Claims:1. A two-stage process for synthesis of a diamide derivative, wherein the process comprises:
(i) reacting an ester of malonic acid (Formula II) with sulfonyl chloride to obtain a reaction mass 1 comprising 2-chloromalonate derivative (Formula III), and
,
wherein R = -CH3, -CH2CH3;

(ii) reducing the 2-chloromalonate derivative (Formula III) with aqueous ammonia to obtain a reaction mass 2 comprising the diamide derivative, wherein the diamide derivative is 2-aminomalonamide (Formula I);
,
wherein R = -CH3, -CH2CH3;
wherein the ester of malonic acid is selected from diethyl malonate and dimethyl malonate; and
wherein the 2-chloromalonate derivative is a diethyl-2-chloromalonate or dimethyl-2-choloromalonate.
2. The process as claimed in claim 1, wherein the sulfonyl chloride in step (i) is added as neat or in presence of an organic solvent.
3. The process as claimed in claim 2, wherein the organic solvent is selected from the group consisting of dichloromethane, Chloroform, toluene, carbontetrachloride and neet.
4. The process as claimed in claim 1, wherein in step (i) sulfonyl chloride is added dropwise for 1-3 hours at a temperature ranging from 5-25℃.
5. The process as claimed in claim 1, wherein in step (i) the reaction mass 1 is stirred at a temperature ranging from 35-45℃ for 2-5 hours followed by distillation at a temperature ranging from 40-50C.
6. The process as claimed in claim 1, wherein in step (ii) the aqueous NH3 was added at a temperature ranging from 0-250C, preferably at 0-5oC.
7. The process as claimed in claim 1, wherein in step (ii) the reaction mass 2 is maintained for 5-7 hours and cooled at a temperature ranging from 0-5℃.
8. The process as claimed in claim 1, wherein the reaction mass 2 obtained in step (ii) is filtered and washed with cold water to obtain the diamide derivative.
9. The process as claimed in claim 1, wherein the diamide derivative is obtained in an amount upto 78 wt%.
10. The process as claimed in claim 1, wherein the diamide derivative is an intermediate of Favipiravir.
, Description:FIELD OF THE INVENTION

The present invention relates to a process of synthesis of a diamide derivative that serves as an intermediate in the process of preparation of Favipiravir. More particularly, the present invention relates to an improved process for two-stage synthesis of 2-aminomalonamide wherein the process results in higher yield of the end product and prevents formation of any unwanted impurities.

BACKGROUND OF THE INVENTION

Favipiravir is a modified pyrazine analog that was initially approved for therapeutic use in resistant cases of influenza. The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes. Favipiravir not only inhibits replication of influenza A and B, but the drug has shown promising effect in the treatment of avian influenza and may be an alternative option for influenza strains that are resistant to neuramidase inhibitors. It is a prodrug of a purine nucleotide, Favipiravir ribofuranosyl-5'-triphosphate and the agent has demonstrated broad activity against other RNA viruses. Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19. The oral antiviral medication Favipiravir, that prevents the replication phase of the virus life cycle, leads to significant improvement in clinical cure in patients with mild to moderate COVID-19. In June 2020, Glenmark received manufacturing and marketing approval from India’s drug regulator for Favipiravir (FabiFlu), making it the first oral approved medication in India for the treatment of mild to moderate COVID-19. The generally good tolerance of human patients to Favipiravir and the high barrier to the development of resistant viral strains indicate that this drug holds great promise for clinical use around the world.

