Example 4 using diisopropylamine (3.54g) and acetone (30mL). Yield: 7.1g (86.37%); HPLC Purity: 99.94%; Water Content: 0.36%; DSC (°C): Endo 160.22, Exo 184.33; TGA (%): 0-50°C = 0.0442, 50-100°C = 3.019, 100-150°C = 36.16; XRD:

[0244] EXAMPLE 6: Preparation of favipiravir diethylamine salt

The salt was obtained in same way as in Example 4 using diethylamine (2.56g) and acetone (30mL). Yield: 6.2g (84.69%); HPLC Purity: 99.96%; Water Content: 0.25%; DSC (°C): Endo 143.38, Exo 179.48; TGA (%): 0-50°C = 0.022, 50-100°C = 1.93, 100- 150°C = 29.31; XRD:

[0245] EXAMPLE 7: Preparation of favipiravir diisobutylamine salt The salt was obtained in same way as in Example 4 using diisobutylamine (4.52g) and acetone (70mL). Yield: 7.1g (78.0%); HPLC Purity: 99.92%; Water Content: 0.22%; DSC (°C): Endo 179.55, Exo 194.01; TGA (%): 0-50°C = 0.021, 50-100°C = 1.75, 100- 150°C = 37.69; XRD:

[0246] EXAMPLE 8: Preparation of favipiravir cyclopropylamine salt

The salt was obtained in same way as in Example 4 using cyclopropylamine (2g) and acetone (70mL). Yield: 4g (58.7%); HPLC Purity: 99.71%; Water Content: 0.18%

[0247] EXAMPLE 9: Preparation of 3-hydroxy- 6-fluoro-2-pyrazinecarbonitrile

A mixture of 3,6-dichloro-2-pyrazinecarbonitrile (lOg) and anhydrous potassium fluoride (lO.Olg) was added to dimethylformamide (22.5mL). The reaction mixture was heated to about 115°C and allowed to stand for about 8-10h. The reaction was cooled to about 15°C and acetic acid (4.13g), trimethylamine (6.96g) was added. The resulting mixture was maintained for about 2h at about room temperature. To this mixture, 25% ammonia solution (4.5g), water and charcoal was added. The resulting solution was stirred for about lh and was filtered through hyflo with water washing. To this clear filtrate, separately prepared mixture of potassium acetate (3.6g) in water (5.0mL) and 25% ammonia solution (4.5g) was added at about 20°C temperature. The resulting reaction mixture was stirred for about lh at about room temperature and then charged with ethyl acetate (lOOmL) and water (50mL). The pH of the reaction mixture was adjusted to about 1.5 using cone. HC1 under stirring at about room temperature. The two layers were separated and the organic layer was concentrated under reduced pressure. The residue obtained was slurred by diisopropylether, filtered, and dried. Yield: 4g

[0248] EXAMPLE 10: Preparation of sodium salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile

To a suspension of 6-fluoro-3-hydroxy-2-pyrazinecarbnitrile dicyclohexylamine salt (20g) and isopropyl alcohol (150mL) was added sodium hydroxide solution (3.75g in lOmL of water) at about room temperature dropwise. The mixture was stirred at about the same temperature for about three hours. The solid obtained was filtered and dried at about 50°C. Yield: 9.2g (91%) [0249] EXAMPLE 11: Preparation of sodium salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile

To a suspension of 6-fluoro-3-hydroxy-2-pyrazinecarbnitrile (5g) and isopropyl alcohol (30mL) was added sodium hydroxide solution (1.58g dissolved in 3mL water) dropwise at about room temperature. The mixture was cooled to about 10°C and stirred for about lh. The solid obtained was filtered and dried at about 50°C. Yield: 5.7g (98%), Purity: 98.45%

[0250] EXAMPLE 12: Preparation of sodium salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile

To a suspension of 6-fluoro-3-hydroxy-2-pyrazinecarbnitrile (4g) and isopropyl alcohol (20mL) was added sodium hydroxide solution (1.5g in 2.2mL water) at about 10-15°C.

