DESC:FIELD OF THE INVENTION:
The present invention relates to the technical field of chemical synthesis, and particularly relates to an active pharma ingredient Favipiravir and its intermediates synthesis. Favipiravir is a drug that is used in the treatment of Influenza Virus.

BACKGROUND OF THE INVENTION:
There exist many prior arts discussing the synthesis of Favipiravir.

Patent application WO 2010087117 discloses the synthetic process of Favipiravir as described below which involves 2-amino malonamide as a starting material and Favipiravir is prepared through the sequence of steps including: cyclization, bromination, dichlorine substitution and dehydration, difluoride substitution, substitution reaction and hydrolysis reaction.
The synthetic route is shown as follows:

As per the process of above WO ‘117 application, the dichloro intermediate (5) formed in the reaction is not isolated and is taken to the subsequent fluorination. However, the fluorination reactions require a higher purity and stricter moisture free requirements of the substrate [5] otherwise which the fluorination reaction does not undergo favorably.

Patent document EP 2192117B1 discloses a process involving isolating the Difluoro Cyano intermediate as its organic amine salt as shown below:

The process of EP ‘117 involves isolation of the “6-fluoro-3-hydroxy-2-pyrazinecarbonitrile” intermediate [3] as a salt of Dicyclohexyl amine which is subsequently cleaved in the next step and followed by hydrolysis to obtain Favipiravir.

Several other prior arts such as CN 111675663A, CN 111471025A, CN107641106, WO 2012/063931A1 & WO 200904173A1 disclose hydrolysis of the Nitrile group of “6-fluoro-3-hydroxy-2-pyrazinecarbonitrile” intermediate in presence of a base and water or an organic solvent such as t-Butyl alcohol or Isopropyl alcohol or Toluene.

Prior art processes suffer from disadvantages such as:
• The intermediates “Difluoro Cyano intermediate” and “6-fluoro-3-hydroxy-2-pyrazinecarbonitrile” contain traces of fluorine which are hazardous if isolated.
• The Dichloro Cyano intermediate needs a stricter moisture free requirement as the subsequent fluorination reaction may not favour if the input material is not pure and moisture free.
• The purity of Favipiravir isolated is not satisfactory in the prior art processes.

Hence the present inventors have developed a simple, improved process which overcomes the shortcomings of prior art and which yields Favipiravir in high purity at industrial scale.

OBJECT OF THE INVENTION:
An object of the present invention is to provide a process for purification of Favipiravir using a novel solvent system to obtain Favipiravir with pharmaceutical grade purity.

Another object of the present invention is to provide a simple process for the preparation of Favipiravir which avoids formation of organic amine salt of “6-fluoro-3-hydroxy-2-pyrazinecarbonitrile” intermediate. In specific, the present invention avoids isolation of this intermediate of Favipiravir there by rendering the process simple yet effective.

One another object of the present invention is to provide a process for the preparation of “dichloro intermediate” in high purity thereby facilitating the subsequent Fluorination reaction favorably.

Another object of the present invention is to provide a process which effectively removes the impurities that are be formed in the hydrolysis of “6-fluoro-3-hydroxy-2-pyrazinecarbonitrile” to get Favipiravir in high purity.

SUMMARY OF THE INVENTION:

A summary of the present invention can be outlined in a schematic representation as below:

Accordingly, one aspect of the present invention is to provide a process for the preparation of compound of formula II, comprising:
a) Reacting formula I with chlorinating agent in presence of a base to form a compound of formula II;
b) separating the product from the reaction mixture; and
c) isolating compound of formula II from an aliphatic hydrocarbon solvent.

Another aspect of the present invention is to provide a one-pot synthesis for the preparation of Favipiravir, comprising:
i) Reacting formula II with fluorinating agent to prepare formula III;
ii) in-situ hydroxylation of formula III with water in presence of a base to prepare formula IV; and
iii) in-situ hydrolysis of formula IV in presence of a base and a peroxy acid to obtain Favipiravir.

One another aspect of the present invention is to provide a process for the purification of Favipiravir, comprising:
1) Dissolving Favipiravir in a mixture of “ketone and water” or “ketone and DMF” or “alcohol and DMF”;
2) optionally adding water to the reaction mixture of step 1); and
3) isolating pure Favipiravir.