Favipiravir was first synthesized in 2000 by a route consisting of seven steps, involving amination with a costly reagent resulting in very low yield of product. Improved methodologies for the synthesis of Favipiravir have been reported in recent years. A four-step method enabled the synthesis of Favipiravir from commercially available 3-hydroxypyrazine-2-carboxylic acid, which was subjected to esterification and amidation. The nitration of pyrazine ring was followed by reduction of the nitro group in the presence of Raney nickel, allowing to minimize the number of byproducts. Yet, the overall yield of the target product was very low, only 8%. Thus, the primary aim is to obtain significant amount of Favipiravir using non-expensive reagents and in lesser number of steps to same time and money. One of the prime approaches in the process of synthesis of Favipiravir is through the formation of a diamide derivative as intermediate and employing diethyl malonate as the starting material for arriving at the said diamide intermediate. Accordingly, different routes of synthesis of this diamide derivative have been proposed by different groups of researchers with the aim to improve product yield.

US8664405B2 discloses a method for preparing an organic sulfonic acid salt of aminomalonamide by direct recrystallization performed in an alcoholic solvent with the addition of the organic sulfonic acid into a crude product obtained through the reaction of diethyl-2-aminomalonate and ammonia in an organic solvent. The patent discloses synthesis of 2-aminomalonamide (crude product) staring from diethyl-2-aminomalonate using ammonia in methanol as reagent and heating for 19 hours at 60℃ under argon atmosphere. The diethyl-2-aminomalonate employed in the above reaction is obtained by neutralization of hydrochloric acid salt of diethyl 2-aminomalonate.

Wang Huan et al (China Pharmaceutical Industry Journal, 2014,45 (11): 1009-1012) discloses synthesis of Favipiravir employing diethyl amino acid hydrochloride as the starting material that leads to formation of the intermeriate diamide derivative of Favipiravir by treatment with sodium bicarbonate in presence of methylene dichloride followed by reaction with ammonia in ethanol.

Further, US 3306900 discloses a process of synthesis of 4,6-dihydroxypyrimidine which is a valuable starting material for the synthesis of materials related to nucleic acid. The reaction involving formation of 4,6-dihydroxypyrimidine proceeds through the steps of admixing amidating agent selected from the group consisting of ammonia and formamide with di (lower) alkyl malonate in a reaction medium containing a catalyst selected from the group consisting of alkali metal and alkali metal (lower) alkoxide and allowing the ensuing amidation reaction to proceed until completion of the formation of malonic acid diamide.

Wang et al (J. Med. Chem. 2016, 59, 4611−4624) discloses synthesis and anti-influenza activity of pyridine, pyridazine, and pyrimidine C‑Nucleosides as Favipiravir (T-705) analogues based on different reaction schemes involving a nucleophilic addition in the presence of LDA, reduction with triethylsilane in the presence of a strong Lewis acid, oxidative hydrolysis, desilylation reaction and many other complex reaction pathways.

Thus, although many attempts have been made to arrive at the desired drug Favipiravir employing a simple route of synthesis, very few are available which refer to the involvement of a diamide intermediate. Moreover, synthesis of the diamide derivative as available in the prior art does not result in significant yield of the said diamide. Consequently, being a key intermediate in the process of synthesis of the oral anti-retroviral drug, Favipiravir, there remains an unmet need for providing a simple synthetic scheme with improved product yield of the diamide intermediate. Most of the conventional methods involve time consuming procedures of synthesis along with poor commercial scale production of the diamide intermediate. This necessitates for an advanced process of synthesis of diamide derivatives as intermediate in the synthesis of Favipiravir whereby the yield of the desired product is improved even upon employing the process on industrial scale and the process ensures yield of pure intermediate material for subsequent synthesis of anti-retroviral agent.

OBJECTIVES OF THE INVENTION

The primary objective of the present invention is to provide an improved process for synthesis of a diamide derivative which is an intermediate in the process of synthesis of the anti-retroviral drug Favipiravir.

Another objective of the present invention is to provide an improved process for the synthesis of 2-aminomalonamide without involving any expensive reagent and ensuring complete synthesis of the desired product employing minimum number of reaction steps.

A preferred objective of the present invention is to provide an improved process for the synthesis of the diamide derivate with less impurities and high yield.

