DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A NOVEL PROCESS FOR THE PREPARATION OF 3CL PROTEASE INHIBITOR (NIRMATRELVIR)

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF INVENTION

The present invention relates to a novel process for the preparation of 3CL protease inhibitor; PF-07321332 (i.e Nirmatrelvir here onwards) of Formula (X) or its solvates, hydrates and co-crystals thereof, which is industrially viable.

Formula (X)

BACKGROUND OF THE INVENTION
Nirmatrelvir of Formula (X) is an antiviral drug developed by Pfizer which is found to be act as an orally active 3CL protease inhibitor. It is a covalent inhibitor, binding directly to the catalytic cysteine (Cys145) residue of the enzyme. Pfizer announced that its investigational novel COVID-19 oral antiviral candidate, Paxlovid® i.e Nirmatrelvir of Formula (X) in combination with Ritonavir, significantly reduced hospitalization and death, based on an interim analysis of the Phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness.

By early April 2020 the outbreak of COVID-19 has evolved into a global pandemic with over one million people having been confirmed as infected and resulting in over 50,000 deaths and later there have been over 1.5 million deaths globally. The causative agent for COVID-19 has been identified as a novel coronavirus which has been named Severe Acute Respiratory Syndrome Corona Virus 2 (“SARS-CoV-2”).

MedRxiv, preprint (2021), 1-132 reported the synthesis of Nirmatrelvir of Formula (X), which comprises coupling of a compound of Formula (I) with compound of Formula (II) to produce compound of Formula (III) which is further converted to MTBE solvate of Nirmatrelvir, upon recrystallization the MTBE solvate of Nirmatrelvir yields anhydrous Form-I of Nirmatrelvir of Formula (X). The process is shown in the scheme given below:
Scheme-I:

MedRxiv, preprint (2021), 1-132 also discloses the process for preparation of compound of Formula II, which is shown in the scheme given below:

Scheme-II:

In view of this, currently a need of simple, industrially applicable and cost-effective process for the preparation of Nirmatrelvir of Formula (X) and its intermediates.

The present invention is directed towards a novel, simple, cost effective process for the preparation of Nirmatrelvir of Formula (X) and its intermediates or its solvates, hydrates and co-crystals thereof.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a novel process for the preparation of Nirmatrelvir of Formula (X) and its intermediates or its solvates, hydrates and co-crystals thereof, which is industrially viable.
SUMMARY OF THE INVENTION

In an embodiment of the present invention is to provide a novel process for the preparation of compound of Formula (IIA) or its salts,

Formula (IIA)

wherein R1 comprises –OH; —OR3 and R3 is selected from an C1-6 alkyl group; a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; -NH2 which is optionally protected;
which comprises coupling a compound of Formula (IVA) or its salts thereof,

Formula (IVA)
wherein R1 is as defined above;
with compound of Formula (VA) or its salts thereof,

Formula (VA)

wherein R2 comprises, –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers;
to produce compound of Formula (IIA) or its salts thereof.
In other embodiment of the present invention is to provide a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof,

Formula (X)
which comprises, coupling compound of Formula (IIA) or its salts thereof,

Formula (IIA)

wherein R1 is as defined above, with compound of Formula (IA) or its salts thereof,

Formula (IA)

wherein R4 is selected from –CN or CONH2; R5 comprises -NH2 which is optionally protected; –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br; wherein R1 and R5 both cannot be -NH2 at same time;
to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

In yet another embodiment, the present invention provides a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof,

Formula (X)

which comprises,
(i) dehydrating compound of Formula (IC);

Formula (IC)
R6 comprises –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —COOCOR, —COOSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from I, Cl and Br; -NH2 which is optionally protected; or the below moieties;

(ii) isolating Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

In yet another embodiment, the present invention provides a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof, which comprises,
(i) amination of compound of Formula (II) or salts thereof,

