DESC:“ONE POT PROCESS FOR THE PREPARATION OF DICYCLOHEXYLAMINE SALT OF 6-FLUORO-3-HYDROXY-2-PYRIDINE CARBONITRILE”

FIELD OF THE INVENTION

The present invention relates to one pot process for the preparation of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile commercially viable and industrially applicable process in terms of good yield and purity.

BACKGROUND OF THE INVENTION

Favipiravir (Favipiravir, T-705), chemical entitled 6-fluoro-3-hydroxypyrazine-2-methan amide, 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 triphosphote 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 viruses, Bunya virus 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

The present invention relates the process to synthesize this very crucial intermediate (Dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile (15)) of antiviral drug in a very faster way.

Its structural formula is as follows:

Favipiravir is reported in US 6787544 by Toyama chemical. The synthetic process for Favipiravir is reported in US ‘544, which comprises, 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(di phenylphosphino)-1,1'-binaphthyl / benzophenone-imine and Pd2(dba)3 to obtain 6-amino-3-methoxy-2-pyrazine carboxamide (5). The compound of formula (5) is reacted with pyridine hydrofluoride 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 above process is schematically shown as below:

total recovery only 0.44%. Amino replacement used catalyst three (dibenzalacetone) two palladium [Pd2(dba)3] and in method, (S)-(-)-2,2'-(diphenyl phosphine)-1,1'-dinaphthalene costly, and final step reaction is difficult to control, yield only has 4.3%, is unfavourable for suitability for industrialized production.

Chinese Journal of Pharmaceuticals 2013, 44 (9) discloses a process for the preparation of Favipiravir (1), which comprises the compound of formula (7) is reacted with CH3OH in presence of H2SO4 to obtain the compound of formula (8). The compound of formula (8) is reacted with NBS in presence of CH3CN to obtain the compound of formula (2). The compound of formula (2) converts into the compound of formula (9) in presence of NaNO2 / H2SO4 and followed by amination to obtain the compound of formula (10). The compound of formula (10) is reacted with POCl3 in presence of DIPEA to obtain the compound of formula (11). The compound of formula (11) is reacted with KF in presence of DMSO to obtain the compound of formula (12). The compound of formula (12) converts into the compound of formula (13) in presence of CH3COONa.

The above process is schematically shown as below:

Total recovery is 21.8%. This reaction scheme step is longer, and yield is lower, and cost is higher. Be unfavourable for suitability for industrialized production.

US 8168789 of Toyama Chemical explains process for the preparation of Favipiravir (1), which comprises 3,6-difluoro-2-pyrazinecarbonitrile (14) is reacted with water in presence of DMF / potassium acetate / aq. NH3 / acetone and toluene followed by treated with dicyclohexyl amine to obtain dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile (15).

The above process is schematically shown as below:

The major drawback in the prior art processes for preparation of Favipiravir (1) requires excess work ups. Therefore, there remains a need to prepare Favipiravir of good purity and yield where total synthesis time is short and overcoming the drawbacks presented by the processes described in the art.

In view of the foregoing, the present inventors have result of extensive studies, the efficiency is extremely only for the one pot process for the preparation of dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15) from 3,6-difluoro-2-pyrazine carbonitrile (14) in presence of trialkyl ammonium buffers and methyl tertbutyl ether or methyl tertbutyl ketone or ethyl acetate and followed by reacted with dicyclohexyl amine.

In order to evaluate eco-friendly, industrial feasible one pot process for preparation of dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15). our inventors surprisingly found with the use of trialkyl ammonium buffers and methyl tertbutyl ether or methyl tertbutyl ketone or ethyl acetate followed by treated with dicyclohexyl amine in the reaction with advantages good yield and purity and total reaction time is short.

None of the above prior-art processes teaches nor suggests 3,6-difluoro-2-pyrazine carbonitrile (14) in presence of trialkyl ammonium buffers and methyl tertbutyl ether or methyl tertbutyl ketone or ethyl acetate and followed by reacted with dicyclohexyl amine to obtain dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15).

ADVANTAGES:

1. One pot process under complete anhydrous conditions to avoid unwanted side reactions which leads to pure quality of the product.
2. Neat reaction to yield quantitative output with good quality.
3. Avoided the usage of N,N-dimethylformamide, ammonia, toluene, acetone like mixture of solvents and tedious lengthy workup which leads to yield loss.
4. Avoided the usage of metal acetates to avoid the aqueous workups to minimize the yield loss.
5. Commercially and Environmentally benign process.
6. Simple operations and which can save the lot of time cycle at commercial scale and used single solvent for the reaction to recover and reuse purpose.

SUMMARY OF THE INVENTION

The present invention relates to one pot process for the preparation of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile (15) commercially viable and industrially applicable process in terms of good yield and purity.

In one aspect of the present invention, provides to one pot process for the preparation of dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile (15), which comprises 3,6-difluoro-2-pyrazine carbonitrile (14) in presence of trialkyl ammonium buffers / solvent and followed by reacted with dicyclohexyl amine to obtain dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to one pot process for the preparation of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile (15) commercially viable and industrially applicable process in terms of good yield and purity.

In one embodiment of the present invention, provides one pot process for the preparation of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile (15), which comprises 3,6-difluoro-2-pyrazine carbonitrile (14) in presence of trialkyl ammonium buffers / solvent and followed by reacted with dicyclohexyl amine to obtain dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15).

