DESC:F O R M 2

THE PATENTS ACT, 1970 (SECTION 39 of 1970)

COMPLETE SPECIFICATION
(Section 10)

“NOVEL SYNTHESIS OF FAVIPIRAVIRAND ITS INTERMEDIATE”

OPTIMUS DRUGS PVT LTD

2nd Floor, Sy No. 37/A & 37/P, Plot No. 6P, Signature Towers, Kothaguda, Kondapur, Hyderabad-500084, Telangana, India

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

“NOVEL SYNTHESIS OF FAVIPIRAVIRAND ITS INTERMEDIATE”

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of Favipiravir intermediate. The present invention is also relates to an improved, commercially viable and industrially advantageous process for the preparation of highly pure Favipiravir.

BACKGROUND OF THE INVENTION

Favipiravir (T-705), chemical entitled 6- fluoro- 3- Hydroxypyrazine -2- Methanamide, is new RNA polymerase (RdRp) the inhibitor class broad-spectrum antiviral drug that RNA relies on, itself does not have antiviral activity, is existed by metabolism Favipiravir ribonucleosidetriphosphote form can be rapidly converted in vivo, by simulating guanosine triphosphate (GTP) (GTP) competitive inhibition virus The RNA polymerase that RNA relies on, suppression viral genome replicates and transcribes and play antivirus action, Favipiravir nucleoside three phosphorus Sour form also can penetrate into viral gene, plays antivirus action by inducing fatefuluemutation.Favipiravir is to A type influenza (including bird flu and influenza A H1N1 infection), virus had preferable therapeutical effect moreover it is possible to suppress the transcription of other viruses, such as Arenaviruss, yellow fever virus, west Nile viruss, Bunyavirus and hand-foot-mouth disease virus etc., nearest document report it can be effective for treatment of COVID-19.Its structural formula is as follows:

Favipiravir
Document [Furuta Y. Nitrogenous heterocyclic carboxamide derivatives or salts thereof and antiviral agents containing both: WO, 00/10569 [P]. 2003-03-02.] obtain 6-amino-3-methoxypyrazine-2-methane amide with the bromo-3-Aminopyrazine of 6--2-methyl-formiate (4) amino replacement and amidate action under diazotization alcoholysis, palladium chtalyst, replace through diazotization fluorine again, then demethylation obtained 1 under trimethylchlorosilane and sodium iodide effect, total recovery only 0.44%.Amino replacement used catalyst three (dibenzalacetone) two palladium [Pd2 (dba) 3] and (S)-(-)-2 in method, two (diphenyl phosphine)-1 of 2'-, 1'-dinaphthalene costly, and final step reaction is difficult to control, yield only has 4.3%, is unfavorable for suitability for industrialized production.
Document [Chinese Journal of Pharmaceuticals Chinese Journal of Pharmaceuticals 2013,44 (9)], with 3-Aminopyrazine-2-formic acid (2) for raw material, compound (4) is obtained through esterification, NBS bromo, compound (4) obtains the bromo-3-HYDROXYPYRAZINE of 6--2-methane amide (6) through diazotization hydrolysis, ammoniacal liquor amination, obtain 1 through phosphorus oxychloride chloro, Potassium monofluoridefluoro and hydrolysis again, total recovery is 21.8%.This reaction scheme step is longer, and yield is lower, and cost is higher.Beunfavorable for suitability for industrialized production

OBJECT OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Favipiravir and its intermediate.

In one aspect of the present invention, provides a process for the preparation of Favipiravir intermediate represented in below scheme

In another aspect of the present invention, provides a process for the preparation of Favipiravir intermediate represented in below scheme

In yet another aspect of the present invention, provides a process for the preparation of Favipiravir intermediate represented in below schemes

(i)

ii)

iii)

In yet another aspect of the present invention provides a novel intermediate of formula (II) and this key intermediate is useful for the preparation of Favipiravir.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous process of Favipiravir and its intermediate with high purity.

In one embodiment of the present invention, provides a process for the preparation of Favipiravir intermediate, comprising the steps of:

a) diethyl amino malonate hydrochloride is reacting with chloroacetyl chloride in presence of solvent and /or optionally in base to give 2-(Chloroacetylation)propanedioic Acid Diethyl Ester

b) 2-(Chloroacetylation)propanedioic Acid Diethyl Ester is treating with aqueous ammonia to give Mixture 3,6-dioxopiperazine-2-carboxamide and 3,6-dioxo-1,2,3,6-tetrahydropyrazine-2-carboxamide, and
c) Mixture 3,6-dioxopiperazine-2-carboxamide and 3,6-dioxo-1,2,3,6-tetrahydropyrazine-2-carboxamide is treating with chlorinating agent in presence or absence of solvents to give 3,6-dichloropyrazine-2-carbonitrile.
In another embodiment of the present invention, provides a process for the preparation of Favipiravir intermediate, comprising the steps of
a) ethyl 2,2-diethoxyacetate is reacting with 2-aminomalonamide in solvent, water and acid at 50 to 70 for 2 to 4 hrs,
b) followed by neutralization with aqueous ammonium hydroxide until pH >7 to get 3,6-dihydroxypyrazine-2-carboxamide and
c) isolated the pure3,6-dihydroxypyrazine-2-carboxamide

In yet another embodiment of the present invention provides a novel intermediate of formula (II) and this key intermediate is useful for the preparation of Favipiravir.