Formula (II)

to produce compound of Formula (IIB),

Formula (IIB)

(ii) coupling of above compound of Formula (IIB) with compound of Formula (IB) or its salts thereof,

Formula (IB)

Wherein, X comprises –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br;
in the presence of a coupling agent to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

In yet another preferred embodiment, the present invention provides a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof,

Formula (X)
which comprises,
(i) coupling of compound of Formula (IVA) or its salts thereof,

Formula (IVA)

wherein R1 comprises –OH, —OR3 and R3 is selected from an C1-6 alkyl group, NH2 which is optionally protected, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers or NH2 which is optionally protected; with compound of Formula (IA) or its salts thereof,

Formula (IA)
wherein R4 is selected from –CN or CONH2; R5 comprises -NH2 which is optionally protected; –OH, —OR3 and R3 is selected from a C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br; wherein R1 and R5 both cannot -NH2 at same time;
to produce compound of Formula (IIC) or salts thereof,

Formula (IIC)

(ii) coupling of compound of Formula (IIC) or its salts thereof, with compound of Formula (VA) or salts thereof,

Formula (VA)

wherein R2 comprises, –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers;
to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of present invention is to provide a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof using compounds of Formulae (I), (IA), (IB), (II), (IIA), (IIB), (IIC), (IV), (IVA) and (VA).

In a preferred embodiment R1 is selected from –OH, —OR3 and R3 is selected from an C1-6 alkyl group, NH2 which is optionally protected, a leaving group selected from —OTs (p-toluenesulfonate), —OMs (methanesulfonate ), —OCOR (an anhydride) , —OSO2R (sulfuric anhydride), wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers or NH2 which is optionally protected; R2 comprises, –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers;

In another preferred embodiment R4 is selected from –CN or CONH2; R5 comprises -NH2 which is optionally protected; –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br, wherein R1 and R5 both cannot be -NH2 at same time i.e if R5 is –NH2 or protected –NH2 and R1 is other than is –NH2 or protected –NH2 and vice versa.

In another preferred embodiment R6 is selected from –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —COOCOR, —COOSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from I, Cl and Br; -NH2 which is optionally protected; or the below moieties;

In yet another preferred embodiment X is selected from –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br;

In yet another preferred embodiment amino protecting group comprises tert-Butyloxycarbonyl (Boc), N-carboxybenzyl (Cbz), benzyl, benzoyl, benzoyl biphenyl, trifluoro acetyl (Tfa), Alloc, 9-fluorenylmethyloxycarbonyl (Fmoc), 4-toluenesulfonylethyloxycarbonyl (Tsoc), and phthalyl (Pht).

In yet another preferred embodiment the “coupling agent” used in the present invention comprises carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N-N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), 2-(lH-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (7-Azabenzotriazol-1-yloxy)tripyrrolidino phosphonium hexafluorophosphate (PyAOP), Bis(2-oxo-3-xazolidinyl)phosphinic chloride (BOP-Cl), benzotriazol-1-yloxytri(pyrrolidino)phosphoniumhexafluoro phosphate(PyBOP), bromotri(pyrrolidino)phosphoniumhexafluorophosphate (PyBrOP), chlorotri(pyrrolidino)phosphoniumhexafluorophosphate (PyClOP), ethyl-2-cyano-2-(hydroxyimino)acetate(Oxyma Pure), ethyl 1,2-dihydro-2-ethoxyquinoline-1-carboxylate (EEDQ), 1-cyano-2-ethoxy-2-oxoethyl idenaminooxy)dimethylaminomorpholinocarbeniumhexafluorophosphate (COMU), dimethylacetamide (DMA) and 2,6-Lutidine, alkyl phosphonic acid anhydrides or salts or mixtures thereof.

In yet another preferred embodiment the “base” used in the present invention is selected from the group consisting of inorganic base such as sodium carbonate, sodium bicarbonate, calcium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and cesium carbonate, an organic base such as diisopropylamine, triethylamine, diisopropylethylamine and diethylamine, and a mixture thereof or mixtures thereof.

