The present invention relates to an organic amine salt of Favipiravir. Further, the present
invention also relates to a process for the purification of Favipiravir.
BACKGROUND OF INVENTION:
Favipiravir is an anti-viral agent that selectively and potently inhibits the viral RNA-dependent
RNA polymerase (RdRp). It is known under the chemical name 6-fluoro-3-hydroxy-2-
pyrazinecarboxamide. Favipiravir is a compound which is useful for the treatment, such as
prevention or therapy, of a viral infection or, particularly, an influenza viral infection. Favipiravir
and a process for its preparation were first disclosed in WO2000010569.
There are several processes disclosed in the prior art for the synthesis of Favipiravir, for instance
in WO2001060834, WO2000010569 and US8835636B2.
The drawback of these processes is that the purity of the obtained Favipiravir is not satisfactory,
and for this reason a series of purification steps are required to provide a product which meets
the high quality requirements for pharmaceutical active ingredients. Further, after the long and
complex reaction sequence for the preparation of Favipiravir, a column purification is required,
and therefore the overall yield of this multistep reaction is relatively low. Also, in some of the
described processes for the preparation of Favipiravir mentioned in the prior art, it is not easy to
isolate pure Favipiravir in high yield by a simple operation, even more since this compound is
soluble in water.
Therefore, there is a need for a simple, cost-effective process which allows the preparation of
highly pure Favipiravir. Accordingly, the inventors of the present invention have developed a
process for the purification of Favipiravir that affords highly pure Favipiravir for further
pharmaceutical use.
It has now been surprisingly found that the conversion of Favipiravir with an organic amine,
results in the formation of a salt that allows a considerable decrease in the amount of impurities.
More specifically, the inventors of the present invention have found that crude Favipiravir can be
converted to an organic amine salt when reacted with an organic amine. Following this
3

procedure mostly all of the unknown impurities can be removed and the resulting Favipiravir is
obtained in more than 99.6 % purity.
OBJECTIVE OF INVENTION:
The main objective of the present invention is to provide an organic amine salt of Favipiravir.
Another objective of the present invention is to provide a process for the purification of
Favipiravir.
SUMMARY OF INVENTION:
Accordingly, the present invention provides an organic amine salt of Favipiravir.
In one embodiment, the present invention provides a process for the purification of Favipiravir
comprising the steps of:
a) treating crude Favipiravir with a suitable organic amine in the presence of a suitable solvent
to form a corresponding organic amine salt of Favipiravir;
b) isolating the organic amine salt of Favipiravir;
c) treating the organic amine salt of Favipiravir of step (b) with a suitable acid to afford highly
pure Favipiravir.
The organic amine is selected from tertiary amines such as trimethylamine, triethylamine,
tripropylamine, tributylamine, tribenzylamine and N,N-dimethylcyclohexylamine; secondary
amines such as dioctylamine, diheptylamine, morpholine, dimethylamine, diethylamine,
dipropylamine, dibutylamine, dibenzylamine, N-benzylmethylamine and dicyclohexylamine;
primary amines such as methylamine, ethylamine, propylamine, butylamine, benzylamine,
aniline, pyrrolidine, pyridine; and the like.
In a preferred embodiment, the organic amine is selected from dioctylamine, diheptylamine,
morpholine, dimethylamine, diethylamine, dipropylamine, dibutylamine, dibenzylamine, Nbenzylmethylamine
and dicyclohexylamine.
4

The suitable solvent is selected from aliphatic, alicyclic or aromatic halogenated hydrocarbons
such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane,
dichloroethane or trichloroethane; aromatic hydrocarbon like toluene; ethers such as diethylether,
diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-
dimethoxy ethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or
iso-butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, ?,?-
dimethylacetamide, N-methyl formanilide, N-methylpyrrolidone or hexamethylphosphoric
triamide; sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane; alcohols such as
methanol, ethanol, isopropanol, polyethylene glycols; ketones like acetone; water, or mixtures
thereof.
The suitable acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid
and the like.
The purity of the crude Favipiravir is in the range of 95 to 99 %.
The purity of the obtained purified Favipiravir is in the range of 99.5 to 99.9 %.
DECRIPTION OF FIGURES:
Figure 1: DSC of dicyclohexylamine salt of Favipiravir
Figure 2: DSC of morpholine salt of Favipiravir
DETAILED DESCRIPTION OF THE INVENTION:
The definitions provided herein for the terminologies used in the present disclosure are for
illustrative purpose only and in no manner limit the scope of the present invention disclosed in
the present disclosure.
As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”,
“contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover
a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a
composition, mixture, process or method that comprises a list of elements is not necessarily
limited to only those elements but may include other elements not expressly listed or inherent to
such composition, mixture, process or method.
5

