WO2021255681A1

WO2021255681A1 - A simple process for the preparation of favipiravir and its intermediates thereof

Info

Publication number: WO2021255681A1
Application number: PCT/IB2021/055354
Authority: WO
Inventors: Sudhir Nambiar; Goverdhan Gilla; Nageshwar Gunda; Narayan Subhash Chakor; Ramesh Mokal; Rahul Bhalerao; Kiran Avinash Bapat; Hemant Prabhakar PIMPARKAR; Rajamouli Srihari SAMALA
Original assignee: Hikal Limited
Priority date: 2020-06-17
Filing date: 2021-06-17
Publication date: 2021-12-23

Abstract

The present invention relates to a simple process for the preparation of Favipiravir of Formula (I). The present invention further relates to an improved process for the preparation of substantially pure 2-aminomalonamide of formula (II) a key starting material of Favipiravir.

Description

“A SIMPLE PROCESS FOR THE PREPARATION OF FAVIPIRAVIR AND ITS INTERMEDIATES THEREOF”

RELATED APPLICATION

This application claims combined benefit of Indian provisional application no. 202021025469, filed on June 17, 2020, and 202021030969, filed on July 20, 2020; the contents of which were incorporated by reference herein.

FIELD OF INVENTION

(I) (II)

BACKGROUND OF THE INVENTION

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide known as Favipiravir is a compound which is originally useful for the prevention and treatment of viral infectious diseases, particularly influenza viral infectious diseases. Suddenly Favipiravir has become popular because it is said to be a promising compound for the treatment of infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many pharmaceutical companies have urgently started clinical trials to prove the efficacy for treating the said disease using Favipiravir. Hence manufacturing the Favipiravir and substantially pure key starting material 2- aminopropanediamide in a simple and economical process has become urgent priority.

Numerous patents/patent applications such as USRE43748 El, US8168789 B2, EP1256588 Bl, WO 2018/003946 Al, CN 107226794 A, J. Am. Chem. Soc., 1948, vol. 71, page 78-80, WO2007144686A1, US8664405B2, and

JP2010241805A and the like, have disclosed process for preparation of Favipiravir and 2-aminopropanediamide. The known processes, however, have one or the other disadvantages, for example, those as mentioned below: (i) involve more number of reaction steps; (ii) involvement of explosive step i.e, concentrating hydroxyiminomalonate; (iii) the intermediate for manufacturing Favipiravir is either a labile compound or having less purity; (iv) troublesome operations such as extraction, column chromatography and removal of the solvent by distillation are necessary; (v) harmful reaction/reagents involvement and (vi) the yield is low.

To overcome the limitations of the processes known in the art, the inventors of the present invention have developed a simple process to produce Favipiravir in two reaction steps and a substantially pure intermediate of 2-aminomalonamide.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a two-step process for the preparation of Favipiravir of formula (I) from 2-aminomalonamide.

In another aspect, the present invention relates to a process for the preparation of Favipiravir of formula (I) using suitable fluorinating agent.

In another aspect, the present invention relates to a process for the preparation of Favipiravir of formula (I) where the process comprises the steps of:

(a) reacting 2-aminomalonamide of formula (II) with glyoxal in presence of suitable reagent to afford pyrazine-amide of formula (III) where R is hydrogen, metal ion;

(II) (III) (b) fluorinating the pyrazine-amide of formula (III) using suitable fluorinating agent to obtain Favipiravir of formula (I)

In another aspect, the present invention relates to a process for the preparation Favipiravir of formula (I) where pyrazine-amide of formula (III) where R is hydrogen, metal ion; is reacted with suitable fluorinating agent to Favipiravir of formula (I).

In one embodiment of the invention where the 2-aminomalonamide of formula (II) is reacted with glyoxal in presence of suitable reagent to afford pyrazine- amide of formula (III) where R is hydrogen, metal ion.

In one embodiment of the invention where 2-aminomalonamide of formula (II) is substantially pure having purity greater than 95%, where dimer impurity less than 5%, and a cyclic amide impurity less than 0.5%.

In another aspect, the present invention relates to a process for the preparation of a substantially pure 2-aminopropanediamide of formula (II) having a dimer impurity less than 5% and a cyclic amide impurity less than 0.5%.