According to the embodiment of the present invention one pot process for the preparation of dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15) from 3,6-difluoro-2-pyrazine carbonitrile (14) in presence of trialkyl ammonium buffers /solvent, the reaction carried out at 50-75ºC for 1-4 hrs, the reaction mixture was cooled to 0-15ºC and followed by reacted with dicyclohexyl amine, the reaction carried out at 0-20ºC for 1-4 hrs.

In an embodiment of the present invention provides, wherein the trialkyl ammonium buffers are selected from trialkylammoniumacetate and trialkylammoniumformate; which are diisopropylethylammonium acetate, triethylammonium acetate, pyridinium acetate, tributyl ammonium acetate, diisopropylethylammoniumformate, triethylammoniumformate and tributylammoniumacetate.

In an embodiment of the present invention provides, wherein the solvents are selected from methyltertbutylether, methyltertbutylketone, toluene. Isopropyl alcohol, isobutyl alcohol, tetrahydrofuran, isopropyl acetate, isobutyl acetate, ethyl acetate etc.

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

EXAMPLES

Example – 1:

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Disiopropylethylammonium acetate (161 gm, 0.8505 mol) was added to a tert-butyl methyl ether, solution of 3,6-difluoro-2-pyrazinecarbonitrile (100 gm, 0.7088 mol diluted in 500 ml of tert-butyl methyl ether) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC, added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with tert-butyl methyl ether (50.0 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 218.0 gm (96%)

Purity: 99.8%

Example-2:

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Tributylammonium acetate (208.7 gm, 0.8505 mol) was added to a tert-butyl methyl ether, solution of 3,6- difluoro-2-pyrazinecarbonitrile (100 gm, 0.7088 mol diluted in 500 ml of tert-butyl methyl ether) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC, added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with tert-butyl methyl ether (50 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 215.70 gm (95%)

Purity: 99.9%

Example-3:

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Triethylammonium acetate (137.1 gm, 0.8505 mol) was added to a tert-butyl methyl ether, solution of 3,6-difluoro-2-pyrazinecarbonitrile (100 gm, 0.7088 mol diluted in 500 ml of tert-butyl methyl ether) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC, added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with tert-butyl methyl ether (50 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 220.0 gm (96.8%)

Purity: 99.8%

Example-4:

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Disiopropylethylammonium formate (149 gm, 0.8505 mol) was added to a tert-butyl methyl ether, solution of 3,6- difluoro-2-pyrazinecarbonitrile (100 gm, 0.7088 mol) diluted in 500 ml of tert-butyl methyl ether) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC, added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with tert-butyl methyl ether (50.0 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 211 gm (92.9%)

Purity: 99.7%

Example-5

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Tributylammonium formate (196.8 gm, 0.8505 mol) was added to a tert-butyl methyl ether, solution of 3,6- difluoro-2-pyrazinecarbonitrile (100 gm, 0.7088 mol diluted in 500 ml of tert-butyl methyl ether) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC and added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with tert-butyl methyl ether (50 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 217 gm (95.5%)

Purity: 99.8%

Example-6:

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Triethylammonium formate (125 gm, 0.8505 mol) was added to a tert-butyl methyl ether solution of 3,6-difluoro-2-pyrazinecarbonitrile (100 gm, 0.7088 mol diluted in 500 ml of tert-butyl methyl ether) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC, added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with tert-butyl methyl ether (50 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 219 gm (96.4%)

Purity: 99.7%

Example-7:

Preparation of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile Dicyclohexylamine salt

Triethylammonium formate (150 gm, 0.8605 mol) was added to a ethyl acetate solution of 3,6-difluoro-2-pyrazinecarbonitrile (120 gm, 0.7288 mol diluted in 600 ml of ethyl acetate) at 5 to 15ºC. Then the reaction mass was stirred at 60-65ºC for 2-3 hrs. The reaction mixture was cooled to 5-10ºC, added dicyclohexylamine (128.5 gm, 0.7088 mol) and stirred at 5-10ºC for 2-3 hrs. The precipitate was filtered, washed with ethyl acetate (50 ml) and dried the solid at 45-50ºC for 5-6 hrs.

Yield: 229.0 gm (97.4%)

Purity: 99.8%
,CLAIMS:
1. One pot process for the preparation of dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyridine carbonitrile (15), which comprises 3,6-difluoro-2-pyrazine carbonitrile (14) in presence of trialkyl ammonium buffers / solvent and followed by reacted with dicyclohexylamine to obtain dicyclohexyl amine salt of 6-fluoro-3-hydroxy-2-pyradine carbonitrile (15).

2. The process as claimed in claim 1, wherein the trialkyl ammonium buffers are selected from trialkylammoniumacetate and trialkylammoniumformate; which are diisopropyl ethyl ammonium acetate, triethylammonium acetate, pyridinium acetate, tributyl ammonium acetate, diisopropylethylammoniumformate, triethylammoniumformate and tributylammoniumacetate.

3. The process as claimed in claim 1, wherein the solvents are selected from methyltert butylether, methyltertbutylketone, toluene. isopropyl alcohol, isobutyl alcohol, tetrahydrofuran, isopropyl acetate, isobutyl acetate, ethyl acetate etc.