In yet another preferred embodiment the “acid” used in the present invention is selected from the group consisting of HCl, HBr, H2SO4 or H3PO4.

In yet another preferred embodiment the “solvent” used in the present invention is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetonitrile; ethyl acetate; methylene chloride; chloroform, carbon tetrachloride (CCl4), N,N-dimethylformamide (DMF), N,N-dimethyl sulfoxide (DMSO) or mixture thereof.

In a preferred embodiment of present invention is to provide a novel process for the preparation of compound of Formula (IIA) or its salts thereof.

The process comprises coupling compound of Formula (IVA) or its salts thereof with compound of Formula (VA) or its salts thereof in the presence of a coupling agent to produce compound of Formula (IIA) or its salts thereof, wherein the coupling agent is defined above.

In yet another embodiment the coupling is carried out using a base in the presence or absence of a solvent, wherein the base and solvent are defined above.

In another preferred embodiment of present invention is to provide a novel process for the preparation of compound of Formula (II) or its salts thereof.

The process comprises treating compound of Formula (IV) or its salts thereof is hydrolyzed, followed by coupling with compound of Formula (VB) to give compound of Formula (II).

Formula (VB)

The hydrolysis is carried out in presence of a base or an acid, which are defined above. The coupling is carried out using a base in the presence or absence of a solvent which are defined above.

In yet another embodiment of present invention is to provide a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

The process comprises the coupling of compound of Formula (IIA) or its salt thereof, with compound of Formula (IA) or its salts thereof in the presence of a coupling agent to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof, wherein the coupling agent is defined above.

In yet another preferred embodiment the coupling is carried out using a base in the presence or absence of a solvent, which are defined above.

In yet another embodiment of present invention is to provide a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

The process comprises dehydration of a compound of Formula (IC) or its salts thereof, which is carried out in the presence of a suitable dehydrating agent.
In yet another preferred embodiment the dehydrating agent comprises trifluoroacetic anhydride (TFAA), Phosphorus pentoxide (P2O5); Palladium(II) acetate (Pd(OAc)2), palladium trifluoroacetate (Pd(OCCF3)2, N-methyl-N-(trimethylsilyl)trifluoroacetamide(MSTFA)/Zn or Cu; Tris(dimethylamino)-phosphine (P(NMe2)3), triphenyl phosphite (P(OPh)3); vanadium oxide supported on hydrotalcite (V/HT), dimethoxymethylsilane (DMMS)/ 1,2-bis(dicyclohexylphosphino)ethane (DCyPE)/copper(II) acetate (Cu(OAc)2) triethoxysilane/iron ((EtO)3SiH/Fe); phosphorus trichloride (PCl3), Oxalyl chloride ((COCl)2), thionyl chloride (SOCl2), Aluminium chloride-sodium iodide or potassium iodide (AICI3-Nal or KI), Zinc chloride (ZnCl2), cyanuricchloride ((NCCl)3), ethyl dichlorophosphate (C2H5OP(O)Cl2); phenyl dichlorophosphate (C6H5OP(O)Cl2); N,N-dimethylphosphoramidic dichloride (DMPADC) N,N-dimethylphosphoramidous dichloride, Palladium(II) chloride (PdCl2), chloridotris(triphenylphosphine)rhodium(I) (RhCl(PPh3)3)-dialkyl urea, silazanes, aminosilanes, alkoxysilanes, and chlorosilanes and, hexamethylphosphoric triamide (HMPT).

In yet another preferred embodiment the dehydration may optionally carried out using a base in the presence or absence of a solvent, which are defined above.

In another preferred embodiment, the present invention provides a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

The process comprises, aminating of the compound of Formula (II) or its salts thereof to produce compound of Formula (IIB) or its salts thereof, which is coupled with compound of Formula (IB) or its salts thereof in the presence of a coupling agent.

