WO2023148747A1

WO2023148747A1 - Improved processes for preparation of nirmatrelvir and intermediates thereof

Info

Publication number: WO2023148747A1
Application number: PCT/IN2022/050417
Authority: WO
Inventors: Srinivas ORUGANTI; Vishnu Vardhana Vema Reddy EDA; Manish M. SHINDE; Karuna Veeramani; Balachennaiah DARAPANENI; H Rama Mohan; Madarapu SRINIVAS; Saikat Sen
Original assignee: Dr Reddy S Institute Of Life Sciences
Current assignee: Dr Reddy S Institute Of Life Sciences
Priority date: 2022-02-07
Filing date: 2022-05-03
Publication date: 2023-08-10
Anticipated expiration: 2024-08-07

Abstract

The present application provides improved processes for preparation of Nirmatrelvir and intermediates thereof. The claimed process is commercially viable, advantageous and provides novel intermediates for the preparation of Nirmatrelvir. The improved processes do not specifically involve reagents which require special handling, storage conditions and are difficult to procure commercially.

Description

“IMPROVED PROCESSES FOR PREPARATION OF NIRMATRELVIR

AND INTERMEDIATES THEREOF”

FIELD OF THE INVENTION

The present invention relates to the improved processes for preparation of Nirmatrelvir and intermediates thereof. The improved processes do not specifically involve reagents which require special handling, storage conditions and are difficult to procure commercially.

BACKGROUND OF THE INVENTION

The compound is having International Nonproprietary Name (INN) as Nirmatrelvir (or PF-07321332). The IUPAC name of Nirmatrelvir is ( 1/ ,2S,5S)-N- {(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[(2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide, and is represented by the structure of Formula I.

Nirmatrelvir is an irreversible inhibitor of SARS-CoV-2 viral protease M^pro. It is a part of the oral combination therapy Paxlovid, which has been developed by Pfizer for the treatment of patients with mild to moderate COVID- 19. Paxlovid has even shown promising in-vitro activity against the SARS-CoV-2 variant Omicron.

The synthetic process, solid state forms, pharmaceutical composition and method of use are described in WO 2021/250648 Al. The end game process described in WO 2021/250648 Al is schematically represented below:

(lR,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3- azabicyclo [3.1.0]hexane-2-carboxylic acid is reacted with 3-[(3S)-2- oxopyrrolidin-3-yl]-L-alaninamide at 25 °C for 16 h in presence of 2- hydroxypyridine 1-oxide (HOPO), N,N-diisopropylethylamine (DIPEA) and l-[3- (dimethylamino)propyl] -3 -ethylcarbodiimide hydrochloride (EDC-HC1) to furnish (lR,2S,5S)-N-{(2S)-l-amino-l-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}- 6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane- 2-carboxamide. The product obtained was reacted with Burgess reagent (methyl N- (triethylammonio sulfonyl) carbamate, inner salt) at 25 °C for 4 h to obtain Nirmatrelvir.

The end-game process described in WO 2021/250648 Al employs expensive and difficult to handle reagents such as the Burgess reagent or involves prolonged reaction times which increases the possibility of impurity formation owing to epimerization. Further, similar end game process is reported in the art Science 2021, 374, 1586-1593. Hence, there remains a need to provide commercially viable and advantageous processes, and novel intermediates for the preparation of Nirmatrelvir. The inventors of the present invention have developed improved processes which do not specifically involve reagents which require special handling, storage conditions and are difficult to procure commercially. The processes, particularly when coupled with flow chemistry techniques, offer significant reduction in reaction time. The novel intermediate disclosed paves way for the introduction of the sensitive N-trifluoroacetyl-L-tert-leucine fragment towards the end of the synthesis and therefore allow an improved synthesis of Nirmatrelvir.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for preparation of the Nirmatrelvir intermediate of Formula II. The process comprising the steps of: a) reacting compound of Formula III with compound of Formula IV to provide compound of Formula V,

b) optionally, isolating compound of Formula V, c) converting compound of Formula V to compound of Formula II,

Wherein Pi is a suitable nitrogen protecting group known in literature such as Greene's Protective Groups in Organic Synthesis, 4^th Ed., pp. 696-926 (J. Wiley & Sons, 2007).

