Claims:
1. A cost effective two steps process for the preparation of Molnupiravir of Formula1 comprising;

Formula 1
a) protection of Uridine (Formula 3) with 2,2 dimethoxypropane, followed by esterification with isobutyric anhydride and triazolation with 1,2,4-triazole sequentially in presence of inorganic acids, bases, dehydrating agents & phase transfer catalyst transfer catalyst in suitable organic solvents to obtain, ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl) pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl) methylisobutyrate, (Formula 2);

Formula 2

b) hydroxyl amination of the ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl)pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3] dioxol-4-yl)methyl isobutyrate intermediate of Formula 2 with reducing agent in presence of an organic or inorganic base followed by de-protection using an organic or inorganic acid in aqueous polar solvents to obtain ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate (Molnupiravir) (Formula 1).

2. The process as claimed in claim 1, step (a), wherein the solvent is selected from the group consisting of Methylene chloride, acetone, acetonitrile, isopropyl alcohol, methanol or ethanol alone or in combinations thereof.
3. The process as claimed in claim 1, step (a), wherein the inorganic acid is selected from the group consisting of sulphuric acid, hydrochloric acid, nitric acid etc.
4. The process as claimed in claim 1, step (a), wherein the base is, selected from triethylamine or liquor ammonia..
5. The process as claimed in claim 1, step (a), wherein the dehydrating agent is selected from the group consisting of phosphoric oxychloride, phosphorous pentachloride, phosphorous trichloride, thionyl chloride etc.
6. The process as claimed in claim 1, step (a), wherein the phase transfer catalyst is selected from the group consisting of 4-dimethylamino pyridine, tetra butyl ammonium bromide or tri ethyl benzyl ammonium chloride.
7. The process as claimed in claim 2, step (b) wherein the reducing agent(s) is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine sulphate, hydroxylamine solution (50%) etc.
8. The process as claimed in claim 2, step (b) wherein the organic or inorganic base(s) for maintaining pH of reaction system is selected from ammonia solution, sodium hydroxide or potassium hydroxide etc.
9. The process as claimed in claim 2, step (b) wherein the organic or inorganic acids for maintaining pH of reaction system is selected from sulphuric acid, hydrochloric acid, trifluoro acetic acid, para toluene sulfonic acid etc.
10. The process as claimed in claim 2, step (b), wherein the aqueous polar solvent is selected from the group consisting of isopropyl alcohol, acetonitrile, methanol and ethanol either alone or in combinations thereof.
, Description:FIELD OF THE INVENTION:
The present invention relates to novel commercial process for the synthesis of Molnupiravir (Formula-1) with increased efficiency in terms of yield and purity. More particularly, the present invention provides two step synthesis for the production of Molnupiravir and hence suitable for commercial synthesis.

BACKGROUND OF THE INVENTION:
Molnupiravir (EIDD-2801/MK-4482) is an investigational, orally bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19. Molnupiravir has been shown to be active in several models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission, as well as SARS-CoV-1 and MERS.

Molnupiravir (MK-4482, EIDD-2801) is in development by Merck after licensing from Ridgeback Biopharmaceuticals as an orally dosed antiviral for the treatment of COVID-19. Animal studies have shown successful inhibition of SARS-CoV-2 as well as prevention of viral transmission. It proves to be safe and effective in ongoing clinical trials. This drug would be important to encounter SARS-CoV-2 virus pandemic; hence it will be useful for treating non-hospitalized patients with laboratory-confirmed COVID-19.

As density of the population is quite high in many cities of India; control of the spread of COVID-19 remains challenging. A deadly 2nd wave of COVID-19 is overwhelming India. New cases have hit per day, and people have lost their lives. Even after the pandemic subsides, there is a possibility of a resurgence of COVID-19 with new variants at any given time. Therefore, it is important to contain the spread of emergence of new variants of novel coronavirus or other viruses at a future date is also extremely important. The quantum of drugs required is quite huge and challenging for commercial-scale production especially for active pharmaceutical ingredients (APIs) like Molnupiravir which involves complex chemistry. Therefore, the development of cost-effective process is the need of the hour for the synthesis of API Molnupiravir to cater to the demand in India and the rest of the world. Moreover, India is among very few countries in the world that produces APIs and always takes responsibility to provide APIs to other pharmaceutical producers of the world during any crisis or epidemic. Therefore, there exists a huge need and potential for the production and commercialization of API Molnupiravir. There is ample literature available on the synthesis of Molnupiravir, as discussed herein below.

