DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF FAVIPIRAVIR”

Glenmark Life Sciences Limited,
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.


FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Favipiravir, also known as, 6-fluoro-3-hydroxypyrazine-2-carboxamide, is represented by the structure of formula I.
I III
6-Fluoro-3-hydroxy-2-pyrazinecarbonitrile, a compound of formula III, is one of the key intermediates in the preparation of favipiravir.
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.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of favipiravir, a compound of formula I and salts thereof.
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.
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.
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,
(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,
(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

VII VIII VI V IV
(f) hydrolyzing the compound of formula IV with a hydrolyzing agent to give favipiravir, the compound of formula I.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is characteristic XRPD of sodium salt of 3-hydroxy-6-fluoro-2-pyrazinecarbonitrile as obtained in Example 9.
Figure 2 is characteristic XRPD of potassium salt of 3-hydroxy-6-fluoro-2-pyrazinecarbonitrile as obtained in Example 10.
DETAILED DESCRIPTION OF THE INVENTION
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.
In one embodiment, the metal element is selected from alkali metal, alkaline earth metal and transition metal.
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.
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.
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.
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.
In one embodiment, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.
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.
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.
In one embodiment, in step (b), the hydrolyzing agent is selected from hydrogen peroxide, organic or inorganic acid, organic or inorganic base.
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.
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.
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.
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, 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.
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.
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.
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.
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.
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.
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.
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.
In one embodiment, the anti-solvent is selected such that the salt of favipiravir is precipitated out from the solution.
In one embodiment, the anti-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.
In one embodiment, 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.
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.
In one 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.
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.
In one embodiment, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.
In one embodiment, the esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides are as discussed supra.
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.
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
(iii) treating the mixture of step (a) with an anti-solvent, optionally cooling and stirring the obtained mixture.
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.
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.
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.
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.
In one embodiment, the anti-solvent is as discussed supra.
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.
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.
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.
In one embodiment, the organic base in step (a) is a formula of NR1R2R3; wherein R1, 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 R1 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.
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.
In one embodiment, wherein in step (a), the solvent is selected from esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides, water, or mixtures thereof.
In one embodiment, the esters, hydrocarbons, ethers, ketones, alcohols, haloalkanes, amides, sulfoxides are as discussed supra.
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
(iii) treating the mixture of step (a) with an anti-solvent, optionally cooling and stirring the obtained mixture.
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.
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.
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.
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.
In one embodiment, the anti-solvent is as discussed supra.
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.
In one embodiment, the sodium salt of 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with a chlorinating agent to obtain 3,6-dichloro-2-pyrazinecarbonitrile.
In one embodiment, the potassium salt of 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with a chlorinating agent to obtain 3,6-dichloro-2-pyrazinecarbonitrile.
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.
In one embodiment, the chlorinating agent includes but is not limited to chlorine, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, or mixtures thereof.
In one embodiment, the reaction is carried out in presence or absence of solvent.
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.
In one embodiment, the base selected is triethylamine, diisopropylethylamine.
In one embodiment, the chlorination is carried out with a chlorinating agent in presence of a base and absence of solvent.
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.
In one embodiment, the chlorinating agent is as discussed supra.
In one embodiment, the chlorinating agent in step (a) is phosphorus oxychloride.
In one embodiment, in step (a), the reaction is carried out in presence or absence of solvent.
In one embodiment, the solvent includes but is not limited to ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-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.
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.
In one embodiment, the base selected is triethylamine.
In one embodiment, the base selected is diisopropylethylamine.
In one embodiment, in step (a), the chlorination is carried out with a chlorinating agent in presence of a base and absence of solvent.
In one embodiment, the 3,6-dichloro-2-pyrazinecarbonitrile obtained in step (a) is not isolated and carried forward for further reaction.
In one embodiment, the fluorinating agent includes but is not limited to fluorine gas, potassium fluoride, tetrabutylammonium 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.
In one embodiment, in step (b), the fluorinating agent is potassium fluoride.
In one embodiment, the reaction in step (b) is carried out in presence of a solvent.
In one embodiment, the solvent includes but is not limited to ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-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.
In one embodiment, the step (b) is carried out without using any additional additive.
In one embodiment, the 3,6-difluoro-2-pyrazinecarbonitrile obtained in step (b) is not isolated and carried forward for further reaction.
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.
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.
In one embodiment, the reaction may be carried out in presence of water.
In one embodiment, the reaction may be carried out in presence of organic solvent.
In one embodiment, the reaction may be carried out in absence of water.
In one embodiment, the reaction may be carried out in presence of organic solvent and absence of water.
The product obtained may include the tautomer 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile.
In one embodiment, the product obtained after treatment with base is subjected to workup. The workup may comprise treating with base like ammonia with optional use of water and charcoalization followed by filtration. 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.
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.
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;
(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,
(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,
(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 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;
(f) hydrolyzing the compound of formula IV with a hydrolyzing agent to give favipiravir, the compound of formula I.
In one embodiment, the steps (a) to (f) are carried out as discussed supra.
In one embodiment, the favipiravir is obtained in a purity of =99.0%.
In one embodiment, the favipiravir is obtained in a purity of =99.9%.
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
EXAMPLE 1: 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; 1H NMR: d 10.90 (brs, 1H), 7.83-7.81 (d, 1H), 6.98 (brs, 1H); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
9.38 9.42 42.54 27.23 3.27 100.00
12.93 6.84 5.17 27.62 3.22 7.58
13.53 6.54 58.37 28.30 3.15 26.96
14.64 6.04 39.05 30.25 2.95 10.71
15.01 5.89 85.42 30.62 2.91 5.72
18.79 4.72 8.12 31.16 2.86 4.52
20.71 4.28 1.22 32.07 2.79 0.73
21.37 4.15 3.09 33.28 2.69 34.99
23.80 3.73 15.76 34.30 2.61 3.77
25.93 3.43 6.53 34.83 2.57 7.54
26.30 3.38 4.14 36.70 2.44 11.19