In another aspect, the present invention provides a process for preparation of the Nirmatrelvir intermediate of Formula II, comprising the steps of: a) reacting compound of Formula Illa with compound of Formula IV to provide compound of Formula Va in presence of propanephosphonic acid anhydride (T3P),

b) optionally, isolating compound of Formula Va, c) converting compound of Formula Va to compound of Formula Ila in presence of T3P.

The reaction of compound of Formula III with compound of Formula IV to provide compound of Formula V can be carried out in batch or preferably, in continuous flow. Likewise, the conversion of compound of Formula V to the Nirmatrelvir intermediate compound of Formula II can also be carried out batch or preferably, in continuous flow.

In another aspect, the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I. The process comprising the steps of: a) reacting compound of Formula VI with compound of Formula IV to provide compound of Formula VII in presence of T3P and an amine (R1R2R3N),

b) optionally, isolating compound of Formula VII, c) converting compound of Formula VII to compound of Formula I in presence of T3P and an amine (R1R2R3N).

Wherein Ri, R2 and R3 may independently be an alkyl, aryl or arylalkyl group, or a part of a saturated heterocyclic ring.

In another aspect, the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in a continuous flow. The process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P, with another solution, containing compound of Formula IV and an amine (R1R2R3N), by passing them through individual tubings in to flow reactor to provide compound of Formula VII, b) isolating compound of Formula VII from the product stream obtained in Step (a), c) converting compound of Formula VII to compound of Formula I by passing a solution, containing compound of Formula VII, T3P and an amine (R1R2R3N), through a flow reactor. In another aspect, the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P, with another solution, containing compound of Formula IV and an amine (R1R2R3N), by passing them through individual tubings in to flow reactor to provide compound of Formula VII, b) passing the product stream obtained in Step (a) in to a second flow reactor to provide a compound of Formula I.

In another aspect, the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the step of reacting a solution, containing compound of Formula VI and T3P, with another solution, containing compound of Formula IV and an amine (R1R2R3N), by passing them through individual tubings in to flow reactor to provide compound of Formula I.

In another aspect, the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the step of reacting a solution, containing compound of Formula VI, compound of Formula IV and an amine (R1R2R3N), with a solution of T3P by passing them through individual tubings in to flow reactor to provide compound of Formula I.

Another aspect of the present invention relates to compound of Formula II and its use for the preparation of Nirmatrelvir compound of Formula (I) or pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the block diagram of the continuous flow apparatus for the single-step synthesis of compound of Formula I from compound of Formula VII as illustrated in Example 9. Figure 2 illustrates the block diagram of the continuous flow apparatus for the two- step dual-feed synthesis of compound of Formula I from compound of Formula VI and compound of Formula IV as illustrated in Example 10.

Figure 3 illustrates the block diagram of the continuous flow apparatus for the two- step single-feed synthesis of compound of Formula I from compound of Formula VI and compound of Formula IV as illustrated in Example 12.

DETAILED DESCRIPTION OF THE INVENTION

An aspect of the present invention provides a process for preparation of the Nirmatrelvir intermediate of Formula II. The process comprising the steps of: a) reacting compound of Formula III with compound of Formula IV to provide

b) optionally, isolating compound of Formula V, c) converting compound of Formula V to compound of Formula II.

Wherein Pi is a suitable nitrogen protecting group.

In another aspect of present invention, compound of Formula III may be prepared according to any of the methods known in the art such as Tetrahedron 2017, 73, 4285-4294. In another aspect of present invention, compound of Formula IV may be prepared according to any of the methods known in the art such as Science 2021, 374, 1586-1593.

In another aspect of present invention, in step a), compound of Formula V is obtained by reacting compound of Formula III with compound of Formula IV in a suitable solvent and in presence of a suitable base and a suitable coupling agent.

The suitable solvent may include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. The suitable base may include but not limited to triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like. The suitable coupling agent may include but not limited to carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), propanephosphonic acid anhydride (T3P), O-(benzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-CI), 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), N-(dimethylaminopropyl)-N'-ethyl-carbodiimide.