WO2019173602-discloses 4’-halogen containing nucleotide and nucleoside therapeutic compositions of general formula I and uses related thereto. WO’602 explains derivatives of 4’-halogen nucleosides optionally conjugated to a phosphorus oxide or salts thereof, prodrugs or conjugate compounds or salts thereof comprising an amino acid ester, lipid or a lipid or derivative linked by a phosphorus oxide to a nucleotide or nucleoside.

Formula I
WO2019113462 discloses four stage synthesis of Molnupiravir (EIDD-2801), namely Protection, Esterification, Triazolation and Deprotection starting from Uridine. However, this process results in Molnupiravir in poor yields of 17%. The synthesis is shown in below scheme.

CN112608357 discloses a process for production of Molnupiravir by reacting Cytidine based intermediate with an enzyme. It is basically bio-catalyzed esterification reaction, carried out in micro–channel reactor to obtain Molnupiravir.

CN112552288 discloses a process of preparation method of 4-Oxime-s’ (2-methylpropionyl) Uridine and Molnupiravir.

An article titled “A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2” by V. Gopalsamuthiram et al. published in Synlett 2020, 31, A–C, DOI: 10.1055/a-1275-2848; Art ID: st-2020-v0498-l disclose the process for preparation of Molnupiravir from cytidine as depicted in the scheme below. However, this process results in Molnupiravir in poor yields of 44%.

Another article titled “Toward a Practical, Two-Step Process for Molnupiravir from Cytidine” by V. Gopalsamuthiram https://chemrxiv.org/engage/chemrxiv/article-details/60c753c6842e650f12db400d disclose the process for preparation of Molnupiravir from Cytidine with overall 60% yield as depicted in the scheme below. However, this process employs expensive biocatalysts and thus escalates the cost of the process.

Yet another article titled “A High-Yielding Synthesis of EIDD-2801 from Uridine” by V. Gopalsamuthiram https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/ejoc.202001340 disclose the process for preparation of Molnupiravir from uridine with overall 61% yield as depicted in the scheme below

The processes for the synthesis of Molnupiravir disclosed therein in the cited prior arts do not provide a cost-effective process suitable to be carried out on a commercial scale for the synthesis of Molnupiravir.

Further handling of reagents and biocatalyst is difficult; also the reactions are carried out at micro scale level which is not commercially viable. Also, the efficiency in terms of yield of the process of the cited prior arts is comparatively low.

Therefore, the present inventors felt that there is a scope to provide a more industrially feasible chemical process for the synthesis of Molnupiravir by employing reaction conditions that would be more feasible to carry out on a commercial scale as compared to the process disclosed by V. Gopalsamuthiram et al.

In view of the above, the present inventors have devised a process that can be extended successfully to accomplish a highly efficient process with a high yield of Molnupiravir. Further, the process of the present invention avoids use of bio-catalyst (enzymes) as reported in the cited prior arts. The use of economical raw materials with less number of reaction steps contributes towards better yield and sustainable product and thus can be offered on a commercial scale.

OBJECTS OF THE INVENTION
Therefore, the main object of the present invention is to provide a novel process for the synthesis of Molnupiravir using low cost raw materials and reagents and also to provide a convenient, economical process with only two manufacturing steps instead of four steps process for the preparation of high-quality compound, with increased efficiency in terms of yield.

Another object of the present invention is to provide a process for synthesis of Molnupiravir using environment-friendly reagents which are cost effective, does not involve use of expensive bio-catalyst enzyme and thus increases the overall reaction efficiency in terms of yield of Molnupiravir, as well as the reaction time cycle is shortened.