The invention will now be described in detail in connection with certain preferred and optional
embodiments, so that various aspects thereof may be more fully understood and appreciated.
In accordance with the above defined objectives, the present invention provides an organic amine
salt of Favipiravir.
The organic amine salt of the Favipiravir can be produced by subjecting Favipiravir to a reaction
with an organic amine. This reaction is usually carried out in the presence of a suitable solvent.
All types of solvents can be used for the reaction provided that their presence is not detrimental
to the reaction in any way.
In a preferred embodiment, the present invention provides a dicyclohexylamine salt of
Favipiravir.
In another preferred embodiment, the present invention provides a morpholine salt of
Favipiravir.
In one embodiment, the present invention provides a process for the synthesis of an organic
amine salt of Favipiravir, which comprises treating Favipiravir with a suitable organic amine, in
the presence of a suitable solvent to afford an organic amine salt of Favipiravir.
In one embodiment, the present invention provides a process for the purification of Favipiravir
comprising the steps of:
a) treating crude Favipiravir with a suitable organic amine in the presence of a suitable solvent
to form a corresponding organic amine salt of Favipiravir;
b) isolating the organic amine salt of Favipiravir;
c) treating the organic amine salt of Favipiravir of step (b) with a suitable acid to afford highly
pure Favipiravir, wherein the purity of the obtained purified Favipiravir is in the range of
99.5 to 99.9 %.
The suitable organic amine is selected from tertiary amines such as trimethylamine,
triethylamine, tripropylamine, tributylamine, tribenzylamine and N,N-dimethylcyclohexylamine;
secondary amines such as dioctylamine, diheptylamine, morpholine, dimethylamine,
diethylamine, dipropylamine, dibutylamine, dibenzylamine, N-benzylmethylamine and
6

dicyclohexylamine; primary amines such as methylamine, ethylamine, propylamine, butylamine,
benzylamine, aniline, pyrrolidine, pyridine; and the like.
The suitable acid as used in present invention is selected from hydrochloric acid, sulfuric acid,
phosphoric acid and nitric acid.
The suitable solvents as used in any of the process steps of the present invention are selected
from, but are not limited to aliphatic, alicyclic or aromatic halogenated hydrocarbons such as
chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane,
dichloroethane or trichloroethane; aromatic hydrocarbon like toluene; ethers such as diethylether,
diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-
dimethoxy ethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or
iso-butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, ?,?-
dimethylacetamide, N-methyl formanilide, N-methylpyrrolidone or hexamethylphosphoric
triamide; sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane; alcohols such as
methanol, ethanol, isopropanol, polyethylene glycols; ketones like acetone; water, or mixtures
thereof.
In one embodiment, the present invention provides a process for the purification of Favipiravir
which comprises converting the crude Favipiravir into a salt with an organic amine followed by
treatment with a suitable acid to afford highly pure Favipiravir.
In a preferred embodiment, the present invention provides a process for the purification of
Favipiravir which comprises converting the crude Favipiravir into a salt with dicyclohexylamine
followed by treatment with a suitable acid to afford highly pure Favipiravir.
For the extraction of the dicyclohexylamine salt of Favipiravir, the pH of the reaction mixture
may be adjusted to 8 to 11, e.g. = 9, such as 9 to 11, e.g. 10 to 11, e.g. by use of a base,
preferably by an inorganic base, such as e.g. an alkali, e.g. a sodium and potassium or earth
alkali hydroxide and carbonate, preferably a hydroxide. The dicyclohexylamine salt of
Favipiravir may be extracted into an organic solvent which is able to form a two-phase system
with water and which is able to dissolve dicyclohexylamine, e.g. partially, in a two-phase system
with water, including e.g. a halogenated hydrocarbon, such as methylene chloride, a ketone, such
7