DEFINITIONS
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degrees Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.

The term “DMF” refers to the solvent N, N-Dimethyl formamide.

The formula POCl3 refers to Phosphorous Oxy Chloride.

DETAILED DESCRIPTION:
One embodiment of the present invention provides a process for the preparation of compound of formula II,
comprising:
a) Reacting formula I with chlorinating agent in presence of a base to form a compound of formula II;

b) separating the product from the reaction mixture; and
c) isolating compound of formula II from an aliphatic hydrocarbon solvent.

In the embodiments of step a) of the above process, the chlorinating agent used may be selected from, but not limited to, PCl5, POCl3 etc.

In the embodiments of step a) of the above process, there is no limitation to the kind of base that can be used. As long as the chlorination reaction is favored, any base can be used. An exemplary list of bases that can be used are selected from organic bases such as: triethylamine; N,N-diisopropylethylamine; 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5); 1,5-diazabicyclo[4.3.0]non-5-ene; 1,4-diazabicyclo[2.2.2]octane imidazole, 1-methylimidazole, triethylamine and N, N-diisopropylethylamine etc.

In the embodiments of step a) of the above process, there is no particular limitations on the solvent used in the reaction, provided the solvent used is an inert solvent that has no adverse effect on the chlorination reaction.

In the embodiments of step b) of the above process, there are no limitations on the separating methods employed to separate the product from the reaction mixture. Any of the conventional methods such as distillation of the reaction mass or quenching the reaction mass into water and/or layer separation and/or distilling out the reaction mass etc can be employed.

In the embodiments of step c) of the above process, the aliphatic hydrocarbon solvent may be selected from, but are not limited to, C5 to C10 straight or branched alkanes or cycloalkanes such as n-pentane, n-hexane, n-heptane, cyclohexane or mixtures thereof.

In the embodiments of step c), isolation of compound of formula II includes addition of aliphatic hydrocarbon to the isolated product of step b) which may be presented in oil form or solid form or residue form.

By using this process, the compound of formula II is isolated in high purity and isolated as a solid and devoid of any traces of water when compared to the prior art process. Further, when this compound of formula II obtained according to this process is used to proceed for the preparation of Favipiravir, the Favipiravir obtained is of high purity.

Another embodiment of the present invention provides a one-pot synthesis for the preparation of Favipiravir, comprising:
i) Reacting formula II with fluorinating agent to prepare formula III;

ii) in-situ hydroxylation of formula III with water in presence of a base to prepare formula IV;

and
iii) in-situ hydrolysis of formula IV in presence of a base and a peroxy acid to obtain Favipiravir.

In the embodiments of step i) of the above process, an optional phase transfer catalyst may also be used.

In the embodiments of step i) of the above process, there is no limitation on the fluorinating agent used in the reaction. An exemplary fluorinating used can be potassium fluoride or Fluorine gas.

In the embodiments of step ii) of the above process, the base used may be selected from, but not limited to, organic bases such as diisopropylethylamine and triethylamine; quaternary ammonium hydroxides such as benzyltrimethylammonium hydroxide; carboxylates such as potassium formate, sodium formate, formic acid-triethylamine, potassium acetate, sodium acetate, acetic acid-triethylamine, sodium propionate, sodium hexanoate, sodium benzoate and benzoic acid-triethylamine; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, dipotassium hydrogenphosphate and tripotassium phosphate. Carboxylates are preferred for use as a base. Potassium formate, formic acid-triethylamine, potassium acetate and acetic acid-triethylamine are more preferred.

In the embodiments of step iii) of the above process, the base used may be selected from, but not limited to, an alkali metal base such as sodium hydroxide and ammonia water or an amine such as aqueous ammonia solution.

In the embodiments of step iii) of the above process, the peracid may be used is hydrogen peroxide, per acetic acid and the like.

In the embodiments of steps i) or ii) or iii), there is no limitation to the type of solvent that can be used during the reaction. As long as the reaction is favored, any kind of solvent can be used. However, the present inventors have developed the process wherein a single solvent is used throughout the steps i), ii) and iii). Further, the inventors have observed that by using a polar solvent such as N,N-Dimethyl formamide, the purity of Favipiravir obtained is high as it is believed that the DMF solvent is able to favor the rate of reaction and also selectively eliminates the impurities that are formed during the reaction.