SUMMARY OF THE INVENTION
In accordance with the above objectives, the present invention provides a two-step synthesis process of Molnupiravir using low cost raw materials and reagents with increased efficiency in terms of yield.

In an aspect, the present invention provides a cost effective process for synthesis of Molnupiravir (Formula 1) which comprises;

a) Protection of Uridine (Formula 3) with 2,2 dimethoxypropane, followed by esterification with isobutyric anhydride and triazolation with 1,2,4-triazole sequentially in presence of inorganic acids, bases, dehydrating agents & phase transfer catalyst in suitable organic solvents to obtain ((3aR,4R,6R,6aR)-6-(4-(hydroxyl amino)-2-oxopyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)methyl isobutyrate (Formula 2);
b) hydroxyl amination of the ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl)pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3] dioxol-4-yl)methyl isobutyrate intermediate of Formula 2 with reducing agent in presence of an organic or inorganic base followed by de-protection using an organic or inorganic acid in suitable aqueous polar solvents to obtain ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate (Molnupiravir) (Formula 1).

In an aspect of the present process, a) Protection, esterification & triazolation; b) Hydroxylamination & deprotection/ dealkylation are performed in two steps instead of four steps in conventional process to give compound of Formula 1.

According to the process of the present invention, only two steps are required to achieve Molnupiravir with better yield & purity with a drastic reduction in the costs involved in isolation/extraction of the intermediates as well as in the reaction time cycle.

The present invention provides a process for synthesis of Molnupiravir using environment-friendly reagents which are cost effective; does not use expensive bio- catalyst, yet, increases the overall reaction efficiency in terms of yield of the final product, Molnupiravir.

Thus, the present invention provides a process for the preparation of Molnupiravir from uridine as starting material by strategically reordering of synthetic steps that can be conducted two steps, thereby improving the atom efficiency and the overall yield of the process to more than 70%.

More specifically, the process disclosed in the present invention involves two steps of manufacturing instead of three/four steps in conventional process using indigenous raw materials which are reasonably at low cost and are easily available. The reaction conditions used during manufacturing of Molnupiravir are also mild and suitable for industrial scale up.

DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be described in detail in its preferred and optional embodiments so that the various aspects therein can be more clearly understood and appreciated.

In an embodiment, the present invention relates to a cost effective two-step process for synthesis of Molnupiravir,
a) Protection of Uridine (Formula 3) with 2,2 dimethoxypropane, followed by esterification with isobutyric anhydride and triazolation with 1,2,4-triazole sequentially in presence of inorganic acids, bases, dehydrating agents & phase transfer catalyst in suitable organic solvents to obtain ((3aR,4R,6R,6aR)-6-(4-(hydroxyl amino)-2-oxopyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)methyl isobutyrate (Formula 2);

b) hydroxyl amination of the ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl)pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3] dioxol-4-yl)methyl isobutyrate intermediate of Formula 2 with reducing agent in presence of an organic or inorganic base followed by de-protection using an organic or inorganic acid in suitable aqueous polar solvents to obtain ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate (Molnupiravir) (Formula 1).

In one embodiment, Protection, esterification and triazolation of uridine to obtain the compound of Formula 2 is conducted in one step/one pot.

In another embodiment of the present process, hydroxylamination & deprotection/ dealkylation of the compound of Formula 2 are performed in one step/ one pot to obtain Molnupiravir in better yield with cost-effectiveness and drastic reduction in the reaction time cycle. Since the process steps are reduced by conducting the reactions sequentially in one pot; the process of the present invention not only results in cost effectiveness but also results in atom-efficiency and thus leads to improved yields when compared to the prior art processes.

