DESC:
FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION: “AN IMPROVED PROCESS FOR THE SYNTHESIS OF MOLNUPIRAVIR THROUGH CATALYSIS”

2. APPLICANTS:
(a) Name :Century Pharmaceuticals Limited
(b) Nationality: India
(c) Address :406, WORLD TRADE CENTRE, SAYAJIGUNJ,
VADODARA PIN CODE 390005,
GUJARAT, INDIA.

PROVISIONAL
The following specification describes the invention.
?COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of invention
The present invention relates to an improved process for the synthesis of Molnupiravir through catalysis. More particularly, the present invention relates to an efficient process for the preparation of Molnupiravir in higher yields and with elevated purity from Cytidine.
Background of invention
Despite the availability of vaccines, there remains an urgent need for antiviral drugs with potent activity against SARS-CoV-2, the cause of COVID-19. Millions of people are immune-suppressed and may not be able to mount a fully protective immune response after vaccination. There is also an increasingly critical need for a drug to cover emerging SARS-CoV-2 variants, against which existing vaccines may be less effective. Here, we describe the cost effective and fast synthesis of Molnupiravir, a broad-spectrum antiviral agent originally designed for the treatment of Alpha virus infections, into a potential drug for the prevention and treatment of COVID-19. At the pandemic beginning in early 2020, Molnupiravir was in pre-clinical development for the treatment of seasonal influenza. As COVID-19 spread, the timeline for the development program was moved forward significantly, and focus shifted to treatment of coronavirus infections.
Molnupiravir (MK-4482) is promising anti-viral drug candidate of increasing interest based on its potential to treat COVID-19. Molnupiravir is currently under investigation in Phase II and III clinical trials. Further, animal studies show high promise. Molnupiravir showed broad-spectrum antiviral activity against SARS-CoV-2 with reduced virus titer in mice and completely blocked SARS-CoV-2transmission in ferrets within 24 hrs of administering the medication. In pragmatic standpoint, Molnupiravir is orally available and is structurally simple compared to remdesivir, making future synthesis considerably less complex. Cytidine possesses the same ribose skeleton as Uridine, though it is cost effective. It is concluded by studies that Synthesis of the Molnupiravir from Cytidine could lead to significant raw material savings as a result to economic significance.
Cytidine possesses the same ribose skeleton as Uridine, having economic benefit of low cost. The sequence of transformations can occur in either order, and esterification was achieved bio catalytically and also through classical chemical methods.
This strategy suffers from two drawbacks with respect to acylation. 1) The enzymatic route employs an expensive acyl donor (iso butyryl acetone Oxime ester) which is added in excess to drive conversion. The cost of solid-supported enzyme is also nontrivial. 2) The chemical acylation projects to be much less expensive; however, region selectivity is not as high as the enzymatic route. Di and tri-esterified by products are observed in >10%, and because the route is so concise, purge of impurities could pose challenges. Continuous developments of alternative strategies are thus desired.
The initially disclosed synthetic route requires improvement, however. The active pharmaceutical ingredient (API) is the synthetic starting point, and the route suffers from low yield which is constructed over five chemical transformations (four isolations). Uridine, an expensive material of limited availability, is the synthetic starting point, and the route suffers from low yield which occurs over the course of five chemical transformations.
Synthesis of Molnupiravirfrom Cytidine has involved with crucial parameters that involved with limitation to the complex process parameter i.e. solvent selection, purification of impurities, stability of intermediates, optimization of transamination reaction, enzyme leaching impurity, temperature control, acyl donor screening etc.
There is in-deed requirement of optimized process for synthesis of Molnupiravir that overcome the limitation of prior art specifically for fast and bulk synthesis.