By using this one-pot synthesis, the present process eliminates the need to isolate the “6-fluoro-3-hydroxy-2-pyrazinecarbonitrile” intermediate of formula IV and eliminates the need to form an acid addition salt of formula IV thereby rendering the process simple. Also, a single solvent is used throughout the process of preparing Favipiravir starting from formula II.

Further, the present one-pot synthesis eliminates the need to isolate the intermediate compounds III & IV which may contain hazardous fluorine traces.

Another embodiment of the present invention provides a process for the purification of Favipiravir, comprising:
1) Dissolving Favipiravir in a mixture of “ketone and water” or “ketone and DMF” or “alcohol and DMF”;
2) optionally adding water to the reaction mixture of step 1); and
3) isolating pure Favipiravir.

In the embodiments of step 1) of the above process, the ketonic solvent used may be selected from, but not limited to, acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone and/or Diethyl Ketone. In one embodiment the preferred solvent used is acetone.

In the embodiments of step 1) of the above process, the alcohol solvent used may be selected from, but not limited to methanol, ethanol, isopropyl alcohol and the like. Preferably methanol is used in the embodiments of step p) when an alcoholic solvent is used.

In the embodiments of step 1) of the above process, dissolving of Favipiravir in the solvent mixture can be achieved either at room temperature or at higher temperatures such as heating to a temperature ranging between 30 oC to 90 oC.

In the embodiments of step 2) of the above process, addition of water can be done at room temperature or at higher temperatures ranging between 30 oC to 90 oC. In a preferred embodiment water was added to the reaction mixture at a temperature of 60 oC - 70 oC.

In the embodiments of step 3) of above process, the reaction mixture of step 2) is cooled before isolation.

In the embodiments of step 3) of above process isolation is carried by any of the conventional techniques such as filtration, distillation of the reaction mass etc.,

The present purification process as in the above embodiment can remove impurities that are present in Favipiravir and helps in achieving Favipiravir with purity greater than 99.95% and with a limit of any individual impurity less than 0.05%.

EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example-1:
Preparation of Compound of formula II

Under nitrogen atmosphere, to a round bottomed flask, added Toluene (1000 ml) and 6-bromo-3-hydroxy Pyrazine carobxamide (500 gm) under stirring. Added slowly phosphorous oxy chloride (1330 gm) to the reaction mass followed by addition of triethyl amine (600 gm) and heated the reaction mass to a temperature of 100 - 110°C. Maintained the reaction mass for 2-3 hrs. After completion of the reaction, the reaction mass was quenched into cool water (5000 ml). Separated the organic and aqueous layers. The organic layer was distilled out under vacuum and n-Heptane was added to the reaction flask and heated the reaction mass to 45 – 55°C. Cooled the reaction mass and filtered the product to obtain a free-flowing powdered material. Dried the product.
Weight of the product: 325 gm.

Example-2:
Preparation of Favipiravir:
Under N2 atmosphere, added Dimethyl Formamide (700 ml) and anhydrous potassium fluoride (168 gm) into a 4-necked round bottomed flask. Distilled out DMF under vacuum at temperature 80-85°C to about 3 to 3.5 v/w of the initial volume. After distillation of DMF, the compound of formula I (100 gm) was added to the reaction flask and further heated the reaction mass to 100-110°C. The reaction mass was maintained at this temperature for 8 hrs. After completion of the reaction, filtered the mass.
To a clean and dry 4-neck reaction flask, added the above filtrate mother liquor containing the product of formula III i.e., 3,6-Difluoropyrazine-2-carbonitrile and further added potassium acetate solution (124 gm potassium acetate in 80 ml process water) to the reaction mass. Stirred the reaction mass at room temperature for 2 hrs.
After completion of the reaction, charged sodium hydroxide solution (70 gms sodium hydroxide in 400 ml water) to the reaction mass. Cooled the reaction mass to 10-20°C. Add slowly Hydrogen peroxide solution (90 gm Hydrogen peroxide in 100 ml water). Maintained the reaction mass for 2 hrs. After completion of the reaction, added concentrated HCl to the mass and adjusted the pH to less than 6.0. Extracted the product into ethyl acetate. Organic layer was distilled out and the crude 6-Fluoro-3-hydroxypyrazine-2-carboxamide was isolated from Water.
Weight = 50 gms.
HPLC purity = > 99.9%.
Example-3:
Purification of Favipiravir:
To a round bottomed flask, added Acetone (200 ml) at room temperature. Favipiravir (25 g) was added followed by addition of water (25ml) to the reaction flask. The reaction mixture was heated to 40-50°C to get clear solution. Water (100 ml) was added slowly to this heated reaction mixture at the same temperature. Cooled the reaction mixture to 0-10° C. Filtered the product and dried the material.
Weight of the solid = 21.7gms
HPLC purity: 99.97%.