In another aspect of present invention, the reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent.

In another aspect of present invention, in step b), the isolated crude compound of Formula V may be purified by techniques known in art like column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization

In another aspect of present invention, in step c), compound of Formula V is converted to compound of Formula II in a suitable solvent and in presence of a suitable base and a suitable dehydrating agent. The suitable solvent may include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. The suitable base may include but not limited to triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like. The suitable dehydrating agent may include but not limited to propanephosphonic acid anhydride (T3P), AICE, P2O5, (COC1)2, cyanuric chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), methanesulfonyl chloride, 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), 1 -chloro-N,N,2-trimethyl- 1 -propenylamine, hexamethylphosphoric triamide (HMPT), trifluoroacetic anhydride, ethyl dichlorophosphate, dimethoxymethylsilane and N-methyl-N-(trimethylsilyl) trifluoroacetamide.

In another aspect of present invention, the reaction may be carried out at a temperature of about 40 °C to about boiling point of the solvent.

Another aspect of present invention provides a process for preparation of the Nirmatrelvir intermediate of Formula II. The process comprising the steps of: a) reacting compound of Formula Illa with compound of Formula IV to provide compound of Formula Va in presence of propanephosphonic acid anhydride (T3P),

b) optionally, isolating compound of Formula Va, converting compound of Formula Va to compound of Formula Ila in presence of T3P,

Another aspect of present invention provides a process for preparation of the Nirmatrelvir compound of Formula I. The process comprising the steps of: a) reacting compound of Formula VI with compound of Formula IV to provide compound of Formula VII in presence of T3P and an amine (R1R2R3N),

b) optionally, isolating compound of Formula VII, c) converting compound of Formula VII to compound of Formula I in presence of T3P and an amine (R1R2R3N),

In another aspect of present invention, compound of Formula VI may be prepared according to any of the methods known in the art such as Science 2021, 374, 1586-1593.

In another aspect of present invention, in step a), compound of Formula VII is obtained by reacting compound of Formula VI with compound of Formula IV in a suitable solvent and in presence of a suitable amine base (R1R2R3N) and T3P as coupling agent.

The suitable solvent may include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. The suitable amine base may include but not limited to triethylamine, diisopropylethylamine (DIPEA) and the like.

In another aspect of present invention, in step b), the isolated crude compound of Formula VII may be purified by techniques known in art like column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization In another aspect of present invention, in step c), compound of Formula VII is converted to compound of Formula I in a suitable solvent and in presence of a suitable amine base (R1R2R3N) and T3P as dehydrating agent.

Another aspect of the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P, with another solution, containing compound of Formula IV and an amine (R1R2R3N), by passing them through individual tubings in to flow reactor to provide compound of Formula VII, b) isolating compound of Formula VII from the product stream obtained in Step (a), c) converting compound of Formula VII to compound of Formula I by passing a solution, containing compound of Formula VII, T3P and an amine (R1R2R3N), through a flow reactor.

In another aspect of present invention, in step a), a solution, containing compound of Formula VI and T3P in a suitable solvent, is mixed with another solution, containing compound of Formula IV and an amine (R1R2R3N) in a suitable solvent, in a flow reactor to provide compound of Formula VII. The suitable solvent may include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. The suitable amine base may include but not limited to triethylamine, diisopropylethylamine (DIPEA) and the like. The reactant solutions are passed through individual tubing in to flow reactor with defined flow rates. The flow rate may be about 0.1 mL/min to about 50 mL/min.

In another aspect of present invention, formation of compound of Formula VII in step a) may be carried out at system back pressures of about 0.5-40 bar in the flow reactor.

In another aspect of present invention, formation of compound of Formula VII in step a) may be carried out at a temperature of about 0 °C to about 120 °C.

In another aspect of present invention, in step b), the isolated crude compound of Formula VII may be purified by techniques known in art like column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization

In another aspect of present invention, in step c), a solution, containing compound of Formula VII, T3P and an amine (R1R2R3N) in a suitable solvent, is passed through a flow reactor to provide compound of Formula I.