Object of invention
The main object of the present invention is to an improved process for the manufacturing of Molnupiravir.
Another object of the invention is to provide process withan efficient parameter for the preparation of Molnupiravir in higher yields and with elevated purity as per the standard guideline.
Yet another object of the invention is to provide process with easy isolation form widely available raw materials with added economic significance.
Yet another object of the invention is to provide simple step extraction of Molnupiravir with higher yield and purity.
Yet another object of the invention is to provide the process for synthesis of Molnupiravir from catalysts that are ecofriendly and available at low cost.
Yet another object of the present invention is to provide catalytic reaction byacetonide deprotection in the intermediate with low chances of impurity due to inertness property of catalyst.
A still further object of the present invention is to provide process for isolation of Molnupiravir from catalystBiCl3, Amberlyst 15, Camphor sulphonic acid, Para toluene sulphonic acid monohydrate and CeCl3 to perform Acetonide deprotection.
Further object of the present invention is to provide process that devoid the use of chromatography isolation that lead tofast and yet high yield Molnupiravir.
Summary of invention
The present invention relates to an improved process for the preparation of Molnupiravir. More particularly, the present invention relates to an efficient process for the preparation of Molnupiravir in higher yields wherein the said Molnupiravir is obtained with purity greater than 99.00%, preferably greater than 99.50% and wherein any unknown impurity is controlled below 0.25%, preferably 0.15% which is as per ICH limit. The process parameter particularly follows catalytic Acetonide deprotection with the use of any one catalyst or combination from BiCl3, Amberlyst 15, Camphor sulphonic acid, Para toluene sulphonic acid monohydrateand CeCl3. The use of solvent CPME solvent (Cyclopentyl Methyl Ether) in the present process provides unique advantage in the process parameter. The added advantage of process includes use of ecofriendly and low-cost raw material and solvents to isolate the Molnupiravir.
Brief Description of the Drawings
The present invention is readily understood with reference to the following specifications and attached drawings wherein:
Figure 1 shows High performance liquid chromatography graph indicating the purity of Molnupiravir respectively.
Figure 2 shows Carbon-13 (13C) Nuclear Magnetic Resonance (NMR) indicating structural elucidation of Molnupiravir respectively.
Figure 3 shows Proton (1H) Nuclear Magnetic Resonance (NMR) indicating structural elucidation of Molnupiravir respectively.
Figure 4 shows Mass spectrum of Molnupiravir respectively.
Figure 5 shows graphic presentation of elemental analysis of Molnupiravir respectively.
Detailed description of the invention
The nature of the invention and the manner in which it is performed is clearly described in the specification. The invention has various components and clearly described in the following pages of the complete specification. The preferred embodiments of an improved process for the synthesis of Molnupiravir through catalysis are described for a better understanding of the invention without any limitations.
The distinctive properties of the invention and all advantages introduced shall be understood more clearly by virtue of the description given below and therefore evaluation should be performed taking this detailed description into consideration. Before explaining the present invention, it is to be understood that the invention is not limited in its application.
The process of isolation or route of synthesis of Molnupiravir from widely available Cytidine is depicted in following chain reaction.
The present invention specifically focuses on the fast and effective breaking of Molnupiravir acetonide ester Formula (II) into the final product Molnupiravir.

