WO2022029585A1

WO2022029585A1 - Improved process for the preparation of a compound useful as anti-viral compound

Info

Publication number: WO2022029585A1
Application number: PCT/IB2021/057014
Authority: WO
Inventors: Harikrishna MUDDULURU; Munisekhar Reddy SANNAREDDY; Subrahmanyam GONUGUNTA; Ananda Kumar VILASAGARAPU
Original assignee: Ocimum Labs Private Limited
Priority date: 2020-08-01
Filing date: 2021-07-31
Publication date: 2022-02-10

Abstract

The present invention relates to an improved process for the preparation of a compound useful in the preparation of anti-viral compound. The present invention specifically relates to an improved process for the preparation of compound having the Formula (I) or its salts. The present invention also relates to an improved process for the preparation of Favipiravir having the Formula (II) or its salts.

Description

IMPROVED PROCESS FOR THE PREPARATION OF A COMPOUND

USEFUL AS ANTI-VIRAL COMPOUND

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of a compound useful in the preparation of anti-viral compound.

The present invention specifically relates to an improved process for the preparation of compound having the Formula (I)

Formula (I) or its salts.

The present invention also relates to an improved process for the preparation of

Favipiravir having the Formula (II)

Formula (II) or its salts.

BACKGROUND OF THE INVENTION

Favipiravir, sold under the brand name Avigan among others, is an antiviral medication used to treat influenza in Japan. Favipiravir also known as T-705 or Favilavir, developed by Toyama Chemical (Fujifilm group) of Japan with activity against many RNA viruses. Favipiravir has shown activity against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses. Favipiravir was also being studied in China for experimental treatment of the emergent COVID-19 (novel coronavirus disease). Chinese officials suggested that the drug had been effective in treating COVID in Wuhan and Shenzhen. The importance of Favipiravir arises due to its approval in India for the treatment of COVID-19.

The chemical name of Favipiravir is 6-fluoro-3-hydroxypyrazine-2-carboxamide, its molecular formula is C₅H₄FN₃O2, the molecular weight for drug substance is 157.104 g/mol and having molecular structure of:

Formula (II)

US RE43,748 El (Re-issue of US 6,787,544 B2) claims Favipiravir product generically as a nitrogen-containing heterocyclic carboxamide compound represented by the following formula or a pharmaceutically acceptable salt thereof.

wherein: each occurrence of R' is a halogen atom or a hydroxyl group which is linked to a carbon atom of the nitrogen-containing heterocycle in said formula; R¹ represents O or OH; R² is selected from the group consisting of a hydrogen atom, an acyl group, an optionally substituted carbamoyl alkyl group, and an optionally substituted carboxyalkyl group; n is 1 or 2; the broken line in the ring represents a single bond when R¹ is O and a double bond when R¹ is OH; and the broken line between R¹ and the ring is a single bond when R¹ is OH and a double bond when R¹ is O. JP 5559604 B2 discloses bromination process comprising reacting 3-hydroxy-2- pyrazinecarboxamide or a salt thereof with bromine in the presence of base to obtain 6- bromo-3-hydroxy-2-pyrazinecarboxamide, which is shown below:

Formula (III) Formula (I)

The process specifically involves reacting 3 -hydroxy- 2-pyrazinecarboxamide with bromine using base and / or acid at 80 to 100 ° C and stirred at the same temperature. The process of this step is homogenous step, however, the reaction is carried out using an organic base and / or acid. The use of bases disclosed in this patent results in genotoxic impurities such as NDMA, NDEA, NDIPA, NDIPA, NDBA and NMBA are other N- Nitroso analogues. Further, the use of organic base is problem as it is difficult to remove from the reaction mass and is very tedious as it causes environmental pollution. Quenching of the pyridine also requires more amount of hydrochloric acid and it leads to more effluent

US 8,586,741 B2discloses bromination process which is for the preparation of compound of Formula (III)

Formula (III)

The reaction solvents used in the bromination step result in Heterogenous reaction medium. Because of heterogeneous nature of the reaction mass, monitoring of reaction completion was very difficult for commercial scale up batches and it lead to lesser yields. Starting material removal also very difficult for scale up batches.

