The present invention relates to an improved process for the preparation of Molnupiravir having Formula I. This process is feasible and cost effective for the preparation of Molnupiravir. This process is simple and efficient process for the preparation of Molnupiravir substantially free of undesirable nitrosamine impurities.

O. ^ // "OH
o
HO OH

Formula I BACKGROUND OF THE INVENTION
Molnupiravir is an orally active antiviral agent which is being investigated for treating covid-19 infection. The chemical name for Molnupiravir is ((2i?,3*S',4i?,5i?)-3,4-dihydroxy-5-(4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate.
Molnupiravir was developed at Emory University by the Drug innovation ventures at Emory and is under clinical development in partnership with Ridgeback Biotherapeutics and Merck and Co. This drug is SARS-CoV2 polymerase inhibitor.
PCT patent application WO2016106050A1 relates to N4-hydroxycytidine derivatives. This patent application discloses Molnupiravir generically.
PCT patent application WO2019113462A discloses the synthetic route of Molnupiravir, as depicted in Scheme 1 wherein Uridine is used as starting material. In this process, the dihydroxy group of Uridine is protected by acetone followed by the esterification reaction with isobutyric anhydride. The resulting compound reacts with 1,2,4-triazole in

phosphorus oxychloride and followed by reaction with hydroxylamine. Finally, acidolysis/deprotection of acetonide using formic acid is performed to obtain the Molnupiravir.
Scheme 1:

O H
*° 1) Acetone, HZS04 2) NMe3

n n

1)NEt3, DMAP 2) 0 O

HO"' 'OH

V

f=N
0Vy° n vw

o j v
yNy.NHOH q ^ °y VNHOH
HCO
^° HN
HO OH
°x°

The prior art process provides low yield and release carbon monoxide during the reaction with formic while performing acetonide deprotection. It is also known in literature that formic acid is source of carbon monooxide and mere storing it for a longer time results in liberation of carbon monooxide (containers are to be vented frequently). Hence, this process is not industrially feasible and yields are low and not suitable for scale-up production.
Therefore, the said process suffers from the problems such as low yield and cumbersome purification by column chromatography. In view of the same, there is a need for simple, industrially scalable, cost effective and environmentally-friendly processes for the preparation of Molnupiravir that is free from above mentioned drawbacks and achieves high yield and purity.

Despite the progress in the manufacturing operations for Active Pharmaceutical Ingredients, various controls applied to make the drugs acceptable for human consumption. In the past several drug companies voluntarily recalled their drugs after finding trace amount of unexpected impurities i.e. nitrosamine, thus in light of probable contamination of nitrosamine impurities particularly N-nitrosodimethylamine (NMDA/NDMA) of and N-nitrosodiethylamine (NEDA/NDEA) of, particularly when the manufacturing process lead to the formation of a nitrosamine or when recycled raw materials / solvents can create unacceptable contamination or due to probable saturation of nitrosamine in environment, it becomes inevitable to identify potential cross contamination risks for drugs manufactured, to include enhanced evaluation of impurity controls and to demonstrate a capability of predicting, controlling, and preventing impurities in the drug substance and subsequently in the drug product.
In the process of the prior arts triethylamine, diisopropylethyl amine is used during preparation compound of formula IV. Triethylamine, diisopropylethyl amine is direct source of secondary amines resulting in the formation of highly toxic Nitrosamines (N-Nitrosodipropylamine, N-Nitrosodiisopropylamine, N-Nitrosoethylisoproplymiane, N-Nitrosodimethylamine, N-Nitrosodiethylamine) which are highly carcinogenic and are point of concern as per ICH M7. The processes disclosed in the prior art fail to provide the control of impurities/genotoxic nitrosamine impurities. Consequently, there is a need for an improved process for the preparation of Molnupiravir, which not only overcomes the problems in the prior art processes as mentioned above, but also is simple, environment friendly, economically viable and industrially feasible for the preparation of Molnupiravir having a good control over control over impurities/genotoxic nitrosamine impurities.
Therefore, a method which has a simple process route and having low cost, is beneficial to synthesizing high-purity product and is suitable for industrial production still needs to be found.