According to an embodiment of the present invention, wherein the solvent is selected from Dichloromethane, toluene, cyclohexane, methanol, diethyl ether, water, acetone, ethanol, isopropanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.
According to an embodiment of the present invention, wherein the base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, aniline, N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),5-diazabicyclo[4.3.0]non-5-ene (DBN).
According to an embodiment of the present invention, wherein the chlorinating agent is selected from phosphorus pentachloride, phosphoryl chloride, phosphorus oxychloride, thionyl chloride, aluminium chloride, methyl sulfonyl chloride, acetyl chloride, chlorine gas, phosgene, diphosgene, triphosgene, sodium hypochlorite, cyanuric chloride and N-chlorosuccinimide.
According to an embodiment of the present invention, wherein the acid is selected from acetic acid, formic acid, trifluoroacetic acid and hydrochloric acid.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:
Preparation of 2-(Chloroacetylation)propanedioic Acid Diethyl Ester.

To a mixture of diethyl amino malonate hydrochloride (30g, 140mmol) and Chloroacetyl chloride (11g, 100mmol) suspended in Dichloromethane (300ml) at 0—5°C was added slowly a solution of Triethylamine (30g, 300mmol) in Dichloromethane (100ml). After the addition was complete, the mixture was brought the boiling point and then allowed to stand overnight. Triethylamine hydrochloride was removed by ?ltration, then the ?ltrate was washed with 2% hydrochloric acid and water. It was dried with sodium sulfate, the solvent was removed in vacuum, and the resultant residue was recrystallized from cyclohexane to give 22g.

Example -2:
Preparation of Mixture 3,6-dioxopiperazine-2-carboxamide and 3,6-dioxo-1,2,3,6-tetrahydropyrazine-2-carboxamide.

To a solution of 2-(Chloroacetylation) propanedioic acid diethyl Ester (50 g,) was taken into a methanol and Aq Ammonia solution (50.0ml) the reaction mixture heated in a high pressure reactor at 50 °C overnight. After evaporation of the solvent under reduced pressure, the crude residue was precipitated in methanol. The solid was filtered and washed successively with methanol and diethyl ether to afford title compound (40 g,).

Example -3:
Preparation of 3,6-dihydroxypyrazine-2-carboxamide.

To a suspension of ethyl 2,2-diethoxyacetate (5.0g) and 2-aminomalonamide in methanol (30 ml) was added. To this reaction mass water (10.0ml) and cat. Amount of acetic acid was added. The reaction mixture was stirred at 65 °C for 3 h, then cooled down to room temperature. After neutralization with 15% NH4OH solution until pH > 7, H2O2 was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The precipitate was filtered, washed with acetone and crystallized in water to give the desired pure pyrazine compound (3.6 g).

Example -4:
Preparation of 3,6-dichloropyrazine-2-carbonitrile

50.0g compound 2 or Compound 3 was suspended in 200 ml of toluene and 140.0 g of phosphorus oxychloride was then added to the suspension. The resulting mixture was heated to 60° C., and stirred for 30 minutes at 60° C. The mixture was then stirred for a further 2.5 hours at a temperature of 90 to 100° C. Following cooling to room temperature, 50 ml of toluene was added to the reaction mixture, and a distillation was then performed under reduced pressure. The distillation was continued until no more distillate was produced, 200 ml of toluene and 100 ml of water were then added to the residue, the resulting mixture was stirred at 50° C. for 2.5 hours, and a separation was then performed. The organic layer was washed with water, washed with a 5% solution of sodium bicarbonate, and then washed with a 10% sodium chloride solution, yielding 3,6-dichloropyrazine-2-carbonitrile of 45 g.
,CLAIMS:WE CLAIM:

1. A process for the preparation of Favipiravir intermediate, comprising the steps of:
a) diethyl amino malonate hydrochloride is reacting with chloroacetyl chloride in presence of solvent and /or optionally in base to give 2-(chloroacetylation)propanedioic Acid Diethyl Ester,
b) 2-(Chloroacetylation)propanedioic Acid Diethyl Ester is treating with aqueous ammonia to give Mixture 3,6-dioxopiperazine-2-carboxamide and 3,6-dioxo-1,2,3,6-tetrahydropyrazine-2-carboxamide, and
c) Mixture 3,6-dioxopiperazine-2-carboxamide and 3,6-dioxo-1,2,3,6-tetrahydropyrazine-2-carboxamide is treating with chlorinating agents in presence or absence of solvents to give 3,6-dichloropyrazine-2-carbonitrile.
2. A process for the preparation of Favipiravir intermediate, comprising the steps of
a) ethyl 2,2-diethoxyacetate is reacting with 2-aminomalonamide in solvent, water and acid at 50 to 70 for 2 to 4 hrs,
b) followed by neutralization with aqueous ammonium hydroxide until pH >7 to get 3,6-dihydroxypyrazine-2-carboxamide and
c) isolated the pure 3,6-dihydroxypyrazine-2-carboxamide

3. A novel compound of formula (II),

4. The process as claimed in claim 1 and 2, wherein the solvent is selected from Dichloromethane, toluene, cyclohexane, methanol, diethyl ether, water, acetone, ethanol, isopropanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.

5. The process as claimed in claim 1, wherein the base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, aniline, N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),5-diazabicyclo[4.3.0]non-5-ene (DBN).

6. The process as claimed in claim 1, wherein the chlorinating agents is selected from phosphorus pentachloride, phosphoryl chloride, phosphorus oxychloride, thionyl chloride, aluminium chloride, methyl sulfonyl chloride, acetyl chloride, chlorine gas, phosgene, diphosgene, triphosgene, sodium hypochlorite, cyanuric chloride and N-chlorosuccinimide.
7. The process as claimed in claim 2, wherein the acid is selected from acetic acid, formic acid, trifluoroacetic acid and hydrochloric acid.

8. The process as claimed in claim 1 and 2, process further converted into Favipiravir.