EXAMPLE 2: 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%; 1H NMR: d 9.89 (brs, 1H), 7.92-7.90 (d, 1H), 7.13 (brs, 1H); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.84 12.91 3.32 24.25 3.66 53.41
10.87 8.13 0.54 24.37 3.65 44.35
11.86 7.45 46.76 25.70 3.46 29.94
12.10 7.31 100.00 27.05 3.29 2.93
12.26 7.21 56.51 29.34 3.04 5.18
13.38 6.61 27.14 30.28 2.95 2.46
13.62 6.50 54.89 31.56 2.83 6.48
15.66 5.65 20.23 34.69 2.58 14.11
18.17 4.88 0.62 35.10 2.55 48.64
20.92 4.24 4.42 36.68 2.44 51.46
22.68 3.91 15.26 36.77 2.44 49.74
23.11 3.84 85.67 37.19 2.41 12.52
EXAMPLE 3: 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: 10g (92.8%); HPLC Purity: 99.96%; Water Content: 0.45%; DSC (°C): Endo 184.63, Exo 213.23; TGA (%): 0-50°C = 0.0908, 50-100°C = 0.780, 100-150°C = 11.15; 1H NMR: 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)
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
4.88 18.10 5.86 16.34 5.42 58.83
6.02 14.66 4.97 17.10 5.18 9.89
7.04 12.54 5.93 17.54 5.05 15.13
8.73 10.12 4.96 18.07 4.90 17.47
10.38 8.51 11.57 18.80 4.71 75.55
11.01 8.03 24.14 19.34 4.58 31.87
11.45 7.72 18.45 20.05 4.42 100.00
12.08 7.32 46.63 20.90 4.24 29.73
12.73 6.95 71.45 21.29 4.17 14.18
13.28 6.66 15.31 22.11 4.01 14.90
14.28 6.20 8.87 22.78 3.90 7.62
14.44 6.13 15.85 23.69 3.75 22.81
15.11 5.86 38.83 24.17 3.68 12.84
15.81 5.60 18.89 24.83 3.58 19.93