The problem has been solved by the applicant by providing a novel process via the use of nitrophenol ester of isobutyric acid of Formula III, which allows a convenient and efficient synthesis of Molnupiravir.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon limitations in the prior arts by providing a novel process for the preparation of Molnupiravir.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing Molnupiravir, in high yield and purity.
It is still another object of the present invention to provide an improved and commercially viable process for the preparation of Molnupiravir, using nitrophenol ester of isobutyric acid of Formula III.
It is still another object of the present invention to provide compound of Formula X and its use for the preparation of Molnupiravir.
It is another object of the present invention to provide Molnupiravir substantially free of
nitrosamines, wherein nitrosamine is selected from the group comprising of N-
Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine
(NDIPA/DIPNA), N-Nitrosoethylisopropylamine (EIPNA), N-Nitrosomethylethylamine
(NMEA), N-Nitrosodipropylamine (NPDA), N-Nitrosodibutylamine (NBDA), N-
Nitrosomethyldodecyl amine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-
methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, N-
[methyl(nitroso)amino]butanoic acid (NMBA).
It is another object of the present invention to provide a simple and efficient process for the preparation of Molnupiravir substantially free of nitrosamines, wherein nitrosamine is

selected from the group comprising of N-Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine (NDIPA/DIPNA), N-Nitrosoethylisopropylamine (EIPNA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodipropylamine (NPDA), N-Nitrosodibutylamine (NBDA), N-Nitrosomethyldodecylamine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, N-[methyl(nitroso)amino]butanoic acid (NMBA).
It is yet another object of the present invention to provide Molnupiravir substantially free of nitrosamines, which is efficiently prepared by preparing compound of Formula IV in presence of an inorganic base.
It is still another object of the present invention to provide Molnupiravir substantially free from impurities.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a simple and efficient process for the preparation of Molnupiravir substantially free of nitrosamines, wherein nitrosamine is selected from the group comprising of N-Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine (NDIPA/DIPNA), N-Nitrosoethyl-isopropylamine (EIPNA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodipropyl¬amine (NPDA), N-Nitrosodibutylamine (NBDA), N-Nitrosomethyldodecylamine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, N-[methyl(nitroso)amino]butanoic acid (NMBA).
According to one aspect of the present invention there is provided a novel and cost effective process for the preparation of Molnupiravir of Formula I, as shown in Scheme
2.

Scheme 2:
HO^O
°2N—<\ /)— OH Y
02N—<\ A

HO" 'OH
Uridine

Step (a)

Formula
Step (b)

X °

Formula I

Formula IV

Step (c)

Step (e)
OH
I
NH


o, h
Formula VI Step (f)

H If OH

\ v-' V 0
HO OH
Formula V
i un OH

\ v-' V 0
HO OH
Formula I (Molnupiravir)
> un fiH

It has been found that Molnupiravir is efficiently prepared using nitrophenol ester of isobutyric acid of Formula III as shown in Scheme 2. This compound of Formula III is easily prepared via esterification of nitrophenol with isobutyric acid. This compound of Formula III results in synthesis of intermediate of Formula IV, which finally help in achieving Molnupiravir in better yield and purity.
According to another aspect of the present invention there is provided a novel and cost effective process for the preparation of Molnupiravir of Formula I, as shown in Scheme 3.