The process described in the prior-art involves either heterogenous medium or use of additional reagents such as base or acid. These processes are not feasible commercially as the reaction is not completed and batch to batch variations were observed in HPLC. Further, >6 to 20 % of unreacted 3 -hydroxy- 2-pyrazinecarboxamide was observed in HPLC monitoring. Accordingly, there is a need for development of a commercially viable process for preparing Favipiravir which is simple and environmental friendly.

The inventors of the present invention have surprisingly found a simple, convenient and economical feasible process which involves easily available raw materials and further is homogenous process by avoiding the use of additional base / acid in the bromination stage. Further, the process is better in terms of quality as purity of final Favipiravir obtained by using intermediate compound of formula (I) is better.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of a compound useful in the preparation of anti-Viral compound.

Another objective of the present invention is to provide an improved process for the preparation of compound having the Formula (I)

Formula (I) or its salts which is commercially feasible / industrially scalable which involves use of simple and easily available starting materials.

Yet another objective of the present invention is to provide an improved process for the preparation of Favipiravir having the Formula (II)

Formula (II) or its salts with a high yield and high purity.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of a compound useful in the preparation of anti-Viral compound.

The present invention relates to an improved process for the preparation of compound having the Formula (I)

Formula (I) or its salts which comprises brominating the compound of Formula (III)

Formula (III) in a solvent system wherein the reaction medium is homogenous during the reaction, wherein the reaction does not involve use of a base / acid.

Formula (III) in a solvent system wherein the reaction medium is homogenous during the reaction, wherein the reaction does not involve use of a base / acid followed by purification using a polar protic solvent.

Formula (I) or its salts which comprises

(a) brominating the compound of Formula (III)

O

N t. *j^NH₂

N ONa Formula (III) in a solvent system wherein the reaction medium is homogenous during the reaction, wherein the reaction does not involve use of a base / acid,

(b) treating the reactions mass with chilled water,

(c) filter the solid followed by treating with methanol, and

(d) filter the solid and wash with methanol.

In still another aspect, the present invention relates to preparation of Favipiravir having the Formula (II)

Formula (II) or its salts by converting intermediate compound of formula (I) to Favipiravir.

In another aspect, the present invention relates to highly pure Favipiravir compound of Formula (II) prepared by the process of the present invention. DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The brominating agent is selected from but not limited to one or more of Br₂, N- bromosuccinamide, 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one (TBCD). The molar ratio of the brominating reagent and compound of formula (I) may vary based on the brominating agent used. The molar ratio may be in the range of 1:1 tol:10. The bromination reaction may be carried out at a temperature in the range of 25°C -150°C or reflux temperature of the solvent used.

The solvent system used in the reaction medium is one or more polar aprotic solvents selected from "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; “Amide solvents” such as formamide, dimethylformamide, dimethylsulfoxide, dimethyl acetamide N-methyl-2- pyrrolidone, N-methylformamide, 2-pyrrolidone, 1 -ethenyl-2-pyrrolidone.

The polar protic solvents used in the purification of the intermediate compound of formula (I) is selected from water, methanol, ethanol, n-propanol, isopropanol, n- butanol and t-butanol and the like or mixtures thereof.

The advantages of the present invention involve avoidance of base / acid in the reaction and the reaction medium is homogenous. The process of the present invention results in 100% completion of the reaction whereas the reported processes reaction conversions are up to 80%. The process of the present invention is high yielding, thereby decreasing the turnaround time of the batch cycle and increasing the batch cycle Further, avoidance of organic base has significant on the quality of the product by decreasing the possibility of formation of potential toxic impurities, which might carried forward into the final API.

The process avoids the distillation operations in the total synthesis which are not suitable in commercial operations, resulting in an increased overall yield

Further, the process results in intermediate compound with high quality thereby the final Favipiravir obtained also is in high purity.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Preparation of 6-bromo-3-hydroxypyrazine-2-carboxamide:

Dimethylformamide (DMF)(400mL) and acetonitrile (lOOmL) were added into a RBF at 30°C (30±5°C), followed by addition of sodium 2-carbamoylpyrazine-3- hydroxylate(lOOg). The reaction mixture was cooled to 20°C (20+5 °C). After cooling the reaction mass from 30°C to 20°C (20±5°C) bromine (118.12 g) was slowly added to the reaction mass at 20°C over 40 min and stirred for 1 h at 22°C (22+3 °C). The reaction progress was monitored by HPLC.