(dimer impurity) (cyclic amide impurity) In another aspect, the present invention where Favipiravir of formula (I) is prepared from readily available 2-aminomalonamide of formula (II) or prepared by a process disclosed in present invention.

In another aspect, the present invention relates to a substantially pure 2- aminomalonamide (II), which is prepared by a process comprising steps of:

(a) reacting a dialkyl malonate (1) wherein Ri is Ci-C4alkyl, with sodium or potassium nitrite in water in presence of acid to obtain dialkylhydroxyiminomalonate(2);

(b) reducing dialkyl hydroxyiminomalonate(2) using hydrogenating agent in a solvent to obtain dialkyl aminomalonate (3), which is further treated with ammonia in solvent to obtain 2-aminomalonamide of formula (II)

In another aspect, the invention where Favipiravir of formula (I) is prepared from pyrazine-amide of formula (III) where R is hydrogen, metal ion.

In another aspect, the invention where pyrazine-amide of formula (III) is isolated as free acid or corresponding metal ion salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The term solvent used herein, refers to the single solvent or mixture of solvents.

In another embodiment the process for the preparation of Favipiravir of formula (I) is illustrated in following synthetic scheme:

(II) (III) (I) where R is hydrogen or metal

In one embodiment of the invention where glyoxal which is used in less than 50% concentration.

In another embodiment of present invention, wherein the suitable reagent in preparation of compound formula (III) is a base which is selected from inorganic base or organic base.

In another embodiment of present invention, wherein inorganic base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, and organic base is selected from triethyl amine, diisopropylethylamine amine and tert-butyl amine.

In another embodiment of the invention, wherein metal ion salt is sodium or potassium.

In another embodiment of present invention, wherein preparation of compound (III) is carried out at ambient to reflux temperature, and for 4-6 hours (hrs.). In another embodiment of the invention, wherein fluorinating reaction is carried- out in presence or absence of phase transfer catalyst (PTC).

In another embodiment of the invention, wherein phase transfer catalyst (PTC) is selected from 18 crown ethers, tetrabutylphosphonium bromide, tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium fluoride (TBAF), tetrabutyl ammonium chloride, tetrabutyl ammonium iodide or any other PTC known in the art.

In another embodiment of the invention, wherein fluorination is carried out using any suitable fluorinating agent which is known to a person skilled in the art.

In another embodiment of the invention, wherein suitable fluorinating agent is selected from selectfluor (l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate)), 1 -Fluoropyridinium tetrafluoroborate, 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis

(hexafluorophosphate) (FTEDA-PF6), l-methyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoro borate) (Selectfluor II), l-methyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (Selectfluor II- PF6), N-fluorobenzenesulfonimide (NFSI) and Me-NFSI, l-fluoro-4-hydroxy- l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (NFTh) and (l-fluoro-1,3- dihydro-3 ,3-dimethyl- 1 ,2-benziodoxle) fluorobenziodoxole.

In another embodiment of present invention, wherein fluorinating reaction is carried-out in presence solvent, which is selected from acetone, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, isopropyl ether, cyclohexane, heptane, toluene, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, and dimethyl sulfoxide.

In another embodiment of present invention, wherein fluorinating reaction is carried out at ambient to reflux temperature, and for 10-12 hours.

In another embodiment the process for the preparation of substantially pure 2- aminomalonamide of formula (II) is illustrated in the following synthetic scheme:

In another embodiment of the present invention, wherein the dialkyl malonate (1) wherein Ri is C1-C4 alkyl is preferably dimethyl malonate and diethyl malonate.

In another embodiment of the invention, wherein the acid used for preparation of compound (2) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or methanesulfonic acid.

In another embodiment of the invention, wherein the solvent used for isolation of compound (2) is selected from ether solvent such as diethyl ether, diisopropyl ether, methyl-t-butyl ether, methoxybenzene; ester solvent such as ethyl acetate, n-butyl acetate; aliphatic hydrocarbons such as hexane, heptane, cyclohexane; and halogen solvent such as chloroform and methylene chloride.

In another embodiment of the invention, wherein reduction reaction is performed by using hydrogen in presence of catalyst, which is selected from nickel, palladium, ruthenium, rhodium, with or without support; platinum oxide, sodium borohydride, Lithium aluminium hydride; preferably from palladium on carbon, platinum on carbon, Raney nickel.