Scheme 3

02N

OH "V°
'A

02N

NH2
0
HO OH Step (a)
Cytidine

-■ - o
Formula II'

NH,

Formula I
Step (b)

°\^N' 'I
_ -^CTr
Formula IV

NH2

Step (c)
Step (e)

Formula VI

H
If 0H
^^CrY
\ <■' '; o
i HH DH
Step (f)
H
r K
0. .k', K OH N
^hr^fY

HO OH
Formula I (Molnupiravir)

NH2

It has been found that Molnupiravir is efficiently prepared using nitrophenol ester of isobutyric acid of Formula III as shown in Scheme 3. This compound of Formula III is easily prepared via esterification of nitrophenol with isobutyric acid. This compound of Formula III results in synthesis of intermediate of Formula IV, which finally help in achieving Molnupiravir in better yield and purity.
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can

be more readily understood through reading the following detailed description of the invention and study of the included examples.
Nitrosamines are potent carcinogens in animals and probable carcinogens in humans. The probable reason of formation of nitrosamine as impurities is that they can form when certain reaction conditions are met such as use of organic amines during the reaction. According to one of the possible concepts, use of secondary amines resulting in the formation of highly toxic Nitrosamines (N-Nitrosodipropyl amine, N-Nitrosodiisopropylamine, N-Nitrosoethylisoproplymiane, N-Nitrosodimethylamine, N-Nitrosodiethylamine) which are highly carcinogenic and are cohort of concern as per ICH M7. ICH M7 recommends that these mutagenic carcinogens be controlled at or below the acceptable cancer risk level. Due to their known potent carcinogenic effects, and because it is feasible to limit these impurities by taking reasonable steps to control or eliminate their presence, the goal is to have no quantifiable nitrosamine impurities or well within the declared limits which is safe for human consumption.
Understanding the limitations of prior art, there is a need for the development of an advantageous process for the preparation of Molnupiravir and the best optimized process would always have better control on the formation of impurities/nitrosamine impurity rather than the removal of such impurities by purification, since such impurities once formed are difficult to remove and their removal adds up to the cost of process, making the process inefficient in several ways.
The inventors of the present invention devised the conditions suitable for preparing Molnupiravir substantially free of nitrosamine impurities by involving the use of inorganic base in place of organic base as used in the process of the prior arts. Specifically, use of an inorganic base during the preparation of compound of Formula IV eliminates the source of Nitrosamines resulting in Nitrosamines free process.
This approach has shown very efficient control on formation of nitrosamine impurities. Furthermore, the process of present invention also reduces the requirement of

purifications and thereby reduces solvent consumption, operational step and the time cycle and effluent generation, making the process cost effective and environmentally efficient.
The present invention (Scheme 2) relates to an improved process for the preparation of Molnupiravir comprising the steps of:
(a) converting Uridine to compound of Formula II;

^ N^ NH --- -- O
HO \ / jr o, ,0
o
HO OH
Uridine Formula II

O
NH

(b) reacting compound of Formula II with nitrophenol ester of isobutyric acid of Formula III to obtain the compound of Formula IV; and

^crv
1 -NH


Formula III Formula IV
(c) converting compound of Formula (IV) to Molnupiravir of Formula (I).
The present invention (Scheme 2) relates to an improved process for the preparation of Molnupiravir from compound of Formula IV, further comprising the steps of: (a) deprotecting the compound of Formula IV to obtain compound of Formula V;



«/xrv
-, o
HO OH

NH

Formula V
(b) reacting the compound of Formula V with hydroxylamine sulfate in presence of imidazole to obtain Molnupiravir of Formula I


H N
o^cr
O. .^ // "OH
N
_> <~
o
HO OH

Formula I
with or without isolation of compound of Formula X; and

q o ' rN^N
HO° 't)H ° Formula X
(c) optionally purifying Molnupiravir of Formula I.
The present invention (Scheme 2) relates to an improved process for the preparation of Molnupiravir from compound of Formula IV, further comprising the steps of: (a) converting the compound of Formula IV with hydroxylamine sulfate in presence of imidazole to obtain compound of Formula VI


0 o ' //
o 6. h

OH
i
NH

Formula VI
with or without isolation of compound of Formula XI;
* - °- .f rN-N

Formula XI
(b) deprotecting the compound of Formula VI to obtain Molnupiravir of Formula I; and