Accordingly, the process step (a) comprising, protection, esterification & triazolation of the compound of Formula (3), that includes reaction with 2,2-dimethoxy propane, isobutyric anhydride & 1,2,4-triazole thereof sequentially conducted in one pot without isolating the intermediates. The solvent that can be used for this step (a) is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform & acetone either alone or in combinations thereof.
The catalyst used for various reactions according to the process are selected from the group consisting of 4-dimethylamino pyridine, tetra butyl ammonium bromide, triethyl benzyl ammonium chloride, phosphorous oxychloride, phosphorous pentachloride, phosphorous trichloride, thionyl chloride.

Accordingly, the process step (b) comprising hydroxyl amination & deprotection of Formula 2, which includes reaction with a reducing agent selected from, hydroxylamine hydrochloride, hydroxylamine sulphate, and hydroxylamine 50% solution. The aqueous polar solvents that can be used for this reaction include but are not limited to acetonitrile, isopropyl alcohol, methanol, and ethanol either alone or in combinations thereof. The acid is selected from sulphuric acid, hydrochloric acid, trifluoro acetic acid, para toluene sulfonic acid, formic acid and can be used either alone or in combinations thereof. The suitable inorganic bases used for maintaining pH of reaction system is selected from ammonia solution, sodium hydroxide or potassium hydroxide.

Thus the present invention provides a two steps process for the synthesis of Molnupiravir using low cost raw materials and reagents which make the process cost effective and sustainable. The process does not require costly biocatalyst, enzyme, as well as the time of the reaction is further shortened. Further isolation of intermediates in each stage is avoided as no side reaction and byproducts are formed during the reaction which helps in increasing overall reaction efficiency in terms of cost as well as yield of Molnupiravir. The process of the present invention results in Molnupiravir in more than 98% HPLC purity and more than 70% yields; which is much higher than the yields reported in the prior art. The process of the present invention does not involve multiple reactors; multiple extractions of the intermediates; avoids huge requirement of industrial solvents; yet can be completed in two steps thereby results in cost effectiveness.

Also, the process of the present invention uses mild reaction conditions, simple and convenient operations, easy separation for product and low cost reagents having lower environmental impact, reduced amount of by-product and impurities generation, lower investment cost, does not use expensive catalyst, as well as the time of reaction is shortened and increases the overall reaction efficiency in terms of yield of Molnupiravir. Therefore, the process of the present invention is industrially scalable and can be used to prepare Molnupiravir on commercial scale.

The process is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations, alternations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations, alternations, etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification.

EXAMPLES
Reference is now made to the following examples, which together with the above descriptions; illustrate the invention in a no limiting fashion. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

Example 1.
A solution of uridine (100g) in methylene dichloride (600 mL) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature. The solution of 2,2-dimethoxypropane (45g) and Acetone (50ml) was added slowly to obtain homogenous solution of uridine acetonide, to which sulfuric acid (0.5g) was added at ambient temperature. The reaction mass was slowly heated to 52-58°C over the time period of 2 hours. The reaction mixture was further stirred for 4 hours at 52-58°C. After reaction completion, Triethyl amine (1.5g) was added at ambient temperature. The reaction mass was cooled to 25-30°C, then added water (100 ml) into reaction mass. Further separated aqueous and organic methylene dichloride (MDC) layer. The liquid organic layer, i.e. 4-amino-1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl tetrahydro fluoro[3,4-d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one was taken into another reaction flask and Methylene dichloride (600 ml) was added at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Further 4-dimethylaminopyridine (4g) and triethylamine (100ml) was added in to reaction mass slowly under nitrogen atmosphere. The reaction mixture was cooled to 10-15°C and then dropwise addition of isobutyric anhydride (80g) was done under nitrogen atmosphere. The reaction mixture was stirred at 45 to 50°C for 9hrs. The reaction mass was chilled to 0 to 5°C. Quenching of reaction mixture was then done slowly into ice water and the reaction mass was extracted with methylene dichloride [300 mL x 3 times] and the organic layer was separated. The organic layer was then washed with water and was dried over sodium sulphate bed. The insoluble fraction was filtered off and the content ratio of methylene dichloride was decreased by the way of distillation up to 75%. Further 1,2,4-triazole (110g) and triethylamine (1000ml) were slowly added into reaction mass under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C and then drop wise addition of phosphorous oxychloride (115g) was done. The reaction mixture was stirred at 35 to 40°C for 18hrs. The reaction mass was then chilled to 0 to 5°C. Quenching of reaction mixture was then done slowly into ice water and then the reaction mass was extracted with methylene dichloride [250 mL x 3 times] and the organic layer was separated. The organic layer was then washed with sodium chloride and was dried over sodium sulphate bed. The insoluble fraction was filtered off and the content ratio of methylene dichloride was decreased by the way of distillation. Finally isopropyl alcohol (130 ml) was added to the reaction mass and was heated to 60-75°C for 1 hr. The reaction mass was cooled to 25-30°C and heptane (200 ml) was added. The reaction mass was chilled to 0-5°C. The precipitated solid product, an intermediate ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl)pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate was filtered, washed with heptane, and was dried at 50-55°C under vacuum.
Yield: 135g, HPLC Purity > 98%.
Percentage yield: 81.0%