The suitable solvent may include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. The suitable amine base may include but not limited to triethylamine, diisopropylethylamine (DIPEA) and the like. The reactant solutions are passed through individual tubing in to flow reactor with defined flow rates. The flow rate may be about 0.1 mL/min to about 50 mL/min.

In another aspect of present invention, formation of compound of Formula I in step c) may be carried out at system back pressures of about 0.5-40 bar in the flow reactor.

In another aspect of present invention, formation of compound of Formula I in step c) may be carried out at a temperature of about 40 °C to about 120 °C.

Another aspect of the present application provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P, with another solution, containing compound of Formula IV and an amine (R1R2R3N), by passing them through individual tubings in to flow reactor to provide compound of Formula VII. b) passing the product stream obtained in Step (a) in to a second flow reactor to provide a compound of Formula I.

In another aspect of present invention, in step a), a solution, containing compound of Formula VI and T3P in a suitable solvent, is mixed with another solution, containing compound of Formula IV and an amine (R1R2R3N) in a suitable solvent, in a flow reactor to provide compound of Formula VII.

In another aspect of present invention, system back pressures of about 0.5-40 bar in the flow reactor may be employed.

Another aspect of the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the steps of reacting a solution, containing compound of Formula VI and T3P, with another solution, containing compound of Formula IV and an amine (R1R2R3N), by passing them through individual tubings in to flow reactor to provide compound of Formula I.

In another aspect of present invention, a solution containing compound of Formula VI and T3P in a suitable ether solvent, is mixed with another solution, containing compound of Formula IV and an amine (R1R2R3N) in a suitable solvent, in a flow reactor to provide compound of Formula I.

The suitable solvent may include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. The suitable amine base may include but not limited to triethylamine, diisopropylethylamine (DIPEA) and the like. The reactant solutions are passed through individual tubing in to flow reactor with defined flow rates. The flow rate may be about 0.1 mL/min to about 50 mL/min. In another aspect of present invention, formation of compound of Formula I may be carried out at a temperature of about 30 °C to about 110 °C.

Another aspect of the present invention provides a process for preparation of the Nirmatrelvir compound of Formula I in continuous flow. The process comprising the step of reacting a solution, containing compound of Formula VI, compound of Formula IV and an amine (R1R2R3N), with a solution of T3P by passing them through individual tubings in to flow reactor to provide compound of Formula I.

In another aspect of present invention, a solution containing compound of Formula VI, compound of Formula IV and an amine (R1R2R3N) in a suitable solvent, is mixed with a solution of T3P in a flow reactor to provide compound of Formula I.

In another aspect of present invention, formation of compound of Formula VII in step a) may be carried out at a temperature of about 30 °C to about 110 °C.

In another aspect of the present invention, coupling agent and dehydrating agent is T3P. In another aspect of present invention, system back pressures of about 0.5- 40 bar in the flow reactor may be employed.

In another aspect of present invention, the flow processes as disclosed herein provide the following advantages over batch processes:

1. Increase in reactivity and process efficiency.

2. Reduction in reaction time.

3. Reduction in solvent volume.

4. Consistent yield with better control over the process parameters.

The main aspect of the present invention provides a process for preparing the Nirmatrelvir compound of Formula I,

wherein the process comprising the steps of: a) reacting a compound of Formula VI with a compound of Formula IV at an appropriate temperature in presence of a suitable solvent, amine base

(R1R2R3N) and coupling agent to provide compound of Formula VII,

b) optionally, isolating compound of Formula VII as obtained in step (a), c) converting compound of Formula VII to compound of Formula I at an appropriate temperature in presence of solvent, amine base (R1R2R3N) and dehydrating agent,

wherein Ri, R2 and R3 are alkyl, aryl or arylalkyl group, or a part of a saturated heterocyclic ring.

In another aspect of the present invention, the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DM Ac), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the amine base (R1R2R3N) of step (a) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

In another aspect of the present invention, the amine base of step (a) is preferably DIPEA.