The mixture was stirred for about lh. The solid obtained was filtered and dried. Yield: 4.2g; HPLC Purity: 98.92%, Water Content: 10.15%; DSC (°C): Endo 106.07, Exo 188.09; TGA (%): 0-50°C = 0.1752, 50-100°C = 9.76, 100-150°C = 0.22; XRD:

[0251] EXAMPLE 13: Preparation of potassium salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile

To a suspension of 6-fluoro-3-hydroxy-2-pyrazinecarbnitrile dicyclohexylamine salt (20g) and isopropyl alcohol (150mL) was added potassium hydroxide solution (5.25g in lOmL of water) at about room temperature dropwise. The mixture was stirred overnight at about the same temperature. The solid obtained was filtered and dried at about 50°C. Yield: 8.2g (73%); HPLC Purity: 98.27%; Water Content: 1.43%; DSC (°C): Endo 314.31, Exo 331.87; TGA (%): 0-50°C = 0.034, 50-100°C = 0.084, 100-150°C = 0.069; XRD:

[0252] EXAMPLE 14: Preparation of sodium salt of 6-bromo-3-hydroxy-2- pyrazinecarboxamide

A suspension of 6-bromo-3-hydroxy-2-pyrazinecarboxamide (2.5g) and sodium bicarbonate (1.06g) in water (17.5mL) and 2-propanol (17.5mL) was heated to about 75- 80°C. After 2-propanol (35mL) was added dropwise at about 40-45°C, the mixture was cooled to 5°C and stirred at about the same temperature for about one hour. The solid obtained was filtered and dried at about 50°C. Yield: 2.7g (97%); HPLC Purity: 99.96%; Water Content: 10.75%; ¾NMR: d 10.49 (brs, 1H), 7.89 (s,lH), 7.15 (brs, 1H) [0253] EXAMPLE 15: Preparation of potassium salt of 6-bromo-3-hydroxy-2- pyrazinecarboxamide

A suspension of 6-bromo-3-hydroxy-2-pyrazinecarboxamide (lOg) and potassium bicarbonate (5.08g) in water (70mL) and 2-propanol (70mL) was heated to about 75-80°C. After 2-propanol (140mL) was added dropwise at about 40-45°C, the mixture was cooled to about 5°C and stirred at about the same temperature for about one hour. The solid obtained was filtered and dried at about 50°C. Yield: 10. lg (85%); ¹HNMR: d 10.58 (brs, 1H), 7.86 (s, 1H), 7.05 (brs, 1H).

[0254] EXAMPLE 16: Preparation of diisopropylethylamine salt of 6-bromo-3- hydroxy-2-pyrazinecarboxamide To a suspension of 6-bromo-3-hydroxy-2-pyrazinecarboxamide (2.5g) and acetone (15mL) was added diisopropylethylamine (1.62g) dropwise at about room temperature. The mixture was stirred at about the same temperature for about two hours. The solid obtained was filtered and dried at about 50°C. Yield: 3.3g (83%); HPLC Purity: 100%; Water Content: 0.21%; 1H NMR: d 10.21 (brs, 1H), 9.34 (brs, 0.5H), 7.99 (s, 1H), 7.35 (brs, 1H), 3.58-3.53 (m, 2H), 3.09-3.04 (m, 12H), 1.24-1.19 (m, 15H)

[0255] EXAMPLE 17: Preparation of triethylamine salt of 6-bromo-3-hydroxy-2- pyrazinecarboxamide

The salt of 6-bromo-3-hydroxy-2-pyrazinecarboxamide was prepared in same way as in Example 16 by using triethylamine (1.3g). Yield: 2.6g (71.2%); HPLC Purity: 99.45%; Water Content: 0.16%; ¾ NMR: d 10.59 (brs, 1H), 10.09 (brs, 1H), 8.05 (s, 1H), 7.50 (brs, 1H), 3.13-3.076 (m, 6H), 1.19-1.15 (t, 9H)