Example-4:
Purification of Favipiravir:
To a round bottomed flask, added Methanol (10 ml) at room temperature. Added Favipiravir (2.0 gms) and DMF to the reaction flask and heated the reaction mass to 60-70°C to get clear solution. Cooled the reaction mass to 0-10°C. Filtered the product to obtain Pure Favipiravir. Dried the material.
Weight of the solid: 1.9 gms
HPLC purity: 99.95%.

Example-5:
Purification of Favipiravir:
To a round bottomed flask, added Methanol (100 ml) at room temperature. Added Favipiravir (10 g) and DMF (20 ml) into the reaction flask. Heated the reaction mixture to 60-70°C to get clear solution. Slowly added water to the heated solution. Cooled the reaction mass to 0-10° C. Filtered the product and dried the material.
Weight of the solid: 8.6 gms.
HPLC purity: 99.98%.

Example-6:
Purification of Favipiravir:
To a round bottomed reaction flask, added Acetone (280 ml) at room temperature. Added Favipiravir (40 gms) and water (40 ml) to the reaction flask. Heated the reaction mass to 40-50°C to get clear solution. Slowly added water to the reaction mass at the same temperature. Cooled the reaction mass to 0-10°C. Filtered the product and dried the product.
Weight of the solid: 32 gms.
HPLC purity: 99.98%.

Example-7:
Purification of Favipiravir:
To a round bottomed reaction flask, added Acetone (25 ml) at room temperature. Added Favipiravir (5.0 gms) and DMF (5 ml) into the reaction flask. Heated the reaction mixture to 60 – 70°C to get clear solution. Slowly added water to the heated solution. Cooled the reaction mass to 0 – 10°C. Filtered the product and dried the product.
Weight of the solid: 4.1 gms.
HPLC purity: 99.95%. ,CLAIMS:1. A process for preparation of Favipiravir, comprising:
i. Reacting formula II with fluorinating agent to prepare formula III;

ii. in-situ hydroxylation of formula III with water in presence of a base to prepare formula IV;

and
iii. in-situ hydrolysis of formula IV in presence of a base and a peroxy acid to obtain Favipiravir.

2. The process according to claim 1 wherein the compounds of formulae III and IV are not isolated.

3. The process according to claim 1 wherein the in-situ process of steps i), ii) & iii) are carried in N, N-Dimethyl formamide solvent.

4. A process for preparation of compound of formula II, comprising:
a) Reacting formula I with chlorinating agent in presence of a base to form a compound of formula II;

b) separating the product from the reaction mixture; and
c) isolating compound of formula II from an aliphatic hydrocarbon solvent.

5. The process according to claim 4 wherein the chlorinating agent used is Phosphorous Oxy Chloride.

6. The process according to claim 4 wherein the aliphatic hydrocarbon solvent is heptane.

7. A process for purification of Favipiravir, comprising:
1) Dissolving Favipiravir in a mixture of “ketone and water” or “ketone and DMF” or “alcohol and DMF”;
2) optionally adding water to the reaction mixture of step 1); and
3) isolating pure Favipiravir.

8. The process according to claim 7 wherein in step 1) Favipiravir is dissolved in a mixture of "ketone and water".

9. The process according to claim 7 wherein in step 1), the reaction mixture is heated at a temperature between 30° - 90°C.

10. The process according to claim 7 wherein in step 2), the addition of water is carried at a temperature between 30° - 90°C.