as methyl isobutylketone and an ester of a carboxylic acid, such as ethyl acetate, isopropyl
acetate, n-butyl acetate or aromatic hydrocarbon such as toluene. Water may be added to the
reaction mixture, if not present in an amount sufficient to form a two phase system in the
reaction mixture.
According to one aspect of the present invention, the present invention provides the use of
Favipiravir in the form of a salt with an organic amine for the purification of a mixture of
Favipiravir with impurities.
According to another aspect of the present invention, the present invention provides the use of
Favipiravir in the form of a salt with dicyclohexylamine for the purification of a mixture of
Favipiravir with impurities.
According to yet another aspect of the present invention, the present invention provides the use
of Favipiravir in the form of a salt with morpholine for the purification of a mixture of
Favipiravir with impurities.
The purity of the crude Favipiravir is in the range of 95 to 99 %.
The invention is further illustrated with reference to the following examples. It is apparent to
those skilled in the art that many modifications, both to materials and methods, may be practiced
without departing from the scope of the invention. The starting materials according to the present
invention are known compounds that are commercially available or can be prepared in a known
manner.
Following examples are given by way of illustration and therefore should not be construed to
limit the scope of the invention.
Example 1: Synthesis of a dicyclohexylamine salt of Favipiravir:
Crude 6-fluoro-3-hydroxypyrazine-2-carboxamide (15.7 g) (purity: 99.36 %) was dissolved in
acetone (75 g) at 20-25 oC. To this solution, dicyclohexylamine (19.9 g) was added at 25 oC
during 30 minutes. The precipitated solid was filtered, washed with acetone (10 g) and dried to
obtain the Favipiravir dicyclohexylamine salt (28.7 g; purity 99.69 %; yield: 89.9 % with respect
to initial crude Favipiravir).
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Characterization data of the Favipiravir dicyclohexylamine salt: 1H NMR (400 MHz,
DMSO-d6): d 10.52 (s, 1H), 8.46 (broad, 1H), 7.91-7.93 (s,1H), 7.26 (s, 1H), 3.06-3.07 (m,
2H),1.96-1.98 (m, 4H),1.69-1.73 (m, 4H),1.58-1.61 (m, 2H),1.19-1.25 (m, 8H),1.06-1.08 (m,
2H); MP 184.12 °C, Decomposition temperature 215.56 °C.
crude Favipiravir dicyclohexyl amine Favipiravir salt
% purity 99.36 % 99.69 %
Impurity at RRT
0.428
0.411 % 0.008 %
Example 2: Synthesis of a morpholine salt of Favipiravir:
Crude 6-fluoro-3-hydroxypyrazine-2-carboxamide (15.7 g) (purity: 95-99 %) was dissolved in
acetone (75 g) at 20-25 oC. To this solution, morpholine (12 g) was added at 25 oC during 30
minutes. The precipitated solid was filtered and washed with acetone (20 g) and dried to give the
Favipiravir morpholine salt (21 g; purity 99.7 %; yield: 93 % w.r.t. initial crude favipiravir).
Example 3: Purification of crude Favipiravir by using dicyclohexylamine salt:
Crude 6-fluoro-3-hydroxypyrazine-2-carboxamide (15.7 g) (purity: 99.36 %) was dissolved in
acetone (75 g) at 20-25 oC. To this solution, dicyclohexylamine (21.85 g) was added at 25 oC
during 30 minutes. The precipitated solid was filtered and washed with acetone (20 g) and dried
to obtain the Favipiravir dicyclohexylamine salt (30.5 g). The obtained salt was charged in water
(60 g) and basified with sodium hydroxide to pH 13-14 followed by washing with toluene (200
g) and the toluene layer was separated. The aqueous layer was slowly acidified with 20 %
sulfuric acid to pH 2.0 to 2.5 to obtain a solid which was filtered, washed with water and dried to
obtain pure 6-fluoro-3-hydroxypyrazine-2-carboxamide (13.85 g) (purity: 99.69 %; 88 % yield
with respect to initial crude).
Characterization data of 6-fluoro-3-hydroxypyrazine-2-carboxamide: 1H NMR (400 MHz,
DMSO-d6): d 13.41 (bs, 1H), 8.75 (bs, 1H), 8.52 (bs, 1H), 8.50 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 168.78, 159.80, 152.19, 135.96, 127.39; M/Z= 158.0 M+1; IR: 3348.98 (OH),
9