[0256] EXAMPLE 18: Preparation of 3,6-dichloro-2-pyrazinecarbonitrile

To a suspension of 6-bromo-3-hydroxypyrazine-2-carboxamide (2.5g) and phosphorus oxychloride (7g), triethylamine was added slowly at about below 10°C temperature. The resulting mixture was heated to about 90°C and stirred for about 3h. The reaction mixture was cooled to about room temperature and toluene was added to the reaction mixture. The reaction mass was quenched in a mixture of toluene and water at about below 10°C. The resulting mixture was stirred at about room temperature for about 30min. The two layers were separated and the organic layer was concentrated under reduced pressure. Yield: 20g. [0257] EXAMPLE 19: Preparation of 3,6-dichloro-2-pyrazinecarbonitrile 6-Bromo-3-hydroxy-2-pyrazinecarboxamide sodium salt (lOg) was added to phosphorus oxychloride (25.32g). To this solution, triethylamine (3.35g) was added dropwise and stirred at about 80°C for about 2-3h. After the reaction was completed, the reaction mass was added to the mixture of toluene (20 mL) and water (40 mL) at about 10°C. The separation of the layer was performed. Organic layer was washed with dil. HC1 (10 mL) solution and dried with sodium sulphate. Organic layer was distilled under reduced pressure to obtain pale yellow solid. Yield: 4.2g.

[0258] EXAMPLE 20: Preparation of 3,6-dichloro-2-pyrazinecarbonitrile

6-Bromo-3-hydroxy-2-pyrazinecarboxamide diisopropylethylamine salt (5g) was added to phosphorus oxychloride (3.69g) and stirred at about 80°C for about 2h. After the reaction was completed, the reaction mass was added to the mixture of toluene and water at about 10°C. The two layers were separated and the organic layer was concentrated under reduced pressure. Yield: 1.4g.

[0259] EXAMPLE 21: Preparation of 3,6-dichloro-2-pyrazinecarbonitrile 3,6-dichloro-2-pyrazinecarbonitrile was obtained in same way as in Example 20 using 6- Bromo-3-hydroxy-2-pyrazinecarboxamide triethylamine salt (5g) and phosphorus oxychloride (9.55g). Yield: 1.8g.

[0260] EXAMPLE 22: Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide

To the solution of sodium hydroxide (2.48g) in water (50mL), sodium salt of 6-fluoro-3- hydroxy-2-pyrazinecarbonitrile (5g) was added at about 15 to 25°C and the solution was stirred at about same temperature for about 30min. Then -35% hydrogen peroxide (9.05mL) solution was added dropwise at about 15 to 30°C and stirred for about lh at about 20 to 30°C. The pH of the solution was adjusted to pH 6.5 to 8.0 by hydrochloric acid. The mixture was heated to about 40° C. Activated carbon was added to the reaction mixture which was stirred at about 40° C for about 30min and filtered. The solid was washed with water and hydrochloric acid was added to a mixed solution of a filtrate and a washing solution at an internal temperature of about 35-45°C, so that the pH thereof was adjusted to pH 3 to 4. It was then stirred for about lh. The solid was filtered and washed with water. Yield: 2.0g. (41.0%), Purity: 99.78%, 'H-NMR (DMSO-dr,) d values: 8.50 - 8.51 (2H, d), 8.75 (1H, s), 13.41 (1H, s).