The reaction mass was cooled to 0°C (0+5°C) and chilled process water (1500 mL)was added slowly into reaction mass and stirred for 2 h at 0°C (0+5°C). The solid formed was filtered and washed the solid with process water (200 mL) at 0°C (0+5°C) and suck dried the solid for 30 min. Unload the wet material into the cleaned container. Charge methanol (200mL) and wet material into RBF and stir for 1 h at 30°C (30+5°C). Filter the solid and wash the solid with methanol (50mL) and suck dry for 30 min. Unload the wet material into the cleaned container and dry the solid for 6 h in VTD at 65+5 °C under vacuum. After that cool the dryer temperature to below 35°C unload the dry material into the cleaned containers weigh it.

Result: Dry wt: 95 g; Obtained yield (%): 70.3%; HPLC : 99.6%

Preparation of 6-bromo 3 -hydroxypyrazine- 2- carboxamide :

Dimethylformamide (DMF) (400mL) was added into a RBF at 30°C (30±5°C), followed by addition of sodium 2-carbamoylpyrazine-3-hydroxylate (100g). The reaction mixture was cooled to 20°C (20+5 °C). After cooling the reaction mass from 30°C to 20°C (20+5°C) bromine (118.12 g) was slowly added to the reaction mass at 20°C over 40 min and stirred for 1 h at 22°C (22+3 °C). The reaction progress was monitored by HPLC.

The reactions mass was cooled to 0°C (0+5°C) and chilled process water (1500 mL) was added slowly into reaction mass and stirred for 2 h at 0°C (0+5°C). The solid formed was filtered and washed the solid with process water (200 mL) at 0°C (0+5°C) and suck dried the solid for 30 min. Unload the wet material into the cleaned container. Charge methanol (200mL) and wet material into RBF and stir for 1 h at 30°C (30+5°C). Filter the solid and wash the solid with methanol (50mL) and suck dry for 30 min. Unload the wet material into the cleaned container and dry the solid for 6 h in VTD at 65+5 °C under vacuum. After that cool the dryer temperature to below 35°C unload the dry material into the cleaned containers weigh it.

Result: Dry wt: 70.2 g; Obtained yield (%): 52% HPLC : 99.78%

Preparation of 6-bromo-3-hydroxypyrazine-2-carboxamide:

Dimethylformamide (DMF) (300mL) and acetonitrile (100 mL) were added into a RBF at 30°C (30+5°C), followed by addition of sodium 2-carbamoylpyrazine-3-hydroxylate (100g). The reaction mixture was cooled to 20°C (20+5°C). After cooling the reaction mass from 30°C to 20°C (20+5°C) bromine (118.12 g) was slowly added to the reaction mass at 20°C over 40 min and stirred for 1 h at 22°C (22+3 °C). The reaction progress was monitored by HPLC.

The reaction mass was cooled to 0°C (0±5°C) and chilled process water (1500 mL) was added slowly into reaction mass and stirred for 2 h at 0°C (0±5°C). The solid formed was filtered and washed the solid with process water (200 mL) at 0°C (0±5°C) and suck dried the solid for 30 min. Unload the wet material into the cleaned container. Charge methanol (200mL) and wet material into RBF and stir for 1 h at 30°C (30±5°C). Filter the solid and wash the solid with methanol (50mL) and suck dry for 30 min. Unload the wet material into the cleaned container and dry the solid for 6 h in VTD at 65+5 °C under vacuum. After that cool the dryer temperature to below 35°C unload the dry material into the cleaned containers weigh it.

Result: Dry wt: 82.3g; Obtained yield (%): 60.9% HPLC : 99.78%

Preparation of 6-bromo 3 -hydroxypyrazine- 2- carboxamide :

Dimethylformamide (DMF) (456 L) and acetonitrile (114 L) were added into a reactor at 30°C (30+5°C), followed by addition of sodium 2-carbamoylpyrazine-3-hydroxylate (114 Kg). The reaction mixture was cooled to 20°C (20+5°C). After cool the reaction mass from 30°C to 20°C (20+5°C) bromine (134.6 Kg) was slowly added to the reaction mass at 20°C over 40 min and stirred for 1 h at 22°C (22+3 °C). The reaction progress was monitored by HPLC.