In yet another preferred embodiment, the amination of compound of Formula (II) or its salts thereof is carried out using an aminating agent preferably ammonia.

The amination is optionally carried out using a base in the presence or absence of a solvent which are defined above.

In yet another preferred embodiment, the present invention provides a process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

The process comprises coupling the compound of Formula (IVA) or salts thereof, with compound of Formula (IA) or its salts thereof, to produce compound of Formula (IIC) or salts thereof, which is further coupled with compound of Formula (VA) or salts thereof, to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

The coupling is carried out using a coupling agent as defined above. The coupling is optionally carried out using a base in the presence or absence of a solvent which are defined above. In the above reaction, if dehydration is required, the dehydration reaction is carried out in presence of a dehydrating agent as defined above.

In yet another embodiment of present invention is to provide a novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.
The process comprises coupling of compound of Formula II with compound of Formula I in the presence of a coupling agent to give compound of Formula III which is further dehydrated to give Nirmatrelvir of Formula (X) or its solvates.

Coupling agent and dehydrating agent are defined above.

In yet another preferred embodiment, Nirmatrelvir solvate is converted to Nirmatrelvir.

In yet another preferred embodiment, the compounds of Formulae (IA), (IB), (IB), (IC), (IIA), (IIB), (IIC), (IVA), (VA) used in the present invention are either isolated or carried out in-situ to the next stage.

In yet another preferred embodiment, Nirmatrelvir of Formula (X) or the compounds of Formulae (IA), (IB), (IB), (IC), (IIA), (IIB), (IIC), (IVA), (VA) optionally purified using solvent crystallization or recrystallization or using solvent and anti-solvent method or using drying techniques to produce substantially pure compound.

In yet another preferred embodiment, “salts” or “co-crystals” as mentioned in the present invention are selected from mineral acids such as HCl, HBr, H2SO4, and salts of organic acids selected from maleic acid, succinic acid, glutaric acid and formic acid.

In yet another preferred embodiment, “solvates” as mentioned in the present invention are preferably selected from the solvents as defined above.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention in any manner whatsoever.

Example-I: Preparation of compound of Formula-II
A solution of compound of Formula (IV) (200 g, 0.972 mmol) in an aqueous tetrahydrofuran (740 ml, ~19%) was treated with triethylamine (157.5 g, 1.556 mmol) and stirred for 15 minutes at 20-30°C. The organic layer was separated, and aqueous layer was extracted with tetrahydrofuran (200 ml). Both organic layers were combined and treated with sodium hydroxide solution (46.7 g of NaOH in 100 ml water). The mass was stirred at 40-45°C for 8 hours, after completion the reaction, the reaction mass was cooled to 5-10°C and stirred for 2 hours. The product was filtered and washed with tetrahydrofuran (200 ml) under nitrogen atmosphere. The wet product was dried in vacuum oven at 60-70°C for 8 hours to get carboxylic free acid of compound of Formula (IV) as it sodium salt.
Methane sulfonyl chloride (134.5 g, 1.174 mmol) was added to a solution of compound of Formula (VB) (246.2 g, 1.083 mmol) in isopropyl acetate (2880 ml) at 25-35°C, followed by triethylamine (274.2 g, 2.709 mmol) was added under nitrogen atmosphere at 25-35°C. The reaction mass was stirred for 2 hours at 25-35°C under nitrogen atmosphere, after completion of the reaction the sodium salt of carboxylic free acid of compound of Formula (IV) (160 g, 0.903) was added to the reaction mass and stirred for 3 hours at 25-35°C. A solution of Citric acid (~1440 ml, 448 g of citric acid monohydrate in 1440 ml water) was added to the reaction mass at 20-30°C. The reaction mass was stirred for 15 minutes at 20-30°C and the organic layer was separated. Organic layer was washed with water (960 ml) and distilled the organic layer under vaccum at below 60°C, up to reaction mass ~1200 ml present in the flask. N-heptane (1200 ml) was slowly added to the reaction mass at 55-65°C and stirred the reaction mass for 10 minutes at 55-65°C. Cooled the reaction mass to 5-15°C and stirred the reaction mass for 2 hours at 5-15°C. The product was filtered and washed with pre-cooled (5-15°C) mixer of Isopropyl acetate (80 ml) and n-heptane (80 ml) under nitrogen atmosphere. The wet product obtained was purified in mixture of isopropyl acetate (480 ml) & n-heptane (480 ml) at 55-65°C and isolated at 5-15°C. The wet product was dried in vacuum oven at 55-65°C for 8 hours to get compound of Formula (II).