[0261] EXAMPLE 23: Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide

To the solution of sodium hydroxide (4.3 lg) in water (lOOmL), 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile (lOg) was added at about 15 to 25°C and the solution was stirred at about same temperature for about 30min. Then -35% hydrogen peroxide (13.97mL) solution was added dropwise at about 15 to 30°C and stirred for about 3h at about 20 to 30°C. The pH of the solution was adjusted to pH 6.5 to 8.0 by hydrochloric acid. The mixture was heated to about 40°C. Activated carbon was added to the reaction mixture which was stirred at about 40°C for about 30min and filtered. The solid was washed with water and hydrochloric acid was added to a mixed solution of a filtrate and a washing solution at an internal temperature of about 35-45°C, so that the pH thereof was adjusted to pH 3 to 4. It was then stirred for about lh.The solid was filtered and washed with water and IP A. Yield: 4.90g [0262] EXAMPLE 24: Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide To a stirred solution of sodium hydroxide (1.736g) in water (24.5mL) at about 10°C was added 6-fluoro-3-hydroxypyrazine-2-carbonitrile sodium salt (3.5g) and subsequently, while keeping the internal temperature at about 20 to 30° C, 35.0% v/w hydrogen peroxide (6.33mL) was added dropwise to the mixture. The obtained mixture was stirred at about 25°C for about lh and the pH of the solution was adjusted to pH 6.5 to 8.0 by hydrochloric acid. The mixture was heated to about 40°C. Activated carbon was added to the reaction mixture which was stirred at about 40°C for about 30min and filtered. The solid was washed with water and hydrochloric acid was added to a mixed solution of a filtrate and a washing solution at an internal temperature of about 35-45°C, so that the pH thereof was adjusted to pH 3 to 4. It was then stirred for about lh. The solid was filtered and washed with water. Yield: 1.45g [0263] EXAMPLE 25: Preparation of Favipiravir

A mixture of 6-bromo-3-hydroxypyrazine-2-carboxamide (lOg) and phosphorus oxychloride (28g) was stirred at about 25-35°C. The reaction mixture was cooled to about 10-20°C and trimethylamine (3.71g) was slowly added to it. The reaction mixture was heated to about 85-95°C and stirred for about 3-4 hours. The reaction mixture was then cooled to about 20-60°C and toluene was added to it. The reaction mixture was cooled to about 10-20°C and was added to a stirred mixture of toluene (40mL) and water (40mL) cooled at about 0-10°C. The reaction mixture was heated to about 45-55°C and stirred for about 3 hours. The reaction mixture was cooled to about 25-35°C and the two layers were separated. The organic layer was cooled to about 15-25°C and a mixture of water (5mL), concentrated hydrochloric acid (5mL) and toluene (2mL) was added to it. The reaction mixture was stirred for about 15-30 minutes. The two layers were separated and hyflosupercell was added to the organic layer. The reaction mixture was filtered and concentrated under vacuum. The residue was cooled to about 25-45°C and dimethylformamide was added to it under nitrogen atmosphere. A solution of potassium fluoride (5.33g) in dimethylformamide was added to the reaction mixture at about 40- 45°C. The reaction mixture was heated to about 105-120°C and stirred for about 8-9 hours. The reaction mixture was cooled to about 10-15°C and acetic acid (4.13g) and triethylamine (3.96g) were slowly added to it. The reaction mixture was stirred at about 25-35°C for about 4 hours. After completion of reaction and followed by work-up, the product 6-fluoro-3-hydroxy2-pyrazinecarbonitrile was then converted to favipiravir using hydrogen peroxide. Purity: 99.8%; Water content: 0.08%w/w; Melting point: 182-186°C XRPD table of crystalline favipiravir:

[0264] EXAMPLE 26: Preparation of 6-bromo-3-chloro-2-pyrazinecarbonitrile

Phosphorus oxychloride (14.85mL) and diisopropylethylamine (31 93mL) were added to 6-bromo-3-hydroxy-2-carboxamide (lOg) in chlorobenzene (lOOmL) at about 0°C. The reaction mixture was stirred at about 85-90°C for about 1 hour. The reaction mixture was cooled to about room temperature and was quenched in ice cold water. The two layers were separated. The organic layer was dried and concentrated under reduced pressure. The residue obtained was degassed to remove traces of solvents to give the title compound. Yield: 6.5g (65%); Purity: 93% [0265] EXAMPLE 27: Preparation of 6-bromo-3-chloro-2-pyrazinecarbonitrile