3219.15 ( NH), 1672.87 ( C=O), 1560.83 ( C=C), 1439.43 (NH), 1265.67 (C=N), 1231.64 ( CF),
1187.23 ( CO), 929.02 ( CH).
crude
Favipiravir
dicyclohexyl amine
Favipiravir salt
final Favipiravir after
salt breaking
% purity 99.36 % 99.69 % 99.69 %
Impurity at RRT
0.428
0.411 % 0.008 % Not detected on HPLC
Example 4: Purification of crude Favipiravir by using morpholine salt:
Crude 6-fluoro-3-hydroxypyrazine-2-carboxamide (15.7 g) (purity: 95-99 %) was dissolved in
acetone (75 g) at 20-25 oC. To this solution, morpholine (10.44 g) was added at 25 oC during 30
minutes. The precipitated solid was filtered, washed with acetone (20 g) and dried to obtain the
Favipiravir morpholine salt (21.4 g). The obtained salt was charged in water (60 g), basified by
sodium hydroxide to pH 13-14 and washed with toluene (200 g) and the toluene layer was
separated. The aqueous layer was then slowly acidified with 20 % sulfuric acid to pH 2.0 to 2.5
to obtain a solid which was filtered and washed with water and dried to obtain pure 6-fluoro-3-
hydroxypyrazine-2-carboxamide (14.60 g) (93 % yield with respect to initial crude) (purity:
>99.7 %).
Characterization data of 6-fluoro-3-hydroxypyrazine-2-carboxamide: 1H NMR (400 MHz,
DMSO-d6): d 13.41 (bs, 1H), 8.75 (bs, 1H), 8.52 (bs, 1H), 8.50 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 168.78, 159.80, 152.19, 135.96, 127.39; M/Z= 158.0 M+1; IR: 3348.98 (OH),
3219.15 ( NH), 1672.87 ( C=O), 1560.83 ( C=C), 1439.43 (NH), 1265.67 (C=N), 1231.64 ( CF),
1187.23 ( CO), 929.02 ( CH).
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WE CLAIM:

1) An organic amine salt of Favipiravir.
2) The organic amine salt of Favipiravir as claimed in claim 1, wherein said organic amine salt
is a dicyclohexylamine salt of Favipiravir or a morpholine salt of Favipiravir.
3) A process for the purification of Favipiravir comprising the steps of:
a) treating crude Favipiravir with a suitable organic amine in the presence of a suitable
solvent to form a corresponding organic amine salt of Favipiravir;
b) isolating the organic amine salt of Favipiravir;
c) treating the organic amine salt of Favipiravir of step (b) with a suitable acid to afford
highly pure Favipiravir.
4) The process for the purification of Favipiravir as claimed in claim 3, wherein said organic
amine is selected from tertiary amines like trimethylamine, triethylamine, tripropylamine,
tributylamine, tribenzylamine and N,N-dimethylcyclohexylamine; secondary amines like
dioctylamine, diheptylamine, morpholine, dimethylamine, diethylamine, dipropylamine,
dibutylamine, dibenzylamine, N-benzylmethylamine and dicyclohexylamine; primary amines
like methylamine, ethylamine, propylamine, butylamine, benzylamine, aniline, pyrrolidine,
pyridine; and the like.
5) The process for the purification of Favipiravir as claimed in claim 4, wherein the said organic
amine is selected from dioctylamine, diheptylamine, morpholine, dimethylamine,
diethylamine, dipropylamine, dibutylamine, dibenzylamine, N-benzylmethylamine,
dicyclohexylamine and the like.
6) The process for the purification of Favipiravir as claimed in claim 3, wherein said suitable
solvent is selected from aliphatic, alicyclic or aromatic halogenated hydrocarbons selected
from chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane,
dichloroethane or trichloroethane; aromatic hydrocarbon like toluene; ethers selected from
diethylether, diisopropylether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane,
tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxyethane or anisole; nitriles selected from
acetonitrile, propionitrile, n- or iso-butyronitrile or benzonitrile; amides selected from N,Ndimethylformamide,
?,?-dimethylacetamide, N-methyl formanilide, N-methylpyrrolidone or
hexamethylphosphoric triamide; sulfoxides selected from dimethyl sulfoxide or sulfones like
11

sulfolane; alcohols selected from methanol, ethanol, isopropanol, polyethylene glycols;
ketones like acetone; water, or mixtures thereof.
7) The process for the purification of Favipiravir as claimed in claim 3, wherein said suitable
acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the
like.
8) The process for purification of Favipiravir as claimed in claim 3, wherein purity of the crude
Favipiravir is in the range of 95 to 99 %.
9) The process for purification of Favipiravir as claimed in claim 3, wherein purity of the
obtained purified Favipiravir is in the range of 99.5 to 99.9 %.