H
O o. .N' lT NX0H
o
HO OH
Formula I
(c) optionally purifying Molnupiravir of Formula I.
In step (a) of Scheme 2, protection of Uridine is carried out with 2,2-Dimethoxypropane or acetone in presence of p-TSA or sulfuric acid.
In step (b) of Scheme 2, the compound of Formula II is transesterified with nitrophenol ester of isobutyric acid of Formula III in presence of magnesium chloride, base and

solvent to obtain the compound of Formula IV. The base is an inorganic base selected from the group comprising of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and the like. The solvent is selected from the group comprising of tertrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, Toluene, acetonitrile, methyl-tert butyl ether, dioxane and the like.
Nitrophenol ester of isobutyric acid of Formula III is prepared via esterification of nitrophenol with isobutyric acid in presence of DCC/DMAP in solvent such as TUF.
In step (c) of Scheme 2, compound of Formula IV is deprotected with acid in solvent to obtain compound of Formula V. The acid is selected from the group comprising of inorganic acid such as hydrochloric acid, hydrogen bromide, hydrogen fluoride, hydrogen phosphate, hydrogen sulfate and the like or organic acid such as p-Toluenesulfonic acid, 5-sulfosalicylic acid and the like. The solvent is selected from the group comprising of tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, Toluene acetonitrile, methyl-tert-butyl ether and dioxane.
In step (d) of Scheme 2, compound of Formula V is reacted with hydroxylamine sulfate and imidazole in presence of the organosilicon compound to obtain Molnupiravir of Formula I. The organosilicon compound is selected from the group comprising of hexamethyldisilazane (HMDS) or hexamethyldisiloxane (HMDSO).
In step (e) of Scheme 2, compound of Formula IV is reacted with hydroxylamine sulfate and imidazole in presence of the organosilicon compound to obtain compound of Formula VI. The organosilicon compound is selected from the group comprising of hexamethyldisilazane (HMDS) or hexamethyldisiloxane (HMDSO).
In step (f) of Scheme 2, compound of Formula VI is deprotected with acid in solvent to obtain Molnupiravir of Formula I. The acid is selected from the group comprising of inorganic acid such as hydrochloric acid, hydrogen bromide, hydrogen fluoride, hydrogen phosphate, hydrogen sulfate and the like or organic acid such as p-Toluenesulfonic acid,

5-sulfosalicylic acid and the like. The solvent is selected from the group comprising of tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, Toluene acetonitrile, methyl-tert-butyl ether and dioxane.
Molnupiravir obtained from above process (Scheme 2) is optionally further purified by techniques already known in prior art such as crystallization. The solvent used for purification is selected from the group comprising of ester such as ethyl acetate, isopropyl acetate and the like; ether such as di-ethyl ether, methyl-tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like, acetonitrile, acetone, water and mixture thereof.
The present invention (Scheme 3) relates to an improved process for the preparation of Molnupiravir comprising the steps of:
(a) converting Cytidine to compound of Formula II';
NH2

HO

N
HO" OH
Cytidine

NH2

HO

Y"
Formula II'

(b) reacting compound of Formula IF with nitrophenol ester of isobutyric acid of Formula III in presence of base and solvent to obtain the compound of Formula IV;


02N


\\ //

T

o

O^ Q

NH2

Formula

Formula IV

(c) converting compound of Formula (IV) to Molnupiravir of Formula (I).

The present invention (Scheme 3) relates to an improved process for the preparation of Molnupiravir from compound of Formula IV, further comprising the steps of: (a) deprotecting the compound of Formula IV to obtain compound of Formula V;


o ' ,rNHz
yN
o
HO OH
Formula V

(b) reacting the compound of Formula V with hydroxylamine sulfate in presence of imidazole to obtain Molnupiravir of Formula I
^\ H

0 ^/V « OH
o
HO OH
Formula I
with or without isolation of compound of Formula X; and

o 0 / ,rN^N
HO° bH ° Formula X
(c) optionally purifying Molnupiravir of Formula I.
The present invention (Scheme 3) relates to an improved process for the preparation of Molnupiravir from compound of Formula IV, further comprising the steps of:

(a) converting the compound of Formula IV with hydroxylamine sulfate in presence of imidazole to obtain compound of Formula VI


<~0-Y
CX .0

N

OH
I NH

Formula VI
with or without isolation of compound of Formula XI;


Y
* "N. &

N^N

Formula XI
(b) deprotecting the compound of Formula VI to obtain Molnupiravir of Formula I; and


H N
CX .£ II "OH
o
HO OH

Formula I
(c) optionally purifying Molnupiravir of Formula I.