Example-II: Nirmatrelvir MTBE Solvate
A solution of compound of Formula (II) (200 g, 0.548 mmol) in methylene chloride (1600 ml) was treated with compound of Formula (I) (119.7 g, 0.576 mmol) and 2-hydroxypyridine-N-oxide (45.7 g, 0.411 mmol), triethyl amine (83.3 g, 0.823 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (136.8 g, 0.713 mmol) at 20-30°C under nitrogen atmosphere and stirred for 6 hours at 20-30°C under nitrogen atmosphere. After the reaction was completed, sodium chloride solution (600 ml, 5%) was added to the mass at 20-30°C and stirred for 15 minutes and separated the organic layer. The organic layer was again washed with sodium chloride solution (600 ml, 5%) and distilled the organic layer under vacuum at below 50°C, followed by co-distillation with isopropyl acetate (300 ml) twice at below 60°C. The reaction mass was cooled to 20-30°C and isopropyl acetate (1100 ml) was added, followed by N-methyl morpholine (277.6 g, 2.744 mmol) was added to the mass. The reaction mass was cooled to 10-15°C under nitrogen atmosphere and treated with trifluoracetic anhydride (288.2 g, 1.372 mmol) and the reaction mass was stirred for 2 hours at 10-25°C under nitrogen atmosphere. After the reaction completed, water (600 ml) was added to the reaction mass at 10-25°C and the organic layer was separated and washed twice with water (600 ml). The organic layer was distilled under vacuum at below 60°C, up to reaction mass 600 ml present in the flask. Methyl tert-butyl ether (2000 ml) was added to the mass at 40-50°C and the mass was cooled, stirred for 3 h at 20-30°C. The product was filtered and washed with n-heptane (400 ml). The wet product was dried in vacuum oven at 55-65°C for 10 hours to get Nirmatrelvir MTBE solvate.

Example-III: Nirmatrelvir
A solution of Nirmatrelvir MTBE solvate (150 g) in isopropyl acetate (525ml) was subjected to carbon (7.5 g) treatment at 60-65°C. n-Heptane (1050 ml) was added to the mass at 60-65°C. The mass was cooled to 20-30°C and stirred for 5 hours at 20-30°C. The product was filtered and washed with n-heptane (150 ml). The wet product was dried under vacuum at 55-65°C for 10 hours to get Nirmatrelvir. ,CLAIMS:WE CLAIM:
1. A process for the preparation of compound of Formula (IIA) or its salts thereof;

Formula (IIA)

wherein R1 comprises –OH; —OR3 and R3 is selected from an C1-6 alkyl group; a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; —NH2 which is optionally protected;
which comprises coupling a compound of Formula (IVA) or its salts thereof,

Formula (IVA)

wherein R1 is as defined above;
with compound of Formula (VA) or its salts thereof,

Formula (VA)
wherein R2 comprises, –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers;
to produce compound of Formula (IIA) or its salts thereof.

2. The process as claimed in claim 1, wherein the coupling of compound of Formula (IVA) with compound of Formula (VA) is carried out in presence of a coupling agent.