The reaction mass was cooled to 0°C (0+5°C) and chilled process water (1710 L) was add slowly into reaction mass and stirred for 2 h at 0°C (0+5°C). The solid formed was filtered and washed the solid with process water (228 L) at 0°C (0+5°C) and suck dried the solid for 30 min. Unload the wet material into the cleaned container. Charge methanol (228 L) and wet material into RBF and stir for 1 h at 30°C (30+5 °C). Filter the solid and wash the solid with methanol (57 L) and suck dry for 30 min. Unload the wet material into the cleaned container and dry the solid for 6 h in VTD at 65+5 °C under vacuum. After that cool the dryer temperature to below 35°C unload the dry material into the cleaned containers weigh it.

Result: Dry wt: 115.3 g; Obtained yield (%): 85.4% and 99.75% and single maximum impurity 0.08% HPLC assay: above 99%

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

10 kg of 3-hydroxy-6-bromopyrazine-2-carboxamide and 28.1 kg of Phosphorous oxychloride were suspended in 50 L of chlorobenzene and the resulting mixture was stirred at 60° C for 30 min. To this add 17.7 kg of N,N-Diisopropylethylamine, the resulting mixture stirred at 100°C for 4-5h, further 30 L of toluene was then added and distilled the solvent completely. 30L of toluene was added once again removed by distillation, the resulting mass add into 100 L process water at below 15°C, temperature raised to RT, stirred 2h. To this solution 50L toluene was added, layers separated. The aqueous layer was again extracted with toluene 30 L. The total organic layer washed with process water 50L, saturated bicarbonate solution 50L and with process water 50L. Total organic solvent distilled completely and the resulting crude was suspended in 30L cyclohexane, heated to 80°c and stirred for 30 min. The reaction mass was cooled to 10°C, precipitated solid was filtered and collected to give pure 3,6-dichloropyrazine-2- carbonitrile of 6.0 kg (yield: 75.9%, HPLC purity: 99.2%).

Preparation of 3,6 difluoropyrazine-2-carbonitrile:

35 g of potassium fluoride and 13.5 g of tetrabutyl ammonium bromide were suspended in a mixed solvent containing 400 ml of toluene and 200 ml of dimethyl sulfoxide. The toluene was subsequently removed by distillation at normal pressure. A further 400 ml of toluene was then added and once again removed by distillation, thereby removing moisture from the system. 140 g of a toluene solution of 3,6-dichloropyrazine-2- carbonitrile with a concentration of 24.7% was then added to the reaction system, and the resulting mixture was stirred at 60° C for 2.5 hours. Subsequently, 200 ml of toluene and 300 ml of water were added, and separation was performed. The organic layer was washed with 200 ml of water, followed by addition of 200 ml of water and concentrated hydrochloric acid to the organic layer to adjust the pH to 1.6, and another separation was performed. The organic layer was then washed with 200 ml of a 5% sodium chloride solution. Quantitative analysis by HPLC of the obtained organic layer revealed an equivalent yield of pure 3,6-difluoropyrazine-2-carbonitrile of 26.0 g (yield: 92.3%, HPLC purity:99.81%).

Preparation of 3,6 difluoropyrazine-2-carbonitrile DCHA salt:

40 ml of acetic acid was added at 5 to 15 °C to a 175 ml N,N-dimethylformamide solution of 50 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 72.7 g of triethylamine was added drop wise and the solution was stirred for 2hours. 38 ml of water and 3.8 ml of ammonia water were added to the reaction mixture, and then 150 ml of water and 3.8 g of active carbon were added. The insolubles were filtered off and the filtered cake was washed with 110 ml of water. The filtrate and the washings were combined, the pH of the combined solution was adjusted to 9.2 with ammonia water. To this 150 ml of acetone and 75 ml of toluene were added, followed by dropwise addition of 77.1 g of dicyclohexylamine. Then 105 ml of water was added dropwise, the solution was cooled to 5°C, and the precipitate was filtered and collected to give 96.8 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product (85% yield, HPLC purity:99.91%).