In step (a) of Scheme 3, protection of cytidine is carried out with 2,2-Dimethoxypropane or acetone in presence of p-TSA or sulfuric acid.
In step (b) of Scheme 3, the compound of Formula IF is transesterified with nitrophenol ester of isobutyric acid of Formula III in presence of magnesium chloride, base and solvent to obtain the compound of Formula IV. The base is selected from the group comprising of inorganic base such as potassium carbonate, sodium carbonate, potassium bicarbonate and the like. The solvent is selected from the group comprising of tertrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, Toluene, acetonitrile, methyl-tert butyl ether, dioxane and the like.
Nitrophenol ester of isobutyric acid of Formula III is prepared via esterification of nitrophenol with isobutyric acid in presence of DCC/DMAP in solvent such as TUF.
In step (c) of Scheme 3, compound of Formula IV is deprotected with acid in solvent to obtain compound of Formula V. The acid is selected from the group comprising of hydrochloric acid, hydrogen bromide, hydrogen fluoride, hydrogen phosphate and hydrogen sulfate. The solvent is selected from the group comprising of tetrahydrofuran, acetonitrile, methyl-tert-butyl ether and dioxane.
In step (d) of Scheme 3, compound of Formula V is reacted with hydroxylamine sulfate and imidazole in presence of the organosilicon compound to obtain Molnupiravir of Formula I. The organosilicon compound is selected from the group comprising of hexamethyldisilazane (HMDS) or hexamethyldisiloxane (HMDSO).
In step (e) of Scheme 3, compound of Formula IV is reacted with hydroxylamine sulfate and imidazole in presence of the organosilicon compound to obtain compound of Formula VI. The organosilicon compound is selected from the group comprising of hexamethyldisilazane (HMDS) or hexamethyldisiloxane (HMDSO).

In step (f) of Scheme 3, compound of Formula VI is deprotected with acid in solvent to obtain Molnupiravir of Formula I. The acid is selected from the group comprising of inorganic acid such as hydrochloric acid, hydrogen bromide, hydrogen fluoride, hydrogen phosphate, hydrogen sulfate and the like or organic acid such as p-Toluenesulfonic acid, 5-sulfosalicylic acid and the like. The solvent is selected from the group comprising of tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate, Toluene acetonitrile, methyl-tert-butyl ether and dioxane.
Molnupiravir obtained from above process (Scheme 3) is optionally further purified by techniques already known in prior art such as crystallization. The solvent used for purification is selected from the group comprising of ester such as ethyl acetate, isopropyl acetate and the like; ether such as di-ethyl ether, methyl-tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like, acetonitrile, acetone, water and mixture thereof.
It is still another object of the present invention to provide compound of Formula X and its use for the preparation of Molnupiravir.


HO° 'OH°

N^N

Formula X
It is still another object of the present invention to provide compound of Formula XI and its use for the preparation of Molnupiravir.
* - °- . <; r^

