DESC: “PURIFICATION PROCESS OF FAVIPIRAVIR”

FIELD OF THE INVENTION

The present invention relates to purification process of Favipiravir. The present invention further relates to an improved, commercially viable, industrially advantageous, and environmental friendly process for the preparation of Favipiravir with highly purity.

BACKGROUND OF THE INVENTION

Favipiravir (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 ribonucleoside triphosphate 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 fatefulue mutation. 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

Favipiravir is reported in US 6787544 by Toyama chemical. The synthetic process and it’s purification process for Favipiravir is reported in US ‘544. methyl 6-bromo-3-amino-2-pyrazine carboxylate of formula (2) is reacted with methanol in presence of H2SO4 / NaNO2 to obtain methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate (3). The compound of formula (3) converts into methyl 6-amino-3-methoxy-2- pyrazine carboxylate (4) in presence of (S)-(-)-2,2 '-bis(diphenylphosphino)-1,1'-binaphthyl / benzophenone-imine and Pd2(dba)3 to obtain 6-amino-3-methoxy-2-pyrazinecarboxamide (5). The compound of formula (5) is reacted with pyridine hydro fluoride in presence of NaNO2 / water and chloroform to obtain 6-fluoro-3-methoxy-2-pyrazine carboxamide (6). The compound of formula (6) converts into Favipiravir (1) in presence of NaI and TMSCl. The obtained compound of Favipiravir is purified by using column chromatography (eluent: hexane: ethyl acetate = 2:1).

The above process is schematically shown as below:

The prior art process described herein leads to the production of Favipiravir with highly unwanted impurities, which requires purification by using column chromatography which enhance the cost and time consuming process.

US 8586741 of Nippon soda discloses a process for the preparation of Favipiravir, which comprises 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) converts into Favipiravir (I) in presence of conc. H2SO4, NaOH and followed by purified with water to obtain pure Favipiravir.

The above process is schematically shown as below:

US 6800629 of Toyama Chemical discloses a process for the preparation of Favipiravir (1), which comprises 6-fluoro-3-hydroxypyrazine- 2-carbonitrile (13) converts into Favipiravir in presence of NaOH / 30% H2O2 and followed by purified with water to obtain pure Favipiravir (1).

The main drawbacks of the prior art process is low purity by using water as solvent for purification process. Therefore, its handling in a larger scale represents a certain risk. Hence, it is not recommendable for industrial process.

Hence, there is an unmet need for an economical process of preparing Favipiravir, which is useful to produce highly pure Favipiravir. Accordingly, it is an object of the present invention to provide a purification process for preparing Favipiravir.

In view of the foregoing, the present inventors have result of extensive studies and found that the organic solvent and water as a purification solvent, which is not carried in prior arts. Hence, the present inventors are concluded that the usage of organic solvent and water reduces the reaction time and simultaneously it produces high yield and purity for the preparation of Favipiravir.

SUMMARY OF THE INVENTION

The present invention relates to purification process of Favipiravir. The present invention further relates to an improved, commercially viable, industrially advantageous, and environmental friendly process for the preparation of Favipiravir with highly purity.

In one aspect of the present invention, provides a purification process of Favipiravir, comprising the steps of:

a) dissolving crude Favipiravir in organic solvent;
b) heating the obtained suspension, a) at 60-100°C and stir for 30-120 minutes,
c) cooling the solution obtained in step c) at 0-5°C, and
d) water added to the obtained reaction mixture,
e) isolate the pure Favipiravir from the solution obtained in step (d).

In another aspect of the present invention, provides highly pure Favipiravir.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to purification process of Favipiravir. The present invention further relates to an improved, commercially viable, industrially advantageous, and environmental friendly process for the preparation of Favipiravir with highly purity.

In one embodiment of the present invention, provides a purification process of Favipiravir, comprising the steps of:

a) dissolving crude Favipiravir in organic solvent;
b) heating the obtained suspension, a) at 60-100°C and stir for 30-120 minutes,
c) cooling the solution obtained in step c) at 0-5°C, and
d) water added to the obtained reaction mixture,
e) isolate the pure Favipiravir from the solution obtained in step (d).

According to the embodiment of the present invention, purification process for the preparation of Favipiravir, which comprises the crude Favipiravir, is dissolved in organic solvent. The obtained solution was allow to heat at 60-100°C and stir for 30-120 minutes. Preferably 50 to 55°C for 30-60 minutes. The obtained reaction mixture was cooled at 0-5°C and water was added to the reaction mass. The reaction mixture was filtered and dried to obtained pure Favipiravir.
According to the embodiment of the present invention, organic solvent is selected from acetone, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetonitrile, n-propanol, isopropanol, n-butanol, pentanol, isobutanol and the like.,

According to the embodiment of present invention, provides Favipiravir is 99.9%

In an embodiment of the present invention, the purification process provides crystalline Favipiravir.

In an embodiment of the present invention, provides a purification process for the preparation of Favipiravir is a commercially viable, industrially advantageous, and environmental friendly process by using mixture of organic solvent and water (1:2 or 2:1).

In another embodiment of the present invention, provides highly pure Favipiravir.

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

Purification process of Favipiravir:

Example 1:

To the solution of crude Favipiravir (100 g) is dissolved in acetone (1000 mL), stir for 30 minutes and filter through micron filter. The mixture was heat at 50 to 55°C for 30-60 minutes and cool the mixture at 0-5ºC and stir for 1-2 hours. Water (500 mL) was added to the reaction mixture. filter the sold wash with water and dried at 80-100ºC for 1-2 hours to obtain pure Favipiravir.

Example-2:

To the solution of crude Favipiravir (250 g) is dissolved in acetone (2500 mL), stir for 30 minutes and filter through micron filter. The mixture was heat 50 to 55°C for 30-60 minutes and cool the mixture at 10-15ºC and stir for 1-2 hours, further cooled to 0-5ºC. Water (1250 mL) was added to the reaction mixture and the solid was filtered and washed with water and dried at 80-100ºC for 1-2 hours to obtain pure Favipiravir.

Example-3:

To the solution of crude Favipiravir (100 g) is dissolved in acetone (2000 mL), stir for 30 minutes and filter through micron filter. The reaction mixture was heated at 50 to 55°C for 30-60 minutes and cool the mixture at 25-30ºC and stir for 30 minutes, further cooled to 0-5ºC, solid precipitation was observed and stir for 1-2 hours. Water (1000 mL) was added to the reaction mixture and the solid was filtered and wash with water and suck dried at 80-100ºC for 1-2 hours to obtain pure Favipiravir.
,CLAIMS:
1. A purification process of Favipiravir, comprising the steps of:

a) dissolving crude Favipiravir in organic solvent;
b) heating the obtained suspension, a) at 60-100°C and stir for 30-120 minutes,
c) cooling the solution obtained in step c) at 0-5°C, and
d) water added to the obtained reaction mixture,
e) isolate the pure Favipiravir from the solution obtained in step (d).

2. The process as claimed in claim 1, wherein the organic solvent is selected from acetone, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetonitrile, n-propanol, isopropanol, n-butanol, pentanol, isobutanol and the like.,

3. The process as claimed in claim 1, provides a process for the preparation of highly pure Favipiravir.

4. The process as claimed in claim 1, provides purity of Favipiravir is 99.9%.

5. The process as claimed in claim 1, the purification process provides crystalline Favipiravir.