Example 2.
A solution of uridine (100g) in methylene dichloride (500 mL) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature. The solution of 2,2-dimethoxypropane (45g) and Acetone (70ml) was added slowly to obtain homogenous solution of uridine acetonide, to which sulfuric acid (0.5g) was added at ambient temperature. The reaction mass was slowly heated to 52-58°C, over the time period of 2 hours. The reaction mixture was further stirred for 4 hours at 52-58°C. After reaction completion, Triethyl amine (1.5g) was added at ambient temperature. The reaction mass was cooled to 25-30°C, then water (100 ml) was added into reaction mass. Further separated aqueous and organic methylene dichloride (MDC) layers. The liquid organic layer, i.e. 4-amino-1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl tetrahydrofluoro[3,4-d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one was taken into another reaction flask and Methylene dichloride (700 ml) was added at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Further 4-dimethylaminopyridine (4g) and triethylamine (100ml) was added slowly in the reaction mass under nitrogen atmosphere. The reaction mixture was slowly cooled to 10-15°C and then dropwise addition of isobutyric anhydride (80g) was done under nitrogen atmosphere. The reaction mixture was stirred at 45 to 50°C for 9hrs. The reaction mass was then chilled to 0 to 5°C. Quenching of reaction mixture was then done slowly into ice water and then the reaction mass was extracted with methylene dichloride [300 mL x 3 times] and the organic layer was separated. The organic layer was then washed with water and was dried over sodium sulphate bed. The insoluble fraction was filtered off and the content ratio of methylene dichloride was decreased by the way of distillation up to 75%. Further 1,2,4-triazole (110g) and triethylamine (1000ml) was slowly added into reaction mass under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C and then slow and drop-wise addition of phosphorous oxychloride (115g) was done. The reaction mixture was stirred at 35 to 40°C for 18hrs. The reaction mass was then chilled to 0 to 5°C. Quenching of reaction mixture was then done slowly into ice water and then the reaction mass was extracted with methylene dichloride [250 mL x 3 times] and the organic layer was separated. The organic layer was then washed with sodium chloride and was dried over sodium sulphate bed. The insoluble fraction was filtered off and the content ratio of methylene dichloride was decreased by the way of distillation. Finally isopropyl alcohol (130 ml) was added and the reaction mass was heated to 60-75°C for 1 hr. The reaction mass was cooled to 25-30°C and heptane (200 ml) was added. The reaction mass was chilled to 0-5°C. The precipitated solid product, an intermediate ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl)pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate was filtered, washed with heptane, and dried at 50-55°C under vacuum.
Yield: 136g, HPLC Purity > 98%.
Percentage yield: 81.6%.