The process of acetonide deprotection through catalyst particularly provides added advantage of fast and effective process parameter in the synthesis of Molnupiravir.
Synthesis of Molnupiravir proceeding through the Cytidine acetonide is desirable for several reasons. First, it eliminates potential of undesired O-acylation, thus simplifying the impurity profile. This also enables the less expensive chemical esterification strategy. Lastly, the increased organic content might render intermediates more amenable to post reaction processing. Intermediates possessing the free diol are hydrophilic, and obtaining high recovery from aqueous layers can be challenging.
The essential process parameter from Formula (II) to Formula (I) using Amberlyst 15 Catalyst has involved with following process steps:
• Dissolving unit dose of Formula (II) in solution of Methanol and charged Amberlyst 15 Catalyst
• Stirring the solution for 4-5 hours at room temperature
• Filtering resultant solution to extract out catalyst Amberlyst 15 from the solution to recycle in next process
• Distilling the resultant solution under vacuum at 45-50 °C to remove methanol that result in slurry of Molnupiravir with impurities
• Dissolving the slurry in Cyclopentyl methyl ether [CPME] by string the slurry mass at room temperature i.e. 25-30°C for 1 hr
• Washing the slurry in solvent i.e. Cyclopentyl methyl ether [CPME] to remove the impurities from the slurry
• Drying the resultant mass under vacuum in oven at 50-55 °C to receive resultant Molnupiravir
• Assessing purity and yield of the Molnupiravir
The essential process parameter from Formula (II) to Formula (I) using Bismuth chloride (BiCl3) has involved with following process steps:
• Dissolving unit dose of Formula (II) in solution of Methanol and charged BiCl3
• Stirring the solution for 4-5 hours at room temperature
• Filtering resultant solution to extract out catalyst Amberlyst 15 from the solution to recycle in next process
• Distilling the resultant solution under vacuum at 45-50 °C to remove methanol that result in slurry of Molnupiravir with impurities
• Dissolving the slurry in Cyclopentyl methyl ether [CPME] by string the slurry mass at room temperature i.e. 25-30°C for 1 hr
• Washing the slurry in solvent i.e. Cyclopentyl methyl ether [CPME] to remove the impurities from the slurry
• Drying the resultant mass under vacuum in oven at 50-55 °C to receive resultant Molnupiravir
• Assessing purity and yield of the Molnupiravir
It is pertinent to note that above-mentioned examples include preferable solvent methanol, though it is apparent to state that the similar results can be obtained by using Ethyl acetate, water and Iso-propyl alcohol (IPA).
The Cyclopentyl methyl ether [CPME] can be substitutedwithwater, Methyl tert-butyl ether (MTBE) or 2-methyltetrahydrofuran, Formic acid, Methanol, Ethanol, Isopropanol, Butanol,Ethyl acetate, Isopropyl acetate, THF, 1,4 Dioxane and 2-Methyl THF (2-Methyltetrahydrofuran).
Further based on the selection of the solvent and process parameters the impurities obtained at final stage can be minimized by using Tween-80 and Ascorbic Acid, BHT (Butylated Hydroxy Toluene) and BHA (Butylated Hydroxy Anisole) etc.
In one embodiment of the present invention is to provide an improved process for the synthesis of Molnupiravir Formula (I) through catalysis. According to the present invention, Cytidine is reacted with anhydrous acetone, followed by 2, 2-dimethoxypropane under nitrogen atmosphere to obtain Cytidine acetonide Formula (IV). Treating Formula (IV) with anhydrous acetonitrile, DMAP (4-Dimethylaminopyridine) and DBU (0]undec-7-ene) to form the ester Formula (III) followed by adding hydroxylamine Sulphate and 40 % IPA (Isopropyl alcohol) to obtain Formula (II). Further Formula (II) is dissolved in methanol and charged with Amberlyst 15 catalyst and washing it with CPME (Cyclopentyl methyl ether) to obtain Molnupiravir Formula (I).
The potential of two-step route from Cytidine to Molnupiravir Formula (I) is shown as below:

According to the present invention, the process parameter particularly follows catalytic acetonide deprotection with the use of any one catalyst or combination from Catalyst in the reaction is selected from the Formic acid, BiCl3 (Bismuth chloride), Amberlyst 15, CeCl3 (Cerium trichloride), PTSA.H2O (p-Toluene sulfonic acid) and CSA (Camphor sulfonic acid).
Initial step of mixing through the stirring and dissolving is optionally comprises at reflux temperature of relevant solvent for 1 hr for reduction of reaction time.
According to the present invention, the solvent used in the reaction is selected from the group of Formic acid, Methanol, CPME (Cyclopentyl methyl ether), 1,4 Dioxane and 2-Methyl THF (2-Methyltetrahydrofuran).
Advantage of the present process:
• Simple process with low-cost reagent and raw material
• Fast process compared to available literature
• Environment friendly solvent and catalyst use in process that satisfy regulatory requirement of pollution control body
• Catalyst can be recovered fully that makes process cost effective compared to available literature
• The process provides high yield and purity compared to available literature
• The process with catalyst specifically eliminates high level of impurities and associated expensive removal procedures.
• The process renders low impurity product compliance with ICH guideline
The invention is illustrated more in detail in the following example. The example describes and demonstrates embodiments within the scope of the present invention. This example is given solely for the purpose of illustration and is not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope.
Example 1: Preparation of Cytidine acetonide Formula (IV) from Cytidine
Cytidine (18.8 g, 77.4 mmol) was taken in a 3 neck 500 mL round bottom flask and anhydrous acetone (240 mL) was added to it, followed by 2, 2-dimethoxypropane (48 mL) under nitrogen atmosphere. Further, neat sulfuric acid (10 mL) was added to the above suspension while vigorous stirring at 1200 rpm and left stirring for 15 hours. The insoluble residue was filtered, and the solid precipitate was washed multiple times with acetone followed by ether. The solid was left drying under vacuum for a day and 29.4 g of crude Formula (IV) was obtained with 95% yield and 98.00% HPLC purity.