In another aspect of the present invention, the coupling agent is selected from carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), propanephosphonic acid anhydride (T3P), O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI), 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), N- (dimethylaminopropyl)-N'-ethyl-carbodiimide and the like and mixtures thereof .

In another aspect of the present invention, the coupling agent is preferably T3P. In another aspect of the present invention, the reaction of step (a) is carried out at a temperature range of 0 °C to 150 °C.

In another aspect of the present invention, the isolated compound of Formula VII in step (b) is purified by column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization.

In another aspect of the present invention, the suitable solvent of step (c) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DM Ac), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the amine base of step (c) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

In another aspect of the present invention, the amine base of step (c) is preferably DIPEA.

In another aspect of the present invention, the dehydrating agent of step (c) is T3P.

In another aspect of the present invention, the reaction of step (c) is carried out at a temperature range of 40 °C to 150 °C.

Yet another aspect of the present invention provides a process for preparing Nirmatrelvir compound of Formula I in a continuous flow,

wherein the process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P in a suitable solvent, with another solution, containing compound of Formula IV and an amine base (R1R2R3N) in a suitable solvent, by passing through individual tubings in to flow reactor at an appropriate temperature to form a product stream containing compound of Formula VII, b) isolating compound of Formula VII from the product stream formed in Step (a), c) converting compound of Formula VII of step (b) to compound of Formula I by passing a solution, containing compound of Formula VII, T3P and an amine base (R1R2R3N) in a suitable solvent, through a flow reactor at an appropriate temperature to obtain a compound of Formula I.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the amine base of step (a) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof. In another aspect of the present invention, the amine base of step (a) is preferably DIPEA.

In another aspect of the present invention, the solutions in step (a) are passed through individual tubing in to flow reactor with defined flow rates ranging from 0.1 mL/min to 50 mL/min.

In another aspect of the present invention, the formation of compound of Formula VII in step (a) is carried out at system back pressure ranging from 0.5 to 40 bar in the flow reactor.

In another aspect of the present invention, the formation of compound of Formula VII in step (a) is carried out at a temperature ranging from 0 °C to 120 °C.

In another aspect of the present invention, the isolated crude compound of Formula VII in step (b) is purified by column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization.

In another aspect of the present invention, the solvent in step (c) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DM Ac), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the suitable amine base in step (c) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

In another aspect of the present invention, the amine base of step (c) is preferably DIPEA. In another aspect of the present invention, the solutions in step (c) are passed through individual tubing in to flow reactor with defined flow rates ranging from 0.1 mL/min to 50 mL/min.

In another aspect of the present invention, the formation of compound of Formula I in step (c) is carried out at system back pressures ranging from 0.5 to 40 bar in the flow reactor.

In another aspect of the present invention, the formation of compound of Formula I in step (c) is carried out at a temperature range of 40 °C to 120 °C.

In another aspect of the present invention, the reactor in steps (a) and (c) is a continuous flow reactor, semi-batch reactor or a combination of either.

In another aspect of the present invention, the continuous flow reactor is a plug flow reactor, mixed flow reactor or a combination of both.

In another aspect of the present invention, the continuous flow reactor has a static mixing element.

In another aspect of the present invention, the static mixing element is passive, active or both.

Yet another aspect of the present invention provides a process for preparing the Nirmatrelvir compound of Formula I in continuous flow, wherein the process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P in a suitable solvent, with another solution, containing compound of Formula IV and an amine base (R1R2R3N) in a suitable solvent, by passing through individual tubings in to flow reactor at an appropriate temperature to provide product stream having compound of Formula VII. b) passing the product stream obtained in step (a) in to a second flow reactor at an appropriate temperature to provide a compound of Formula I.

In another aspect of the present invention, the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DM Ac), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the amine base of step (a) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

In another aspect of the present invention, the amine base is preferably DIPEA.

In another aspect of the present invention, the solutions and product stream from step (a) are passed through individual tubing in to flow reactor with defined flow rates ranging from 0.1 mL/min to 50 mL/min.

In another aspect of the present invention, the formation of compound of Formula VII in step (a) and formation of compound of Formula I in step (b) are carried out at system back pressures ranging from 0.5 to 40 bar in flow reactor.