Yet another objective of the present invention is to provide a process with less reaction time and to obtain the desired product at very competitive market price.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for synthesis of the diamide derivative that serves as an intermediate in the process of preparation of the anti-retroviral drug, Favipiravir. The present invention thus provides a two-stage process involving lesser number of reagents that results in higher yield of the end product without involving formation of any harmful impurities.

The present invention provides a two-stage process for synthesis of a diamide derivative, wherein the process comprises:
(i) reacting an ester of malonic acid (Formula II) with sulfonyl chloride to obtain a reaction mass 1 comprising 2-chloromalonate derivative (Formula III), and
,
wherein R = -CH3, -CH2CH3;

(ii) reducing the 2-chloromalonate derivative (Formula III) with aqueous ammonia to obtain a reaction mass 2 comprising the diamide derivative, wherein the diamide derivative is 2-aminomalonamide (Formula I);
,
wherein R = -CH3, -CH2CH3;
wherein the ester of malonic acid is selected from diethyl malonate and dimethyl malonate; and
wherein the 2-chloromalonate derivative is a diethyl-2-chloromalonate or dimethyl-2-choloromalonate.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: Schematic representation of the process of preparation of the diamide derivative, 2-aminomalonamide (Formula I) employing diethyl malonate as the starting material.
Figure 2: 1H NMR spectra for identification of 2-aminomalonamide (Formula I).

DESCRIPTION OF THE INVENTION

For the purpose of promoting an understanding of the principles of the present disclosure, reference will now be made to the specific embodiments of the present invention further illustrated in the drawings and specific language will be used to describe the same. The foregoing general description and the following detailed description are explanatory of the present disclosure and are not intended to be restrictive thereof.

The present invention relates to a process for the preparation of a diamide derivative that is employed as an intermediate in the process of synthesis of Favipiravir. The present invention advantageously provides an improved two-stage process for the preparation of the said amide with lesser number of impurities and higher yield. The process requires less time, lesser number of reagents and provides better yield of the end product at competitive market price which in turn reduces the cost of production of the anti-retroviral drug, Favipiravir. The present invention thus provides an improved process for two-stage synthetic route of the diamide derivative employing an ester of malonic acid as the starting material, wherein the process is cost effective and prevents formation of any unwanted impurities.

The present invention provides a two-stage process for synthesis of a diamide derivative, wherein the process comprises (Figure 1):
(i) reacting an ester of malonic acid (Formula II) with sulfonyl chloride to obtain a reaction mass 1 comprising 2-chloromalonate derivative (Formula III), and
,
wherein R = -CH3, -CH2CH3;

(ii) reducing 2-chloromalonate derivative (Formula III) with aqueous ammonia to obtain a reaction mass 2 comprising the diamide derivative, wherein the diamide derivative is 2-aminomalonamide (Formula I);
,
wherein R = -CH3, -CH2CH3;
wherein the ester of malonic acid is selected from diethyl malonate and dimethyl malonate; and
wherein the 2-chloromalonate derivative is a diethyl-2-chloromalonate or dimethyl-2-choloromalonate.

In the reaction involving diethyl malonate as the starting material, diethyl-2-chloromalonate is formed in stage 1 followed by formation of 2-aminomalonamide. While in the reaction process involving dimethyl malonate as the starting material, dimethyl-2-chloromalonate is formed in stage 1 followed by formation of 2-aminomalonamide in stage-2.

In an embodiment, the sulfonyl chloride in step (i) is added as neat or in presence of an organic solvent.

In another embodiment, the organic solvent employed in the disclosed process is selected from the group consisting of dichloromethane, Chloroform, toluene, carbontetrachloride and neet. Preferably the organic solvent is dichloromethane.

In a preferred embodiment, in step (i) of the disclosed process the sulfonyl chloride is added dropwise for 1-3 hours at a temperature ranging from 5-25℃.

In yet another embodiment, in step (i) of the disclosed process the reaction mass 1 is stirred at a temperature ranging from 35-45℃ for 2-5 hours followed by distillation at a temperature ranging from 40-500C.