Example 2: Preparation of Ester Formula (III) from Formula (IV)
Formula IV (5.003 g, 98.7% Purity, 13.1 mmol) was taken in a single neck dry100 mL round bottom flask and anhydrous acetonitrile (50 mL)was added. DMAP (4-Dimethylaminopyridine) (327 mg, 2.68 mmol, 0.204 equiv.) was added to the above flask. Further, DBU (0]undec-7-ene) (4.06 mL, 2.1 equiv.) was added upon which the suspension became a clear solution after stirring at room temperature for 5 minutes. Isobutyric anhydride (2.36 mL, 1.1 equiv.) was then added drop wise, and the resultant reaction was left stirring at room temperature overnight. The reaction was then directly concentrated under reduced pressure to afford a waxy solid (12.35 g, 95% assay yield, 35% purity). The resultant material was re-dissolved in dichloromethane and silica gel was added to prepare the dry loaded sample for column chromatography. Purification using 5% methanol in chloroform, then afforded the ester Formula (III)with 3.72 gm, 78% isolated yield corrected for purity and 96% purity.

Example 3: Preparation ofMolnupiravir acetonide ester Formula (II) from Formula (III)
Formula III (2 gm, 83% Purity) was taken in a 100 mL single neck round bottom flask and hydroxylamine sulfate (2.47 g, 3.2 equiv.) was added followed by 40 % IPA (Isopropyl alcohol)(By Karl fisher titration, 24 %water content, 40 mL). The resultant solution was heated to 78°C (internal temperature 72-73 °C) for 17 hours. upon which time, HPLC showed the formation of product. Solvent was removed on a rotary evaporator and acetonitrile (20 mL) was then added. The resulting slurry was sonicated for 5 minutes. The insoluble residue was then filtered, and the filtrate concentrated under reduced pressure to afford crude material. Toluene (20 mL) was added, and concentration done under reduced pressure to remove water azeotropically to obtain a white solid Formula (II)with 1.81 g, 94% purity, and 96% isolated yield corrected for purity.

Example 4: Preparation of Molnupiravir Formula (I)from Molnupiravir acetonide ester Formula (II)
Formula II (10 gm) was dissolved in formic acid (16V) and stirred it for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography), reaction mass was distilled out under vacuum at 45-50 °C completely then stripped out ethanol (16 V) under vacuum at 45-50 °C. To a sticky mass MTBE (Methyl tert-butyl ether) (16V) was added and stirred the reaction mass at room temperature followed by cooling to 0-5 °C. Maintained the reaction mass at 0-5°C for 1 hour then filtered the reaction mass and washed with chilled MTBE (Methyl tert-butyl ether). Then wet cake and D.M. water (Demineralized water) (2.5 V) was heated at 65-70 °C to get clear solution and slowly cooled the reaction mass to 15-20 °C to get solid material after maintaining the reaction mass for 16-18 hours. Filter the reaction mass to get pure Molnupiravir Formula (I). Dried the material in vacuum oven at 50-55 °C to get 2.5 gm yield and97.70%HPLC purity, white color.

Example 5: Preparation of Molnupiravir Formula (I) with solvent formic acid and MTBE
Formula II (10 gm) was dissolved in formic acid (10V) and MTBE (Methyl tert-butyl ether)(10V) and stirred it for 2-3 hours at 40-45°C. After reaction complies on HPLC (High performance liquid chromatography) reaction mass was filtered and wash with Hot MTBE (Methyl tert-butyl ether) then wet cake was introduced into D.M. water (Demineralized water)(2.5 V) and heated at 65-70 °C to get clear solution and slowly cooled the reaction mass to 15-20 ° C to get solid material after maintaining the reaction mass for 16-18 hours, filtered the reaction mass to get pure MolnupiravirFormula (I). Dried the material in vacuumoven at 50-55 °C to get 5 gm yield and98.90%HPLC purity, white color.