EXAMPLE 4: 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; 1H NMR: 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); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.55 13.48 0.64 19.84 4.47 7.19
8.07 10.94 2.03 20.32 4.36 35.62
10.10 8.75 2.19 20.71 4.28 20.78
11.62 7.61 2.53 21.09 4.21 4.50
11.94 7.41 2.37 21.60 4.11 2.54
13.17 6.71 100.00 22.76 3.90 2.46
13.93 6.35 1.55 23.45 3.79 8.28
14.38 6.15 0.96 23.81 3.73 6.56
15.88 5.57 49.90 24.13 3.68 5.69
16.13 5.49 14.55 25.07 3.55 10.44
17.35 5.11 3.94 25.64 3.47 18.23
17.92 4.94 5.23 25.93 3.43 13.59
18.62 4.76 32.27 26.13 3.40 9.21

EXAMPLE 5: 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; 1H 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); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
10.75 8.22 32.44 21.68 4.09 8.36
11.83 7.47 2.34 23.08 3.85 10.10
13.04 6.78 13.62 24.00 3.70 55.63
13.86 6.38 52.88 24.71 3.60 10.99
14.79 5.98 10.21 25.95 3.43 14.48
16.18 5.47 2.87 27.04 3.29 1.99
16.54 5.35 1.17 27.74 3.21 10.21
17.97 4.93 100.00 27.94 3.19 12.33
19.09 4.64 6.81 28.72 3.10 19.16
19.69 4.50 3.27 29.89 2.98 2.86
20.33 4.36 18.44 30.55 2.92 11.91
20.67 4.29 3.56 31.91 2.80 13.42

EXAMPLE 6: 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; 1H NMR: 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); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
8.53 10.36 0.34 21.93 4.05 15.62
11.56 7.65 3.37 22.21 4.00 3.97
12.97 6.82 100.00 22.99 3.86 3.82
13.31 6.65 14.77 23.27 3.82 2.57
15.91 5.56 0.72 24.14 3.68 2.86
17.40 5.09 7.63 24.49 3.63 3.07
18.48 4.79 4.60 24.84 3.58 2.14
20.40 4.35 12.94 26.11 3.41 18.86
20.97 4.23 8.61 26.72 3.33 1.37

EXAMPLE 7: 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%; 1H NMR: 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); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.10 14.47 0.47 18.83 4.71 43.97
8.38 10.54 1.06 19.78 4.48 2.68
9.37 9.43 100.00 20.37 4.35 4.24
10.90 8.11 0.50 21.24 4.18 1.86
11.96 7.39 6.93 22.05 4.02 1.35
12.27 7.21 1.42 22.91 3.88 1.12
12.64 6.99 1.41 24.06 3.69 3.20
13.09 6.76 7.57 24.65 3.61 15.18
13.30 6.65 9.61 25.18 3.53 12.02
13.85 6.38 5.08 25.89 3.44 6.41
14.49 6.10 9.48 26.16 3.40 8.51
14.84 5.96 6.69 26.51 3.36 12.38
15.45 5.73 2.68 26.87 3.31 11.75
16.21 5.46 0.47 27.23 3.27 6.00
16.80 5.27 1.22 27.89 3.19 9.71
17.65 5.02 2.49 28.42 3.14 41.47
17.99 4.92 2.30 29.69 3.00 3.70

EXAMPLE 8: Preparation of 3-hydroxy-6-fluoro-2-pyrazinecarbonitrile
A mixture of 3,6-dichloro-2-pyrazinecarbonitrile (10g) and anhydrous potassium fluoride (10.01g) 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 1h 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 1h at about room temperature and then charged with ethyl acetate (100mL) and water (50mL). The pH of the reaction mixture was adjusted to about 1.5 using conc. HCl 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
EXAMPLE 9: 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 1h. 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; 1H NMR: d 8.00-7.98 (d, 1H); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
10.77 8.21 76.59 23.86 3.73 3.03
11.12 7.96 100 25.42 3.50 2.6
12.81 6.91 25.8 26.23 3.40 4.06
12.96 6.83 19.16 27.23 3.28 2.47
15.55 5.70 2.92 28.48 3.13 11.08
18.62 4.76 1.79 29.03 3.08 1.95
18.97 4.68 1.45 30.03 2.98 1.5
20.44 4.35 10.91 30.54 2.93 3.06
20.86 4.26 2.9 31.30 2.86 2.97
21.24 4.18 10.94 31.63 2.83 2.32
21.61 4.11 14.19 32.20 2.78 2.25
22.27 3.99 22.95 34.37 2.61 19.8
23.40 3.80 4.13 35.21 2.55 15.37