Formula XI

Molnupiravir obtained by the process of the invention is in fact substantially pure, and in particular substantially free from the impurities. The expression "substantially pure" means having a purity degree equal to or higher than 99%.
Detection limit of NMD A is 0.06 ppm and Detection limit of NEDA is 0.016 ppm.
The process for the preparation of Molnupiravir described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Example 1: Preparation of 2',3'-0-isopropylidene Uridine
Uridine (100 g), acetone (1000 mL), p-toluenesulfonic acid monohydrate (13.3 g) and 2,2-dimethoxypropane (200 mL) were added into reactor at ambient temperature and stirred for 3-4 hr. The reaction mass was distilled under vacuum and the residue was dissolved in water (500 mL) and ethyl acetate (500 mL). After adjusting the pH of the reaction mass was adjusted to ~9 using 10% aqueous sodium carbonate solution under stirring, the layers were separated and the organic layer was concentrated under vacuum to obtain product. Yield - 104 g (90%); HPLC purity - 99.5%
Example 2: Preparation of 2',3'-0-isopropylidene Uridine
Uridine (100 g), acetone (1000 mL) and sulfuric acid (1.5 mL) were added into reactor at ambient temperature and stirred for 3-4 hr. The reaction mass was distilled under vacuum and the residue was dissolved in water (500 mL) and ethyl acetate (500 mL). After adjusting the pH of the reaction mass was adjusted to ~9 using 10% aqueous sodium carbonate solution under stirring, the layers were separated and the organic layer was concentrated under vacuum to obtain product. Yield - 104 g (90%); HPLC purity - 99.5%

Example 3: Preparation of compound of Formula IV
Compound of Formula II (100 g), isobutyric anhydride (84.23 g), ethyl acetate (1000
mL), and DMSO (100 mL), potassium bicarbonate (52.83 g) were charged in reactor at
ambient temperature and the reaction mass was stirred at 50-55°C over a period of 5-6 hr.
Then ethyl acetate (300 mL) was added to the reaction mass and washed with water. The
organic layer was concentrated at 50°C under vacuum to obtain the product as oily
residue.
Yield - (110 g, 88.0%). HPLC Purity - 87.3%
Example 4: Preparation of compound of Formula IV
Compound of Formula II (100 g), Compound of Formula III (110 g), DMSO (500 mL), potassium hydrogen carbonate (70.4g) were charged in reactor at ambient temperature and the reaction mass was stirred at 65-70°C over a period of 6-8 hr. Then ethyl acetate was added to the reaction mass. The organic layer was washed with IN HC1 followed by water washing. The organic layer was concentrated under vacuum to obtain the product as oily residue. Yield - (110 g, 88.0%). HPLC purity - 93.2%
Example 5: Preparation of compound of Formula IV
Compound of Formula II (100 g), isobutyric anhydride (84.23 g), ethyl acetate (1000
mL), DMSO (100 mL) and sodium carbonate (56 g) were charged in reactor at ambient
temperature and the reaction mass was stirred at 50-55°C over a period of 5-6 hr. Then
ethyl acetate (300 mL) was added to the reaction mass and washed with water. The
organic layer was concentrated at 50°C under vacuum to obtain the product as oily
residue.
Yield - 105 g (85%); HPLC purity - 86.2%
Example 6: Preparation of compound of Formula V
Compound of Formula IV (100 g) and Acetonitrile (800 mL) were charged and cooled to 0-5°C. Then concentrated Hydrochloric acid (353 mL) was added and the reaction mass was stirred for 3-4 hr. After cooling, the reaction mass was partitioned between ethyl

acetate and 20% potassium hydrogen carbonate and layers were separated. The organic layer was concentrated under vacuum to obtain the product as oily residue. Yield - 71 g (80%), HPLC purity - 92%
Example 7: Preparation of compound of Formula V
Compound of Formula IV (100 g), Acetonitrile (8 V) and p-Toluenesulfonic acid (1.2 mole equivalents) were charged and the reaction mass is heated to 55-60°C for 4-5 hr. After cooling, the reaction mass was partitioned between ethyl acetate and 20% potassium hydrogen carbonate and layers were separated. The organic layer was concentrated under vacuum to obtain the product as oily residue. Yield - 82.5 g (93%); HPLC purity - 97%
Example 8: Preparation of compound of Formula V
Compound of Formula IV (100 g), Acetonitrile (8 V) and 5-Sulfosalicylic acid dihydrate (73.9 g) were charged and the reaction mass is heated to 55-60°C for 4-5 hr. After cooling, the reaction mass was partitioned between ethyl acetate and 20% potassium hydrogen carbonate and layers were separated. The organic layer was concentrated under vacuum to obtain the product as oily residue. Yield - 82.5 g (93%); HPLC purity - 97%
Example 9: Preparation of compound of Formula VI
To a stirred solution of imidazole (1.362 g) in hexamethyldisilazane (HMDS) (68 mL) at 75-80°C, ammonium hydrogen sulfate (11.51 g) was added and stirred. Then hydroxylamine sulfate was added (8.21 g) to reaction mixture. Then compound of Formula IV (12.57 g) was added to it and the reaction mixture was aged with stirring at 75-85°C for 6 hr. After cooling to ambient temperature, reaction mass was quenched with water (30 ml) and the product was extracted with heptane. The organic layer was washed with water (10 ml). The organic layer was heated with Formic acid (6 ml) at 50°C for 1 hr. The reaction mass was diluted with water (35 ml) and washed with heptane (5 ml). The aqueous layer was basified with ammonium hydroxide (1.01 ml). Ethyl acetate (50 ml) and ammonium sulfate (40.0 g) were added, and the mixture was heated to 50°C to