In another embodiment of the invention, wherein the solvent used in reduction reaction is selected from methanol, ethanol, and isopropanol.

In an embodiment, of the present invention, wherein the process for the preparation of substantially pure 2-aminomalonamide of formula (II) having purity greater than 95% and with minimize the formation of dimer impurity less than 5%, preferably less than 3% and a cyclic amide impurity less than 0.5%.

(dimer impurity) (cyclic amide impurity)

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL

Example 1: Preparation of Favipiravir formula (I)

Step-1: Preparation of compound formula (III)

In a Round bottom flask (RBF), sodium hydroxide (25.63 g, 0.6407 mol), water (lOO.OmL) was added and cooled -10 to -5°C. To this solution 2- aminomalonamide (II, 50 gm, 0.4271 mol) added and stirred and a 40% aq. Glyoxal (77.47 gm, 0.5339 mol) was added and further stirred at 20°C to 35°C for 3-4 hrs. To this reaction mixture, methanol (100 mL) was added and cooled to 0°C to 5°C for 3-4 hrs. The obtained solid was filtered and washed with methanol and dried the compound to obtain pure sodium salt of pyrazine compound of formula (III, 51.8 gm, 69 %, 99.78 % HPLC purity).

Step-2: Preparation of Favipiravir formula (I)

In a Round bottom flask (RBF) sodium salt of pyrazines (III, 0.2 g, 1.2 mmol), selectfluor (1.3 lg, 3.7 mmol), and 18 crown ether (cat.) mmol) and MeCN (8ml) were added and reaction mixture was heated at 85 °C for 12 h. The reaction completion was ensured by TLC. After completion, solvent was removed under vacuum and reaction mixture was stirred into a mixture of EtOAc: H20 (10 ml, 1:1) for 10-15 min. The organic layer was separated, and aq. layer extracted with EtOAc. The combined organic layer was dried over sodium sulfate, filtered, and concentrated to obtain Favipiravir. Example 2: Preparation of 2-aminomalonamide formula (II)

Step-1: Preparation of compound formula (2)

In Round bottom flask (RBF), dialkyl malonate (1, 1.0 kg) was charged and cooled at 0°C to 5°C. To this, acetic acid solution (1197 g acetic acid in 1620 ml water) was slowly added maintaining the temperature below 10°C and further cooled to 0°C to 5°C. To the reaction mixture, sodium nitrite (1300g) was charged portion wise under stirring at same temperature. The reaction mixture was allowed to room temperature (RT) and stirred for 15 to 40 min. Further, the temperature was raised to 40°C to 50°C and stirred for 2 to 3 hours. The reaction completion was ensured by GC and cooled to 25°C to 30°C. To the reaction mixture, 2000 ml methyl tert-butylether (MTBE) was charged and stirred for 30 to 40 min. The aqueous and organic layers were separated. To the aqueous layer, 2000 ml MTBE was charged and stirred for 30 to 40 min. The aqueous and organic layers were separated. To the combined organic layers, 2000 ml water were charged and stirred for 30 to 40 min. The aqueous and organic layers were separated. The pH of organic layer was adjusted between pH 7 to 8 by adding sodium bicarbonate solution. The aqueous and organic layers were separated. The organic layer was washed with saturated brine solution. The organic layer was concentrated to obtain oily mass of compound formula [(2) (1.1 Kg, % yield: 93%)].

Step-2: Preparation of 2-aminopropanediamide (II)