Example 6: Preparation of Molnupiravir Formula (I) from Formic acid
Formula II (10 gm) was dissolved in formic acid (16V) and stirred it for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography) reaction mass was distilled out under vacuum at 45-50 °C completely then stripped out ethanol (16 V) under vacuum at 45-50 °C. To a sticky mass add MTBE (Methyl tert-butyl ether)(16V) and IPA (Isopropyl alcohol) (3V) and stirred the reaction mass at room temperature followed by cooling to 0-5 °C. Maintained the reaction mass at 0-5°C for 1 hour then filtered the reaction mass and washed with chilled MTBE (Methyl tert-butyl ether). Then wet cake and D.M. water (Demineralized water) (2.5 V) was heated at 65-70 °C to get clear solution and slowly cooled the reaction mass to 15-20 ° C to get solid material after maintaining the reaction mass for 16-18 hours, filtered the reaction mass to get pure MolnupiravirFormula (I). Dried the material in vacuum oven at 50-55 °C to give 5.4 gm yield and87.25%HPLC purity,white color.
Example 7: Preparation of Molnupiravir Formula (I) from Amberlyst 15 and Methanol
Formula II (10 gm) was dissolved in Methanol and charged Amberlyst 15 Catalyst (15.0 gm) and stirred for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography) reaction mass was filtered and Methanol Mother Liquor treated with activated charcoal after filtering off activated charcoal distilled out methanol under vacuum at 45-50 °C completely, then to a sticky mass CPME (Cyclopentyl methyl ether)(10V) was added and stirred the reaction mass at room temperature. Maintained the reaction mass at 25-30°C for 1 hour then filtered the reaction mass and washed with CPME (Cyclopentyl methyl ether). Dried the material in vacuum oven at 50-55 °C (Yield = 5.7 gm, HPLC purity 99.90%, white color). This is the most preferred embodiment of present invention to get Molnupiravir Formula(I) with 5.7 gm yield and 99.90% purity.

Example 8: Preparation of Molnupiravir Formula (I) from ethanol and charged BiCl3
Formula II (10 gm) was dissolved in Methanol and charged BiCl3(Bismuth chloride)(12.80 gm) and stirred it for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography) reaction mass was filtered and Methanol Mother Liquor treated with activated charcoal after filtering off activated charcoal, distilled out methanol under vacuum at 45-50 °C completely, then to a sticky mass CPME (Cyclopentyl methyl ether)(10V) was added and stirred the reaction mass at room temperature. Maintained the reaction mass at 25-30°C for 1 hour then filtered the reaction mass and washed with CPME (Cyclopentyl methyl ether). Dried the material in vacuum oven at 50-55 °C to get Molnupiravir Formula(I) with 5.0 gm yield and 98.90%HPLC purity, white color.

Example 9: Preparation of Molnupiravir Formula (I) ethanol and charged CeCl3
Formula II (10 gm) was dissolved in Methanol and charged CeCl3(Cerium trichloride) (15.0 gm) and stirred it for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography) reaction mass was filtered and Methanol Mother Liquor treated with activated charcoal after filtering off activated charcoal, distilled out methanol under vacuum at 45-50 °C completely, then to a sticky mass CPME (Cyclopentyl methyl ether)(10V) was added and stirred the reaction mass at room temperature. Maintained the reaction mass at 25-30°C for 1 hour, then filtered the reaction mass and washed with CPME (Cyclopentyl methyl ether). Drying the material in vacuum oven at 50-55 °C to get Molnupiravir Formula(I) with4 gm yield and 98.73%HPLC purity, white color.

Example 10: Preparation of Molnupiravir Formula (I) from Methanol and PTSA
Formula II (10 gm) was dissolved in Methanol and charged PTSA (p-Toluene sulfonic acid)(7.73 gm) and stirred it for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography)reaction mass was filtered and Methanol Mother Liquor treated with activated charcoal after filtering off activated charcoal distilled out methanol under vacuum at 45-50 °C completely, then to a sticky mass CPME (Cyclopentyl methyl ether)(10V) was added and stirred the reaction mass at room temperature. Maintained the reaction mass at 25-30°C for 1 hour then filtered the reaction mass and washed with CPME (Cyclopentyl methyl ether). Drying the material in vacuum oven at 50-55 °C to get Molnupiravir Formula(I) with 3.8 gm yield and 98.60% HPLC purity, white color.