In another embodiment, in step (ii) of the disclosed process the aqueous NH3 was added at a temperature ranging from 0-250C, preferably at 0-5oC.

In another embodiment, in step (ii) of the disclosed process the reaction mass 2 is maintained for 5-7 hours and cooled at a temperature ranging from 0-5℃.

In another embodiment, the reaction mass 2 obtained in step (ii) of the disclosed process is filtered and washed with cold water to obtain the diamide derivative.

In yet another embodiment, the diamide derivative is obtained in an amount upto 78 wt% from the presently disclosed process.

In a further embodiment, the diamide derivative is an intermediate of Favipiravir and is employed in the process of synthesis of the anti-retroviral drug, Favipiravir.

The advantages of the disclosed process include:
• Safe and easy to scale-up in commercial plant.
• 2-aminomalonamide is obtained in a two-step process without requiring the use of any expensive metal catalyst like Raney Ni, Pd, etc.
• Significant reduction of effluent generation.
• The process does not refer to the use of sodium nitrite, thereby no possibility for formation of corresponding nitroso amine impurity.
• Cost competitive process for operating in commercial plant.
• Both dimethyl malonate and diethyl malonate can be used as the starting material in the disclosed process.

Some illustrative non-limiting examples of the present invention are described below.

EXAMPLE

Example 1: Process carried out in presence of organic solvents
To a stirred solution of diethyl malonate (270 kg, 1562 mol) in dichloromethane (810 L, 3 Vol) sulfuryl chloride (300 kg, 1875 mol) was added drop wise for 2 hours at a temperature below 10℃. The resulting reaction mass was stirred at 38-42℃ for 4 hours. After completion of stirring using 20% Ethyl acetate in hexane, the reaction mass was distilled under reduced pressure at a temperature below 50℃ to get the intermediate product as a colourless oil.

The reaction mass was slowly transferred into another reactor, and aqueous NH3 (750 L, 3 Vol) was added at below 30℃. The reaction mass was maintained for 6 hours at room temperature. The reaction mixture was cooled to 0-5℃. The resulting solids are filtered and washed with cold water (50 L) to obtain the product 2-aminomalonamide 154 kg as cream colour solid (yield: 78%).

1H NMR (DMSO-D6, 400 MHz): δ 7.42 (S, 2H), 7.26 (S, 2H), 2.56 (brs, 2H), 3.75 (S, 1H) (Figure 2).

Example 2: Process without use of organic solvents (Neat reaction)
To a stirred solution of diethyl malonate (270 kg, 1562 mol) sulfuryl chloride (300 kg, 1875 mol) was added drop wise for 2 hours at a temperature below 10℃. The resulting reaction mass was stirred at 40-45℃ for 4 hours. After completion of stirring using 20% Ethyl acetate in hexane, the reaction mass was distilled under reduced pressure at a temperature below 50℃ to get the intermediate product as a colourless oil.

The reaction mass was slowly transferred into another reactor, and aqueous NH3 (750 L, 3 Vol) was added at a temperature below 30℃. The reaction mass was maintained for 6 hours at room temperature. Reaction mixture was cooled to 0-5℃. The resulting solids are filtered and washed with cold water (50 L) to obtain the product 2-aminomalonamide 138 kg as cream colour solid (yield: 70%)

Table 1: Comparison of yield of 2-aminomalonamide
Synthetic processes % yield (wt %)
Conventional process 65
Example 1 (in presence of an organic solvent) 78
Example 2 (without using organic solvents) 70

Form Table 1, it can be inferred that the yield of the 2-aminomalonamode (diamide intermediate of Favipiravir) is highest from Example 1 that is carried out as per the present invention in presence of an organic solvent. Further, Example 2 discloses that the method of the present invention can also be carried out neat in the absence of any organic solvent resulting in a yield of 70 wt% of 2-aminomalonamide. However, in both the cases the yield of the end product is much higher as compared to that obtained from the conventional process employed for the synthesis of the diamide derivative.