EXAMPLE 10: 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 10mL 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; 1H NMR: d 7.99-7.97 (d, 1H); XRD:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
8.29 10.67 3.93 26.08 3.42 0.58
10.57 8.37 0.54 27.28 3.27 17.89
11.72 7.55 100 27.61 3.23 31.29
13.74 6.45 36.51 29.61 3.02 3.37
15.04 5.89 0.56 30.35 2.95 1.07
16.58 5.35 3.08 31.24 2.86 0.62
19.88 4.47 37.63 31.98 2.80 0.67
21.96 4.05 22.13 32.45 2.76 1.03
22.35 3.98 28.07 33.44 2.68 37.2
23.49 3.79 9.87 33.75 2.65 2.36
24.30 3.66 0.83 34.26 2.62 0.96
24.93 3.57 6.78 35.53 2.52 56.15
25.28 3.52 10.53 36.17 2.48 0.89

EXAMPLE 11: 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%; 1HNMR: d 10.49 (brs, 1H), 7.89 (s,1H), 7.15 (brs, 1H)
EXAMPLE 12: Preparation of potassium salt of 6-bromo-3-hydroxy-2-pyrazinecarboxamide
A suspension of 6-bromo-3-hydroxy-2-pyrazinecarboxamide (10g) 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: 10.1g (85%); 1H NMR: d 10.58 (brs, 1H), 7.86 (s, 1H), 7.05 (brs, 1H).
EXAMPLE 13: 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)
EXAMPLE 14: 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%; 1H 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)
EXAMPLE 15: 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.
EXAMPLE 16: Preparation of 3,6-dichloro-2-pyrazinecarbonitrile
6-Bromo-3-hydroxy-2-pyrazinecarboxamide sodium salt (10g) 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. HCl (10 mL) solution and dried with sodium sulphate. Organic layer was distilled under reduced pressure to obtain pale yellow solid. Yield: 4.2g.
EXAMPLE 17: 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.
EXAMPLE 18: 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.
EXAMPLE 19: 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 1h 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 1h. The solid was filtered and washed with water. Yield: 2.0g. (41.0%), Purity: 99.78%, 1H-NMR (DMSO-d6) d values: 8.50 - 8.51 (2H, d), 8.75 (1H, s), 13.41 (1H, s).
EXAMPLE 20: Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
To the solution of sodium hydroxide (4.31g) in water (100mL), 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile (10g) 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 1h.The solid was filtered and washed with water and IPA. Yield: 4.90g
EXAMPLE 21: Preparation of Favipiravir
A mixture of 6-bromo-3-hydroxypyrazine-2-carboxamide (10g) 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

,CLAIMS:WE CLAIM
1. A process for the preparation of favipiravir, a compound of formula I or salt thereof, the process comprising:
I
(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;
III IV
(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.
2. The process as claimed in 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.
3. The process as claimed in claim 1, wherein in step (b), the hydrolyzing agent is hydrogen peroxide, organic or inorganic acid, organic or inorganic base.
4. 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.
5. The process as claimed in claim 4, 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, 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 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.
6. 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;
(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.
7. The process as claimed in claim 6, 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.
8. 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:
VIII VII
(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.
9. The process as claimed in claim 8, 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; and wherein the organic base in step (a) is a formula of NR1R2R3; wherein R1, 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 R1 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.
10. 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 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;
(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 V
(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,
(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 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.