Phosphorus oxychloride (8.1mL) and diisopropylethylamine (16mL) were added to 6- bromo-3 -hydroxy -2-carboxamide (5g) in toluene (50mL) at about 0°C. The reaction mixture was stirred at about 80-85°C for about 1 hour. The reaction mixture was cooled to about room temperature and was quenched in ice cold water (50mL) with concentrated hydrochloric acid (0.5mL). The two layers were separated. The aqueous layer was extracted with toluene. The combined organic layer was dried over sodium sulphate and treated with charcoal. The organic layer was concentrated under reduced pressure. The residue obtained was degassed to remove traces of solvents to give the title compound. Yield: 3.5g (70%); Purity: 96% [0266] EXAMPLE 28: Preparation of Favipiravir

To a mixture of 6-bromo-3-chloropyrazine-2-carboxamide (lOg) and anhydrous dimethylformamide (25mL) under nitrogen atmosphere, was added a solution of potassium fluoride (7.9g) in anhydrous dimethylformamide (25mL). The reaction mixture was heated to about 105°C and stirred for about 2-3 hours. The reaction mixture was cooled to about 10-15°C and acetic acid (4.13g) and triethylamine (3.96g) were slowly added to it. The reaction mixture was stirred at about 25-35°C for about 4 hours. After completion of reaction and followed by work-up, the product 6-fluoro-3-oxo-3,4- dihydro-pyrazine2-carbonitrile was then converted to favipiravir using hydrogen peroxide.

Claims

Claims:

1. A process for the preparation of favipiravir, a compound of formula I or salt thereof,

the process comprising:

2. The process of claim 1, wherein the metal element is selected from alkali metal, alkaline earth metal and transition metal.

3. The process of claim 1, wherein the inorganic base in step (a) is selected from the group consisting of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali and alkaline earth metal bicarbonates, transition metal hydroxides and transition metal carbonate, ammonia, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate.

4. The process of claim 1, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.

5. The process of claim 1, wherein in step (b), the hydrolyzing agent is hydrogen peroxide, organic or inorganic acid, organic or inorganic base.

6. A process for the preparation of salt of favipiravir, the process comprising: (a) reacting favipiravir, a compound of formula I, with organic base or inorganic base in presence of a solvent to form a reaction mixture;

(c) isolating the salt of favipiravir with organic base or inorganic base.

7. The process of claim 6, wherein the organic base in step (a) is selected from the group consisting of dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, dibenzylamine, N-benzylmethylamine, dicyclohexylamine, cyclopropylamine, methylamine, ethylamine, propylamine, butylamine, benzylamine, aniline, pyridine, trimethylamine, triethylamine, tripropylamine, tributylamine, trioctylamine, tribenzylamine, N,N- dimethylcyclohexylamine, diisopropylethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, piperazine, picoline, quinolone, N-methyl-di- isopropylamine, l,4-diazabicyclo(2.2.2)octane (DABCO), l,5-diazabicyclo(4.3.0)non-5- ene (DBN), l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N-methylpyrrolidine, N- methylpiperidine, N- methylmorpholine, N,N-dimethylpiperazine, pentamethyl guanidine, 2,6-lutidine, 2,4,6-collidine.

8. The process of claim 6, wherein the inorganic base in step (a) is selected from the group consisting of potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate, lithium carbonate, ammonium carbonate, ammonium bicarbonate, potassium bicarbonate and lithium bicarbonate.