In another aspect of the present invention, the formation of compound of Formula VII in step (a) is carried out at a temperature range of 0 °C to 120 °C.

In another aspect of the present invention, the formation of compound of Formula I in step (b) is carried out at a temperature range of 40 °C to 120 °C.

In another aspect of the present invention, the reactor in steps (a) and (b) is a continuous flow reactor, semi-batch reactor or a combination of either.

In another aspect of the present invention, the static mixing element is passive, active or both. Yet another aspect of the present invention provides a process for preparing Nirmatrelvir intermediate of Formula II, wherein the process comprising the steps of:

Formula II a) reacting compound of Formula III with compound of Formula IV at an appropriate temperature in presence of solvent, an amine base and coupling agent to provide compound of Formula V,

b) optionally, isolating compound of Formula V of step (a), c) converting compound of Formula V of step (b) to compound of Formula II at an appropriate temperature in presence of a solvent, an amine base and a

wherein Pi is a suitable nitrogen protecting group. In another aspect of the present invention, the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DM Ac), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform, and the like and mixtures thereof.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the amine base of step (a) is selected from group comprising triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like and mixtures thereof.

In another aspect of the present invention, the amine base is preferably DIPEA.

In another aspect of the present invention, the coupling agent is selected from a group comprising carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P), O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-CI), 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), N- (dimethylaminopropyl)-N'-ethyl-carbodiimide and the like and mixtures thereof.

In another aspect of the present invention, the coupling agent is preferably T3P.

In another aspect of the present invention, the reaction of step (a) is carried out at a temperature range of 0 °C to 150 °C.

In another aspect of the present invention, the isolated crude compound of Formula V in step (b) is purified by column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization.

In another aspect of the present invention, the solvent of step (c) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

In another aspect of the present invention, the solvent is preferably THF.

In another aspect of the present invention, the amine base is selected from a group comprising triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like and mixtures thereof.

In another aspect of the present invention, the amine base is preferably DIPEA.

In another aspect of the present invention, the dehydrating agent is selected from a group comprising of propanephosphonic acid anhydride (T3P), A1CE, P2O5, (COC1)2, cyanuric chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), methanesulfonyl chloride, 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), 1 -chloro-N,N,2-trimethyl- 1 -propenylamine, hexamethylphosphoric triamide (HMPT), trifluoroacetic anhydride, ethyl dichlorophosphate, dimethoxymethylsilane and N-methyl-N-(trimethylsilyl)trifluoroacetamide and the like and mixtures thereof.

In another aspect of the present invention, the dehydrating agent is preferably T3P.

In another aspect of the present invention, the reaction of compound of Formula III with compound of Formula IV to obtain compound of Formula V is carried out in batch or preferably, in continuous flow.

Yet another aspect of the present invention provides a process for preparing Nirmatrelvir intermediate of Formula II, wherein the process comprising the steps of: a) reacting compound of Formula Illa with compound of Formula IV to provide compound of Formula Va in presence of propanephosphonic acid anhydride (T3P),

b) optionally, isolating compound of Formula Va, c) converting compound of Formula Va to compound of Formula Ila in presence of T3P,

In another aspect of the present invention, the process is carried out in batch or preferably, in continuous flow.

Another aspect of the present invention provides a process for preparing

Nirmatrelvir compound of Formula I in a continuous flow, wherein the process comprises the step of converting compound of Formula VII to compound of Formula I by passing a solution, containing compound of Formula VII, T3P and DIPEA amine base (R1R2R3N) in THF solvent, through a flow reactor to obtain a compound of Formula I.

In another aspect of the present invention, the processes do not specifically involve reagents which require special handling, storage conditions and are difficult to procure commercially.

Another aspect of the present application provides a compound of Formula II and its use for the preparation of Nirmatrelvir of Formula (I) or pharmaceutically acceptable salts thereof. DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.

As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.

The terms “having” and “including” are also to be construed as open ended.

All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES

The scope of the present invention is illustrated by the following examples as disclosed herein which are not meant to restrict the scope of the invention in any manner whatsoever.