Example 11: Preparation of Molnupiravir Formula (I) from Methanol and CSA
Formula II (10 gm) was dissolved in Methanol and charged (Camphor Sulphonic acid) CSA (9.44 gm) and stirred it for 4-5 hours at room temperature. After reaction complies on HPLC (High performance liquid chromatography) reaction mass was filtered and Methanol Mother Liquor treated with activated charcoal after filtering off activated charcoaldistilled out methanol under vacuum at 45-50 °C completely, then to a sticky mass CPME (Cyclopentyl methyl ether)(10V) was added and stirred the reaction mass at room temperature. Maintained the reaction mass at 25-30°C for 1 hour then filtered the reaction mass and washedwith CPME (Cyclopentyl methyl ether). Dried the material in vacuum oven at 50-55 °C to get Molnupiravir Formula(I) with 5.5 gm yield and 99.10%HPLC purity, white color.
Optimization of reagents, solvents and comparison results:
The following table 1 shows the optimization and comparison of experimental data with various Deprotection Reagent:
Sr.No. Batch No. Deprotection Reagent Solvent Yield Purity (%)
01 RD/CPL/MNR/013/21 Formic acid Formic Acid 0.50 87.25
02 RD/CPL/MNR/100/21 BiCl3 Methanol 0.50 98.90
03 RD/CPL/MNR/041/21 Amberlyst 15 Methanol 0.57 99.90
04 RD/CPL/MNR/102/21 Amberlyst 15 CPME 0.50 99.60
05 RD/CPL/MNR/101/21 CeCl3 Methanol 0.40 98.73
06 RD/CPL/MNR/040/21 PTSA.H2O Methanol 0.38 98.60
07 RD/CPL/MNR/039/21 CSA Methanol 0.55 99.10
Table 1
Observation:
As per table 1, the most preferred deprotection reagent is Amberlyst 15 (Batch no. 3) with methanol solvent which gives 0.57w/w yield and 99.90% purity (as mentioned in Example 7).
Advantage of using Amberlyst 15 as a catalyst:
• Amberlyst process is carried out in SSR-316 Reactor as there is no acidic pH.
• Amberlyst is easily reactivated and reuse for next reaction and easily separable from reaction mass and no need of extra precaution for isolation of product.
• Use of Amberlyst is green chemistry;Carbon load on Environment is low.
• Handling of Amberlyst is easy as comparable to other chemicals like BiCl3, PTSA, CSA, Formic acid etc.
• Time cycle is very less than other non-catalytic preparation of Molnupiravir (e.g. formic acid reactionwhich is 4-5 hours).
The use of solid acid catalyst instead of liquids includes many advantages, such as reduced equipment corrosion, ease of product separation, recycling of the catalyst, and environmental acceptability.The present process involves green chemistry (Eco friendly process) with minimum carbon footprint.
Below table 2 shows optimization time for Amberlyst 15 as a catalyst:
Sr.No. Batch No. Amberlyst 15
(Times) Yield (w/w) Purity(%)
01 RD/CPL/MNR/103/21 0.5 0.50 99.60
02 RD/CPL/MNR/104/21 1.0 0.51 99.80
03 RD/CPL/MNR/105/21 1.5 0.57 99.90
Observation:
The table 2 indicates the Amberlyst 15 (1.5 times) used as a catalyst to give maximum yield and purity.
Further below Table 3 shows the optimization and comparison of various solvents with Amberlyst 15:
Sr. No. Batch No. Solvents Yield (w/w) Purity(%)
01 RD/CPL/MNR/105/21 Methanol 0.57 99.90
02 RD/CPL/MNR/102/21 CPME 0.50 99.60
03 RD/CPL/MNR/083/21 1,4 Dioxane 0.30 98.20
04 RD/CPL/MNR/106/21 2- methyl THF 0.28 98.65
Observation:
The table 3 indicates the distinct solvents reacted with Amberlyst 15 to give maximum yield and purity. The preferable solvent in the present embodiment is Methanol which gives 0.57 w/w yield and 99.90 % purity.
Table 4 shows the optimization of volume of solvent:
Sr.No. Batch No. Volume of Solvent(V) Yield (w/w) Purity (%)
01 RD/CPL/MNR/107/21 5 0.46 99.10
02 RD/CPL/MNR/108/21 10 0.50 99.50
03 RD/CPL/MNR/105/21 20 0.57 99.90