Preparation of Favipiravir:

100 mL of toluene and a sodium hydroxide aqueous solution (prepared by dissolving 6.56 g of sodium hydroxide in 200 mL of water) were added to 50.0 g of 3,6- difluoropyrazine-2-carbonitrile dicyclohexylamine salt, and the obtained mixture was then stirred at room temperature for 30 minutes. The reaction solution was left at rest for 10 minutes, and the upper layer was then removed. 100 mL of toluene was added to the lower layer, and it was then stirred and left at rest for 10 minutes. Thereafter, the upper layer was removed. Thereafter sodium hydroxide aqueous solution (prepared by dissolving 5.93 g of sodium hydroxide in 50.0 mL of water) was added to the lower layer. Subsequently, while keeping the internal temperature at 15 to 20° C, 26.8 mL of 40.0% v/w hydrogen peroxide was added dropwise to the mixture. The obtained mixture was stirred at 25° C for 30 minutes, and the pH of the solution was adjusted to pH 6.5 to 8.0 by hydrochloric acid. Thereafter, the mixture was heated to 40° C, so that the solid was completely dissolved in the solution. Thereafter, 2.50 g of activated carbon was added to the reaction solution, and the obtained mixture was then stirred at 40° C. for 30 minutes, followed by filtration. Filtered solid was washed with 50.0 mL of water, and hydrochloric acid was then added to a mixed solution of a filtrate and a washing solution at an internal temperature of 35 to 45° C., so that the pH thereof was adjusted to 3 to 4. The mixed solution was cooled to 0 to 5° C, and it was then stirred for 1 hour. Thereafter, the precipitated solid was filtrated, and it was then washed with 50.0 mL of water and 50.0 mL of isopropyl alcohol, so as to obtain 20.6 g of a white solid (Favipiravir). Yield: 84.0%, HPLC purity: 99.75%

Claims

We Claim :

1. An improved process for the preparation of compound having the Formula (I)

Formula (I) or its salts which comprises brominating the compound of Formula (III) O

₍ ^N ₂

N ONa Formula (III) in a solvent system wherein the reaction medium is homogenous during the reaction, wherein the reaction does not involve use of a base / acid.

2. The process as claimed in claim 1, wherein the brominating agent is Br₂, N- bromosuccinamide, 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one (TBCD) in a molar ratio of 1:1 tol:10 to compound of formula (I).

3. The process as claimed in claims 1 and 2, wherein brominating agent is Br₂.

4. The process as claimed in claim 1, wherein the solvent is selected from acetonitrile, propionitrile, butyronitrile, isobutyronitrile formamide, dimethylformamide, dimethylsulfoxide, dimethyl acetamide N-methyl-2- pyrrolidone, N-methylformamide, 2-pyrrolidone, l-ethenyl-2-pyrrolidone or mixtures thereof.

5. The process as claimed in claims 1 and 3, wherein the solvent is acetonitrile, dimethylformamide, or mixtures thereof.

6. The process as claimed in claim 1, wherein the process for the preparation of compound having the Formula (I)

Formula (I) or its salts comprise brominating the compound of Formula (III) O H₂

N ONa Formula (III) in a solvent system wherein the reaction medium is homogenous during the reaction, wherein the reaction does not involve use of a base / acid followed by purification using a polar protic solvent. The process as claimed in claim 6, wherein polar protic solvent used in the purification of the intermediate compound of formula (I) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or mixtures thereof. An improved process for the preparation of compound having the Formula (I)

Formula (I) or its salts which comprises:

(a) brominating the compound of Formula (III)

Formula (III) in a solvent system wherein the reaction medium is homogenous during the reaction, wherein the reaction does not involve use of a base / acid,

(b) treating the reactions mass with chilled water,

(c) filter the solid followed by treating with methanol, and

(d) filter the solid and wash with methanol. The process for preparing of Favipiravir having the Formula (II)

Formula (II) or its salts comprising the process for preparing compound of Formula (I) as claimed in any of claims 1-8. The process as claimed in claim 9, wherein Favipiravir is in high purity.