Example 1: Synthesis of (lR,2S,5S)-tert-butyl 2-(((S)-l-amino-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-3-carboxylate (Va)

To a suspension of (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (Illa, 1 g), (S)-2-amino-3-((S)-2-oxopyrrolidin-3- yl)propanamide (IV, 0.73 g), diisopropylethylamine (2.02 g) in THF (15 mL) was added T3P (50 % sol. in ethyl acetate, 3.74 mL) at 25 °C and stirred for 4 h at the same temperature. After completion of reaction, water (5 mL) was added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (2 X 5 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (5 mL) and water (5 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (Va, 1.2 g).

Example 2: Synthesis of (lR,2S,5S)-tert-butyl 2-(((S)-l-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-carboxylate (Ila)

To a solution of (lR,2S,5S)-tert-butyl 2-(((S)-l-amino-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (Va, 0.5 g), diisopropylethylamine (0.316 g) in THF (8 mL) was added T3P (50 % sol. in ethyl acetate, 1.5 mL) at 25 °C and stirred for 16 h at 75-80 °C. After completion of reaction, water (3 mL) was added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (2 X 3 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (3 mL) and water (3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (Ila, 0.3 g).

Example 3: Synthesis of (lR,2S,5S)-tert-butyl 2-(((S)-l-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-carboxylate (Ila).

To a suspension of (lR,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (Illa, 2.0 g), (S)-2-amino-3-((S)-2-oxopyrrolidin- 3-yl)propanamide (IV, 1.45 g), diisopropylethylamine (5.44 mL) in ethyl acetate (8 mL) was added T3P (50 % sol. in ethyl acetate, 7.6 mL) at 25 °C and stirred for 3 h at the 50 °C (TLC and mass indicated formation of Va). Thereafter an additional amount of T3P (50 % sol. in ethyl acetate, 7.6 mL) was added to the reaction mixture 50 °C, which was then heated to 80-85 °C for 18-20 h. After completion of the reaction, water (20 mL) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (2 X 20 mL). The combined organic layer was washed with saturated NaHCCh solution (2 X20 mL), followed by water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (Ila, 1.0 g).

Example 4: Synthesis of (lR,2S,5S)-N-((S)-l-amino-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2- trifhioroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (VII)

To a suspension of (lR,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (VI, 200 mg), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (IV, 103 mg), diisopropyl ethylamine (140 mg) in THF (3 mL) was added T3P (50 % sol. in ethyl acetate, 0.52 mL) at 25 °C and stirred for 1-2 h at 40-50 °C. After completion of reaction, water (3 mL) was added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (2X2 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (3 mL) and water (3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (VII, 213 mg).

Example 5: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dhnethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To a solution of (lR,2S,5S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl -3-azabicyclo[3.1.0]hexane-2-carboxamide (VII, 100 mg), diisopropylethylamine (49 mg) in THF (2 mL) was added T3P (50 % sol. in ethyl acetate, 0.18 mL) at 25 °C and stirred for 16 h at 75-80 °C. After completion of reaction, water (2 mL) was added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (2X2 mL). The organic layers were washed with saturated sodium bicarbonate solution (2 mL) and water (2 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain title compound (I, 67.4 mg).

Example 6: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To a solution of (lR,2S,5S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl -3-azabicyclo[3.1.0]hexane-2-carboxamide (VII, 200 mg) and diisopropylethylamine (0.17 mL) in THF (2 mL) was added T3P (50 % sol. in ethyl acetate, 0.5 mL) at 25 °C. The reaction mixture obtained was stirred for 1-2 h at 80- 90 °C. The reaction mixture was then cooled to room temperature and quenched with saturated NaHCCh solution (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2X 5 mL). The combined organic extracts were washed successively with IM HC1 (20 mL), saturated NaHCCh solution (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40-45 °C to obtain title compound (I, 120 mg). Example 7: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To suspension of (lR,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (VI, 200 mg), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (IV, 103 mg), THF (15 vol.) was added diisopropylethylamine (0.284 g), followed by T3P (50 % sol. in ethyl acetate, 0.52 mL) at RT. The reaction mixture obtained was heated to 40-50 °C for 1-2 h. Thereafter an additional amount of T3P (50 % sol. in ethyl acetate, 0.52 mL) was added. The mixture was heated to 80 °C and stirred for 12-16 h at same temperature. After completion of reaction, the reaction mixture was cooled to room temperature. Water (3 mL) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2X2 mL). The organic layers were washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain title compound (I, 165 mg).