3. A process for the preparation of Nirmatrelvir (X) or its solvates, hydrates and co-crystals thereof,

Formula (X)

which comprises, coupling compound of Formula (IIA) or its salts thereof,

Formula (IIA)
wherein R1 is as defined in claim 1, with compound of Formula (IA) or its salts thereof,

Formula (IA)

wherein R4 is selected from –CN or CONH2; R5 comprises -NH2 which is optionally protected; –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br; wherein R1 and R5 both cannot be -NH2 at same time;
to produce compound of Formula (X) or its solvates, hydrates and co-crystals thereof.

4. The process as claimed in claim 3, wherein the coupling of compound of Formula (IIA) with compound of Formula (IA) is carried out in the presence of a coupling agent.

5. A process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof,

Formula (X)

which comprises,
(i) dehydrating compound of Formula (IC);

Formula (IC)

R6 comprises –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —COOCOR, —COOSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from I, Cl and Br; -NH2 which is optionally protected; or the below moieties;

(ii) isolating Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

6. The process as claimed in claim 5, wherein the dehydration is preferably carried out in the presence of a dehydrating.

7. A process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof, which comprises,
(i) amination of compound of Formula (II) or salts thereof,

Formula (II)

to produce compound of Formula (IIB),

Formula (IIB)

(ii) coupling of above compound of Formula (IIB) with compound of Formula (IB) or its salts thereof,

Formula (IB)

Wherein, X comprises –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br;
in the presence of a coupling agent to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

8. The process as claimed in claim 7, wherein the amination of compound of Formula (II) is carried out using an aminating agent is preferably ammonia.

9. A novel process for the preparation of Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof,

Formula (X)
which comprises,
(i) coupling of compound of Formula (IVA) or its salts thereof,

Formula (IVA)

wherein R1 comprises –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers or NH2 which is optionally protected; with compound of Formula (IA) or its salts thereof,

Formula (IA)
wherein R4 is selected from –CN or CONH2; R5 comprises -NH2 which is optionally protected; –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers; a halogen selected from Cl and Br; wherein R1 and R5 both cannot -NH2 at same time;
in the presence of a coupling agent to produce compound of Formula (IIC) or salts thereof,

Formula (IIC)

(ii) coupling of compound of Formula (IIC) or its salts thereof, with compound of Formula (VA) or salts thereof,

Formula (VA)

wherein R2 comprises, –OH, —OR3 and R3 is selected from an C1-6 alkyl group, a leaving group selected from —OTs, —OMs, —OCOR, —OSO2R, wherein R is selected from hydrogen, trifluoromethyl, p-tolyl, methyl, m-nitro-phenyl, alkyl ethers;
in the presence of a coupling agent to produce Nirmatrelvir of Formula (X) or its solvates, hydrates and co-crystals thereof.

10. The process as claimed in any of the proceeding claims, wherein the coupling agent is selected from carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), N-N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), 2-(lH-7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (7-Azabenzotriazol-1-yloxy)tripyrrolidino phosphonium hexafluorophosphate (PyAOP), Bis(2-oxo-3-xazolidinyl)phosphinic chloride (BOP-Cl), benzotriazol-1-yloxytri(pyrrolidino)phosphoniumhexafluoro phosphate(PyBOP), bromotri(pyrrolidino)phosphoniumhexafluorophosphate (PyBrOP), chlorotri(pyrrolidino)phosphoniumhexafluorophosphate (PyClOP), ethyl-2-cyano-2-(hydroxyimino)acetate(Oxyma Pure), ethyl 1,2-dihydro-2-ethoxyquinoline-1-carboxylate (EEDQ), 1-cyano-2-ethoxy-2-oxoethyl idenaminooxy)dimethylaminomorpholinocarbeniumhexafluorophosphate (COMU), dimethylacetamide (DMA) and 2,6-Lutidine, alkyl phosphonic acid anhydrides or salts or mixtures thereof.