Example 3.
A solution of uridine (100g) in methylene dichloride (700 mL) was prepared at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature. The solution of 2,2-dimethoxypropane (45g) and Acetone (50ml) was added slowly to obtain homogenous solution of uridine acetonide, to which Sulfuric acid (0.5g) was added at ambient temperature. The reaction mass was slowly heated to 52-58°C, over the time period of 2 hours. The reaction mixture was further stirred for 4 hours at 52-58°C. After reaction completion, Triethyl amine (1.5g) was added at ambient temperature. The reaction mass was cooled to 25-30°C, then water (100 ml) was added into the reaction mass. Further separated aqueous and organic methylene dichloride (MDC) layers. The liquid organic layer, i.e. 4-amino-1-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl tetrahydro fluoro[3,4-d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one was taken into another reaction flask and added Methylene dichloride (500 ml) at ambient temperature. The reaction mixture was allowed to stir for 30 minutes at ambient temperature to obtain homogeneous solution. Further 4-dimethylaminopyridine (4g) and triethylamine (100ml) was added in reaction mass slowly under nitrogen atmosphere. The reaction mixture was cooled to 10-15°C and then slow drop-wise addition of isobutyric anhydride (80g) was done under nitrogen atmosphere. The reaction mixture was stirred at 45 to 50°C for 9hrs. The reaction mass was then chilled to 0 to 5°C. Quenching of reaction mixture was done slowly into ice water and then the reaction mass was extracted with methylene dichloride [300 mL x 3 times] and the organic layer was separated. The organic layer was then washed with water and was dried over sodium sulphate bed. The insoluble fraction was filtered off and the content ratio of methylene dichloride was decreased by the way of distillation up to 75%. Finally 1, 2, 4-triazole (110g) and triethylamine (1000ml) was added in reaction mass slowly under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C and slow addition of phosphorous oxychloride (115g) was done. The reaction mixture was stirred at 35 to 40°C for 18hrs. The reaction mass was further chilled to 0 to 5°C. Quenching of reaction mixture was then done slowly into ice water and the reaction mass was extracted with methylene dichloride [250 mL x 3 times] and the organic layer was separated. The organic layer was then washed with sodium chloride and was dried over sodium sulphate bed. The insoluble fraction was filtered off and the content ratio of methylene dichloride was decreased by the way of distillation. Finally isopropyl alcohol (130 ml) was added and the reaction mass was heated to 60-75°C for 1 hr. Cooled reaction mass to 25-30°C, heptane (200 ml) was added and the reaction mass was chilled to 0-5°C. The precipitated solid product, an intermediate ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(2-oxo-4-(1H-1,2,4-triazol-1-yl)pyrimidin-1(2H)-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate was filtered, washed with heptane, and dried at 50-55°C under vacuum.
Yield: 138g, HPLC Purity > 98%.
Percentage yield: 82.8%
Example 4.
In clean reactor, Acetonitrile (200ml) & Hydroxyl amine hydrochloride (56gm) was stirred at 25-30°C for 15 min and further cooled to 10-15°C. The pH was adjusted to 7-7.5 with liq. Ammonia. The reaction mass was stirred at 20-25°C for 30 min. and further cooled to 0-5°C. The Stage-I compound (100 gm) was charged at 0-5°C and the reaction mass was maintained for 3 hrs. The TLC was checked for the completion of reaction. Further Acetonitrile (1000 ml) & conc. HCl (28 gm) was added into reaction mass at 25-30°C and stirred for 5 hours. Again TLC was checked for completion of reaction. The reaction mass was cooled to 10-15°C and pH was adjusted to 7-7.5 with liquor ammonia below 15°C. The recovery of acetonitrile was done below 50°C under vacuum. Charged Ethyl acetate (500ml) and removed traces of acetonitrile completely. The sodium sulfate solution (40 ml) was added and the liquid mass was stirred for 30 min at 30-35°C. Settled for 1 hr. & Aqueous layer was extracted with Ethyl acetate. Organic layer was further washed with water and the recovery of ethyl acetate was done to achieve moisture content below 1%. Further, methyl tert-butyl ether (MTBE) (60ml) was charged below 35°C. The temperature was raised up to 60-65°C & maintained for 1 hr. The reaction mass was cooled to 20-25°C & maintained for 4 hrs. Further the reaction mixture was chilled to 0-5°C & maintained for 2 hrs. The precipitated solid product, ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate(Molnupiravir) was filtered, washed with MTBE, and dried at 50-55°C under vacuum.
Yield: 57 g, HPLC Purity > 98%.
Percentage yield: 70.1%