Observation:
The table 4 indicates the different volume of solvents to give maximum yield and purity. The preferable volume of solvent is 20V in the present embodiment which gives 0.57 w/w yield and 99.90 % purity.
Table 5 shows the comparison of recycled Amberlyst 15:
Sr.No. Batch No. Times Recycled Yield (w/w) Purity (%)
01 RD/CPL/MNR/105/21 1st Recycled 0.57 99.90
02 RD/CPL/MNR/109/21 2nd Recycled 0.56 99.92
03 RD/CPL/MNR/110/21 3rd Recycled 0.54 99.90
04 RD/CPL/MNR/111/21 4th Recycled 0.50 99.60
Observation:
The table 5 indicates the recycled amount of time for Amberlyst 15 as a catalyst. The first recycled batch shows the maximum yield and purity.

Table 6 shows the comparison of recycled/recovered solvent:
Sr.No. Batch No. Volume of Solvent Yield Purity
01 RD/CPL/MNR/112/21 Methanol 0.50 99.00
02 RD/CPL/MNR/113/21 Methanol 0.48 98.85
Observation:
The table 6 indicates the recycled volume of solvent i.e., Methanol. The first recycled batch shows the maximum yield and purity. The use of recovered solvent will reduce the carbon load as well as it is environmentally acceptable.
Table 7 shows the comparison of different acidic resins:
Sr.No. Batch No. Acidic Resins Yield Purity
01 RD/CPL/MNR/114/21 Indion 15 0.48 99.44
02 RD/CPL/MNR/115/21 Amberlite IRC120H 0.52 99.50
The product has been tested final product with different testing parameter:
The figures 1 to 5 shows the info graphic representation and indicates the below significance of the observed result in graph:
Figure 1 shows High performance liquid chromatography graph indicating the purity of Molnupiravir respectively.
PDA Ch1 260nm±4nm
Peak# Ret. Time Area Area% Relative Retention Time Name
1 2.424 1970 0.052 0.876
2 2.767 3781509 99.876 1.000 Molnupiravir
3 3.274 2707 0.071 1.183
Total 3786186 100.000

Figure 2 shows Carbon-13 (13C) Nuclear Magnetic Resonance (NMR) indicating structural elucidation of Molnupiravir respectively.
Sr.No. Peak No. of Carbon Remarks
01 19.254 1 Carbon of Methyl group near to ester
02 19.282 1 Carbon of Methyl group near to ester
03 34.957 1 Secondary Carbon near to Ester group
04 64.809 1 2° Carbon sandwich b/w furan ring and Ester group
05 71.288 1 Carbon of Furan ring
06 74.283 1 Carbon of Furan ring
07 82.336 1 Carbon of Furan ring
08 90.255 1 Carbon of Furan ring
09 99.480 1 Carbon of Pyrimidine ring
10 131.664 1 Carbon of Pyrimidine ring
11 146.100 1 Carbon of Pyrimidine ring
12 151.457 1 Carbon of Pyrimidine ring
13 178.247 1 Carbonyl carbon of ester group

Figure 3 shows Proton (1H) Nuclear Magnetic Resonance (NMR) indicating structural elucidation of Molnupiravir respectively.
Sr.No. Peak No. of Hydrogen Pattern Remarks
01 1.17 6 dd Dimethyl Group (11,12)
02 2.61 1 m Hydrogen of Furan ring (13)
03 4.07 2 m Methylene group (18 and –CH group near to ester 9)
04 4.12 1 t Hydrogen of Furan ring (16)
05 4.28 2 d Hydrogen of Furan ring (14)
06 5.60 1 d Hydrogen of Furan ring (15)
07 5.81 1 d Hydrogen of Pyrimidine ring (3)
08 6.90 1 d Hydrogen of Pyrimidine ring (4)
Figure 4 shows Mass spectrum info graphic study of Molnupiravir respectively.