give two homogeneous phases. The phases were separated at 50°C and the aqueous phase was extracted with Ethyl acetate (50 ml). The Ethyl acetate extracts were combined and concentrated under vacuum to obtain the product as oily residue. Yield - 11.8 g (89%); HPLC purity - 85.8%
Example 10: Preparation of Molnupiravir:
Compound of Formula VI (11 g) and Acetonitrile (88 mL) were charged and cooled to 0-5°C. Then cone. Hydrochloric acid (39 mL) was added and the reaction mass and stirred for 3-4 hr. After cooling, the reaction mass was partitioned between ethyl acetate and 20%) potassium hydrogen carbonate and layers were separated. The organic layer was concentrated under vacuum. The resulting slurry was maintained at reflux (75-80°C) for 15 min and gradually cooled to 60°C. MTBE (40.0 ml) was added and the reaction mixture was cooled to 0°C. The slurry was filtered, and the filter cake was washed with MTBE (40.0 ml) and dried to provide crude Molnupiravir. Yield - 8.2 g (83%); HPLC purity - 99.0%
Example 11: Preparation of Molnupiravir:
To a stirred solution of imidazole (1.362 g) in hexamethyldisilazane (HMDS) (68 mL) at 75-80°C, ammonium hydrogen sulfate (11.51 g) was added and stirred for 30 min. Then hydroxylamine sulfate was added (8.21 g) and stirred for 10 min. Then compound of Formula V (12.57 g) was added to it and the reaction mixture was aged with stirring at 75-85°C for 6 hr. After cooling to ambient temperature, reaction mass was quenched with water (30.00 ml) and the product was extracted with heptane. The organic layer was washed with water (10.00 ml). The organic layer was heated with Formic acid (6.00 ml) at 50°C for 1 hr. The reaction mass was diluted with water (35.00 ml) and washed with heptane (5.00 ml). The aqueous layer was basified with ammonium hydroxide (1.01 ml). Ethyl acetate (50.0 ml) and ammonium sulfate (40.0 g) were added, and the mixture was heated to 50°C to give two homogeneous phases. The phases were separated at 50°C and the aqueous phase was extracted with Ethyl acetate (50.0 ml). The Ethyl acetate extracts were combined and concentrated to approximately 40 mL volume. The resulting slurry was maintained at reflux (75-80°C) for 15 min and gradually cooled to 60°C. MTBE