Example 5.
In clean reactor, Acetonitrile (300ml) & Hydroxyl amine hydrochloride (56gm) was stirred at 25-30°C for 15 min and further cooled to 10-15°C. The pH was adjusted to 7-7.5 with liq. Ammonia. The reaction mass was stirred at 20-25°C for 30 min. and further cooled to 0-5°C. The Stage-I compound (100 gm) was charged at 0-5°C and the reaction mass was maintained for 3 hrs. The TLC was checked for the completion of reaction. Further Acetonitrile (900 ml) & conc. HCl (35 gm) was added into reaction mass at 25-30°C and stirred for 5 hours. Again TLC was checked for completion of reaction. The reaction mass was cooled to 10-15°C and pH was adjusted to 7-7.5 with liquor ammonia below 15°C. The recovery of acetonitrile was done below 50°C under vacuum. Charged Ethyl acetate (500ml) and removed traces of acetonitrile completely. The sodium sulfate solution (40 ml) was added and the liquid mass was stirred for 30 min at 30-35°C. Settled for 1 hr. & Aqueous layer was extracted with Ethyl acetate. Organic layer was further washed with water and the recovery of ethyl acetate was done to achieve moisture content below 1%. Further, methyl tert-butyl ether (MTBE) (60ml) was charged below 35°C. The temperature was raised up to 60-65°C & maintained for 1 hr. The reaction mass was cooled to 20-25°C & maintained for 4 hrs. Further the reaction mixture was chilled to 0-5°C & maintained for 2 hrs. The precipitated solid product, ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate(Molnupiravir) was filtered, washed with MTBE, and dried at 50-55°C under vacuum.
Yield: 58 g, HPLC Purity > 98%.
Percentage yield: 71.3%

Example 6.
In a clean reactor, Acetonitrile (400ml) & Hydroxyl amine hydrochloride (56gm) was stirred at 25-30°C for 15 min and further cooled to 10-15°C. The pH was adjusted to 7-7.5 with liq. Ammonia. The reaction mass was stirred at 20-25°C for 30 min. and further cooled to 0-5°C. The Stage-I compound (100 gm) was charged at 0-5°C and the reaction mass was maintained for 3 hrs. The TLC was checked for the completion of reaction. Further Acetonitrile (800 ml) & conc. HCl (30 gm) was added into reaction mass at 25-30°C and stirred for 5 hours. Again TLC was checked for completion of reaction. The reaction mass was cooled to 10-15°C and pH was adjusted to 7-7.5 with liquor ammonia below 15°C. The recovery of acetonitrile was done below 50°C under vacuum. Charged Ethyl acetate (500ml) and removed traces of acetonitrile completely. The sodium sulfate solution (40 ml) was added and the liquid mass was stirred for 30 min at 30-35°C. Settled for 1 hr. & Aqueous layer was extracted with Ethyl acetate. Organic layer was further washed with water and the recovery of ethyl acetate was done to achieve moisture content below 1%. Further, methyl tert-butyl ether (MTBE) (60ml) was charged below 35°C. The temperature was raised up to 60-65°C & maintained for 1 hr. The reaction mass was gradually cooled to 20-25°C & maintained for 4 hrs. Further the reaction mixture was chilled to 0-5°C & maintained for 2 hrs. The precipitated solid product, ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate(Molnupiravir) was filtered, washed with MTBE, and dried at 50-55°C under vacuum.
Yield: 55 g, HPLC Purity > 98%.
Percentage yield: 67.6%

As will be readily apparent to those skilled in the art, the present disclosure may easily be produced in other specific forms without departing from its essential characteristics. The present embodiments are, therefore, to be considered as merely illustrative and not restrictive, the scope of the disclosure being indicated by the foregoing description, and all changes which come within therefore intended to be embraced therein.