Sr.No. Peak (m/e) Value Remarks
01 Base peak 330.25 M+1 Peak
02 Base peak 328.00 M-1 Peak
03 Fragment peak 128.05 C4H4N3O2
Figure 5 shows graphic presentation of elemental analysis of Molnupiravir respectively.
Sr.No. Name of Elements % Theoretical Values % Experimental Values
01 C 47.41 47.01
02 H 5.82 5.998
03 N 12.76 12.54
04 O 34.01 34.46

Observation:
The table 7 indicates the comparison of two different Acidic resins. These acidic resins are used as catalyst to obtain its specific yield and purity although the Amberlyst 15 gives the finest results.

Result and Conclusion:
From the above examples, it is indicated that Example no. 7 is the optimized example considering Amberlyst 15 type of catalyst with methanol as a solvent in the range of 5V-20V provides optimum result with maximum0.57 w/w yield and 99.90 % purity of Formula (I) Molnupiravir.
While the present invention has been described with respect to what is presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. To the contrary, the invention is intended to cover various modifications and equivalent ranges included within the spirit and scope of those skilled in the art. It is expressly understood, however, that such modifications are within the spirit and scope of the present invention as set forth in the following claims.

,CLAIMS:We claim:
1. An improved process for the synthesis of Molnupiravir Formula (I)
through catalysis comprising following steps:
(a) Dissolving Molnupiravir acetonide esterFormula (II)in solution of solvent and charged Catalyst;

(b) Stirring the resultant solution, received from step (a), at room temperature for 4-5 hours;
(c) Checking compliance of reaction for solution, received from step (b), in High performance Liquid Chromatography(HPLC);
(d) Filtering resultant solution after reaction compliance, received from step (c), to extract out catalyst from the solution to recycle in next process;
(e) Treating methanol mother liquor or filtrate, received from step (d), with activated charcoal and filtering the solution to remove impurity;
(f) Distilling the resultant solution or filtrate,received from step (e), under vacuum at 45-50 °C to remove solvent, added in step (a),that result in slurry of Molnupiravir;
(g) Dissolving and washing the slurryof Molnupiravir, received from step (f), in suitable solvent by stirring the slurry mass at room temperature to remove the impurities;
(h) Drying the resultant mass under vacuum in oven at temperature 50-55 °Cto receive resultant Molnupiravir (Formula I); and

(i) Assessing purity and yield of the Molnupiravir.
2. The improved process for the synthesis of Molnupiravir Formula (I) through catalysis as claimed in claim 1, wherein Amberlyst 15 is employedas a Catalyst and Methanol as a solvent provides the optimized yield and purity of Formula (I) as Molnupiravir.
3. The improved process for the synthesis of Molnupiravir Formula (I), wherein the catalyst or combination of catalysts selected from Amberlyst 15, Formic acid, BiCl3 (Bismuth chloride), CeCl3 (Cerium trichloride), PTSA.H2O (p-Toluene sulfonic acid) and CSA (Camphor sulfonic acid).
4. The improved process for the synthesis of Molnupiravir Formula (I), wherein the solvent for step (a) is selected from the group consisting of Methanol,Ethyl acetate, water and Iso-propyl alcohol (IPA).
5. The improved process for the synthesis of Molnupiravir Formula (I), wherein step (b) optionally comprises stirring, the resultant solution received from step (a), at reflux temperature of solvent for 1 hr for reduction of reaction time.
6. The improved process for the synthesis of Molnupiravir Formula (I), wherein the solvent for step (g) is selected from the group of Formic acid, CPME (Cyclopentyl methyl ether), Methanol, Ethanol, Isopropanol, Butanol, Ethyl acetate, Isopropyl acetate, THF, 1,4 Dioxane and 2-Methyl THF (2-Methyltetrahydrofuran).
7. The improved process for the synthesis of Molnupiravir Formula (I) as claimed in claim 2, wherein the catalyst can be substituted with acidic resins such as Indion 15, Amberlite.
8. The improved process for the synthesis of Molnupiravir Formula (I) as claimed in claim 3, wherein the volume of solvent is selected from the range of 5V-20V.
Dated this: 18th day of October 2021