(40.0 ml) was added then the reaction mixture was cooled to 0°C. The slurry was filtered,
and the filter cake was washed with MTBE (40.0 ml) and dried under nitrogen to provide
crude Molnupiravir.
Yield - 8.42 g (65%); HPLC purity - 99.0%
Content of Nitrosamine:
NMDA - Below detection limit;
NEDA - Below detection limit
Example-12: Purification of Molnupiravir
Solution of crude Molnupiravir (100 g) in a mixture of IPA-water (400 mL) was treated with activated charcoal for 30 min at 50°C. The resulting solution after filtration was diluted with water. The precipitated solid was filtered, washed with water and finally dried to provide pure Molnupiravir as white solid. Yield - 96 g (96%); HPLC purity - 99.5% Content of Nitrosamine: NMDA - Below detection limit; NEDA - Below detection limit
Example-13: Purification of Molnupiravir
Solution of crude Molnupiravir (100 g) in a mixture of Acetone-water (400 mL) was treated with activated charcoal for 30 min at 50°C. The resulting solution after filtration was diluted with water. The precipitated solid was filtered, washed with water and finally dried to yield the desired pure Molnupiravir as white solid. Yield - 80 g (80%); HPLC purity - 99.5% Content of Nitrosamine: NMDA - Below detection limit; NEDA - Below detection limit
Example-14: Purification of Molnupiravir
Solution of crude Molnupiravir (100 g) in a mixture of Acetonitrile-water (400 mL) was treated with activated charcoal for 30 min at 50°C. The resulting solution after filtration

was diluted with water. The precipitated solid was filtered, washed with water and finally
dried to yield the desired pure Molnupiravir as white solid.
Yield - 78 g (78%); HPLC purity - 99.5%
Content of Nitrosamine:
NMDA - Below detection limit;
NEDA - Below detection limit

WE CLAIM:

1. A process for the preparation of Molnupiravir of Formula I substantially free of nitrosamine impurities comprising the steps of:

H N
°^cr
O. ^ // "OH
N
o
HO OH
Formula I
(a) converting Uridine to compound of Formula II;

O. N
y
HO' ^ ' V-NH

NH u
HO' \ / J O. ,0
HO" "OH
O
Uridine Formula II

(b) reacting compound of Formula II with nitrophenol ester of isobutyric acid of Formula III to obtain the compound of Formula IV; and

•^irv
1 NH


Formula III Formula IV
(c) converting compound of Formula (IV) to Molnupiravir of Formula (I).

2. The process as claimed in claim 1, for the preparation of Molnupiravir from compound
of Formula IV comprising the steps of:
(a) deprotecting the compound of Formula IV to obtain compound of Formula V;

_ ,0
0 o

*~0*Y
u- N
NH
O
HO OH

Formula V
(b) reacting the compound of Formula V with hydroxylamine sulfate in presence of imidazole to obtain Molnupiravir of Formula I


H
M // X0H
o
HO OH
Formula I
with or without isolation of compound of Formula X; and

o 0 / ,rN^
H0C 'OH °

Formula X
(c) optionally, purifying Molnupiravir of Formula I.

3. The process as claimed in claim 1, for the preparation of Molnupiravir from compound of Formula IV comprising the steps of:
(a) reacting the compound of Formula IV with hydroxylamine sulfate in presence of imidazole to obtain compound of Formula VI;


0 O ' //
o 6. h

OH
I NH

Formula VI
with or without isolation of compound of Formula XI;

Formula XI
(b) deprotecting the compound of Formula VI to obtain Molnupiravir of Formula I; and


H
0 ,^°^N ^ NN0H
o
HO OH
Formula I

(c) optionally, purifying Molnupiravir of Formula I.

4. The process as claimed in claim 1, wherein step (b) is performed with inorganic base selected from the group comprising of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
5. The process as claimed in claim 2, wherein step (a) is performed with acid selected from the group comprising of hydrochloric acid, hydrogen bromide, hydrogen fluoride, hydrogen phosphate and hydrogen sulfate.
6. The process as claimed in claim 3, wherein step (b) is performed with acid selected from the group comprising of hydrochloric acid, hydrogen bromide, hydrogen fluoride, hydrogen phosphate and hydrogen sulfate.
7. Compound of Formula X


o^crv
.ex ,M //
,IN N
HC> OH °

N^N

Formula X
8. Compound of Formula XI
N^N

Formula XI
9. Use of Compound of Formula X for the preparation of Molnupiravir of Formula I.

10. Use of Compound of Formula XI for the preparation of Molnupiravir of Formula I.