In an autoclave, compound formula (2, 1000 g), methanol (3000 ml) were charged. To this, 5% Pd/C (50% wet) (7.5 g in 3.75 ml water and 7.5 ml methanol) was charged. Autoclave was flushed with Nitrogen (minimum 2 Kg/cm²) followed by hydrogen (pressure minimum 2 Kg/cm²). Hydrogen pressure (10-12 Kg/cm²) was applied and maintained for 30 to 40 min. Raised the temperature to 40°C to 45 °C and stirred for 3 to 5 hours or till hydrogen consumption stopped. Ensured the reaction completion by GC, released hydrogen pressure, and flushed with Nitrogen (minimum 2 Kg/cm²). The reaction mixture was cooled to 25°C to 30°C and filtered through hyflo bed. An autoclave was flushed with methanol (100 mL) and the flushing was used for washing the hyflo bed. The filtrate and washings were combined, and it was transferred into the cleaned autoclave (10 L). The autoclave was flushed with Nitrogen (minimum 2 Kg/cm²). The reaction mixture was cooled at -10°C to 10°C. The ammonia gas pressure (2 to 3 Kg/cm²) was applied at temperature below 10°C. The reaction mixture was allowed to 15°C to 20°C and stirred for 4 to 12 hours maintaining the pressure at 2 to 3 Kg/cm². Ensured the completion of reaction by HPLC. The reaction mixture was filtered, washed with methanol (1.0L, 1.0V) and the solid was dried under vacuum for 6 to 8 hours to obtain compound formula (II) [472.2g, % yield - 95%, dimer impurity : less than 5.0%, cyclic amide impurity : less than 0.5%, HPLC purity: >96%].

Claims

CLAIM:

1. A process for the preparation of Favipiravir of formula (I) which comprises steps of: (a) reacting a 2-aminomalonamide of formula (II) with glyoxal in presence of reagent to afford pyrazine-amide of formula (III) where R is hydrogen, metal ion;

(b) fluorinating the pyrazine-amide of formula (III) using a fluorinating agent to obtain Favipiravir of formula (I).

2. The process as claimed in claim 1, wherein the 2-aminomalonamide (II) is prepared by a process comprising steps of:

(a) reacting a dialkyl malonate (1) wherein Ri is C₁-C₄ alkyl, with sodium or potassium nitrite in water in presence of acid to obtain dialkylhydroxyiminomalonate (2);

(b) reducing dialkyl hydroxyiminomalonate (2) using hydrogenating agent in a solvent to obtain dialkyl aminomalonate (3), which is further treated with ammonia in solvent to obtain 2-aminomalonamide of formula (II).

3. The process as claimed in claim 2, wherein the 2-aminomalonamide (II) is substantially pure having purity greater than 95%, where dimer impurity is less than 5%, and a cyclic amide impurity is less than 0.5%.

(dimer impurity) (cyclic amide impurity)

4. A process for the preparation of Favipiravir of formula (I) by reacting pyrazine-amide of formula (III) with a fluorinating reagent, where the pyrazine-amide of formula (III) is prepared by a process claimed in claim 1 (a).

5. The process as claimed in claim 1, wherein said reagent in claim 1 (a) is inorganic base or organic base.

6. The process as claimed in claim 1, wherein pyrazine-amide of formula (III) is isolated as a free acid or metal ion salt where the metal is sodium or potassium.

7. The process as claimed in claim 1 and 4, wherein said fluorinating regent is selected from selectfluor (l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate)), 1 -Fluoropyridinium tetrafluoroborate, 1 -chloromethyl-4-fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (FTEDA-PF6), 1-methyl- 4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro borate) (Selectfluor II), 1- methyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octanebis(hexafluorophosphate) (Selectfluor II-PF6), N-fluorobenzenesulfonimide (NFSI) and Me-NFSI, l-fluoro-4- hydroxy-l,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (NFTh) and (1-fluoro- 1 ,3-dihydro-3 ,3-dimethyl- 1 ,2-benziodoxle) fluorobenziodoxole.

8. The process as claimed in claim 1 and 4, wherein fluorinating reaction is carried out in presence or absence of phase transfer catalyst which is selected from 18 crown ether, tetrabutylphosphonium bromide, tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium fluoride(TBAF), tetrabutyl ammonium chloride, and tetrabutyl ammonium iodide.

9. The process as claimed in claim 1 and 4, wherein the fluorinating reaction is carried out in presence of solvent, which is selected from acetone, methyl isobutyl ketone, acetonitrile, methyl tert -butyl ether, diisopropyl ether, cyclohexane, heptane, toluene, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide.

10. The process as claimed in claim 2, wherein the acid used for preparation of compound (2) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, and methanesulfonic acid.

11. The process as claimed in claim 2, wherein the catalyst used in preparation compound formula (II) is selected from platinum oxide, sodium borohydride, Lithium aluminium hydride, palladium on carbon, platinum on carbon and Raney nickel.

12. The process as claimed in claim 2, wherein the solvent used for the preparation of compound (II) is selected from methanol, ethanol, and isopropanol.