9. The process of claim 6, wherein in step (b), the salt of favipiravir is obtained from the reaction mixture of step (a), the process comprising:

(i) optionally cooling, and stirring the mixture obtained in (a); or

(ii) removing the solvent from the mixture obtained in (a); or

10. A process for the preparation of salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile, a compound of formula IV,

wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation; the process comprising:

(a) reacting 6-fluoro-3 -hydroxy -2-pyrazinecarbonitrile, a compound of formula III;

with inorganic base in presence of a solvent to form a reaction mixture;

11. The process of claim 10, wherein the inorganic base in step (a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, ammonium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate and lithium bicarbonate.

12. The process of claim 10, wherein in step (b), the salt of 6-fluoro-3-hydroxy-2- pyrazinecarbonitrile is obtained from the reaction mixture of step (a), the process comprising:

(i) optionally cooling, and stirring the mixture obtained in (a); or (ii) removing the solvent from the mixture obtained in (a); or

13. A process for the preparation of salt of 6-bromo-3-hydroxypyrazine-2- carboxamide, a compound of formula VIII,

14. The process of claim 13, wherein the inorganic base in step (a) is selected from the group consisting of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali and alkaline earth metal bicarbonates, transition metal hydroxides, transition metal carbonates, ammonium hydroxide, ammonium carbonate and ammonium bicarbonate.

15. The process of claim 13, wherein the organic base in step (a) is a formula of NR1R2R3; wherein Rl, R2, R3 may be independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C18 aryl, optionally substituted with -OH, orRl may be H and R2 and R3 together with the nitrogen atom to which they are attached forms a 4-8 membered heterocyclic ring which may be optionally substituted.

16. The process of claim 13, wherein in step (b), the salt of 6-bromo-3- hydroxypyrazine-2-carboxamide is obtained from the reaction mixture of step (a), the process comprising:

(i) optionally cooling, and stirring the mixture obtained in (a); or

(ii) removing the solvent from the mixture obtained in (a); or

17. Salt of favipiravir with an organic base or an inorganic base; wherein the salt of favipiravir with organic base is selected from the group consisting of cyclopropylamine salt of favipiravir, diisopropylamine salt of favipiravir, diisobutylamine salt of favipiravir, diethylamine salt of favipiravir and dicyclohexylamine salt of favipiravir; and wherein the salt of favipiravir with inorganic base is selected from the group consisting of potassium salt of favipiravir and lithium salt of favipiravir.

18. Salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV,

wherein M⁺ is a cation capable of forming a salt from a metal element or ammonium cation.

19. The salt of claim 18, wherein the metal element is selected from alkali metal, alkaline earth metal and transition metal.

20. Salt of 6-bromo-3-hydroxypyrazine-2-carboxamide, the compound of formula VIII.

wherein X⁺ is a cation capable of forming a salt from a metal element or ammonium cation or organic base.

21. The salt of claim 20, wherein metal element is selected from alkali metal, alkaline earth metal and transition metal.

22. The salt of claim 21, wherein the organic base is a formula of NR1R2R3; wherein Rl, R2, R3 may be independently selected from the group consisting of H, C1-C6 alkyl, C3- C6 cycloalkyl, C6-C18 aryl, optionally substituted with -OH, or Rl may be H and R2 and R3 together with the nitrogen atom to which they are attached forms a 4-8 membered heterocyclic ring which may be optionally substituted.

23. A process for the preparation of favipiravir, a compound of formula I,

I, comprising the steps of:

(a) reacting 6-bromo-3-hydroxypyrazine-2-carboxamide, a compound of formula VII,

VII, with an inorganic base or organic base to obtain the salt of 6-bromo-3-hydroxypyrazine- 2 carboxamide, a compound of formula VIII

wherein X⁺ is a cation capable of forming a salt from a metal element, ammonium cation or an organic base;

(c) reacting 3,6-dichloro-2-pyrazinecarbonitrile, the compound of formula VI with a fluorinating agent to obtain 3,6-difluoro-2-pyrazinecarbonitrile, a compound of formula

V,

(e) reacting 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, the compound of formula III with an inorganic base to give salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula IV,