Example 8: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To suspension of (lR,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (VI, 1.0 g) and (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (IV, 0.61g) in THF (5 mL) was added diisopropylethylamine (1.8 mL), followed by T3P (50 % sol. in ethyl acetate, 2.5 mL) at RT. The reaction mixture obtained was heated to 50-60 °C for 1-2 h. Thereafter an additional amount of T3P (50 % sol. in ethyl acetate, 2.5 mL) was added and the mixture was heated to 80-90 °C for 5-6 h. The reaction mixture was then cooled to room temperature. Saturated NaHCCh solution (20 mL), followed by ethyl acetate (20 mL), were added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layer was washed successively with IM HC1 (10 mL), saturated NaHCCh solution (20 mL), water (10 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40-45 °C to obtain title compound (I, 0.76g).

Example 9: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dhnethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To a solution (lR,2S,5S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (VII, 500 mg) in THF (5.0 mL), diisopropylethylamine (0.390 mL) and T3P (50 % sol. in ethyl acetate, 1.14 mL) were added to yield a homogenous solution. This reaction mass was then pumped through a tubular reactor maintained at 100 °C for a residence time of 30 minutes under 4.0 bar pressure. The reaction mixture exiting from the reactor after attainment of steady state was collected, treated with water and extracted with ethyl acetate. The organic layer was separated and analyzed by HPLC which indicated presence of the title compound (I) to extent of 89.44%.

Example 10: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

Mixture A was prepared by combining together (lR,2S,5S)-3-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (VI, 2.0 g) and T3P (50 % sol. in ethyl acetate, 14.0 mL) in THF (2.0 mL). Mixture B was prepared separately by combining together (S)-2-amino- 3-((S)-2-oxopyrrolidin-3-yl)propanamide (IV, 1.25 g) and diisopropylethylamine (4.8 mL) in THF (11.5 mL). Mixtures A and B were pumped through an agitated flow reactor maintained at 55 °C for a residence time of about 20 minutes. The homogeneous reaction mixture thus obtained was pumped into another tubular reactor maintained at 100 °C for a residence time of 30 minutes under 4.0 bar pressure. The reaction mixture exiting from the reactor was collected, treated with saturated aqueous NaHCCh (40 mL) and extracted with ethyl acetate (2X20 mL). The combined organic layer was washed successively with 3N HC1 (2 X 20 mL), saturated aqueous NaHCCh (40 mL), water (2X20 mL) and brine (40 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound I (420 mg, purity by HPLC: 83.01%).

Example 11: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To a mixture of (lR,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (VI, 1.0 g) in THF (10.0 mL), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (IV, 0.627 g), T3P (50 % sol. in ethyl acetate, 3.5 mL) and diisopropylethylamine (2.4 mL) were added. This mixture was heated at 50 °C for 1 hour to afford a clear solution, to which an additional lot of T3P (50 % sol. in ethyl acetate, 3.5 mL) was added. The resultant reaction mixture was subsequently pumped through a tubular reactor maintained at 100 °C for a residence time of 30 minutes under 4.0 bar pressure. The reaction mixture exiting from the reactor was collected after attainment of steady state. The collected mixture was treated with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layer was washed successively with 3N HC1 (2 X 5 mL), saturated aqueous NaHCCh (5 mL), water (2 X 5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound I (370 mg from 436 mg of VI input at steady state, purity by HPLC: 93%).

Example 12: Synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifhioroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I)

To a mixture of (lR,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (VI, 2.0 g) in THF (20.0 mL), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (IV, 1.5 g), propanephosphonic acid anhydride (50 % sol. in ethyl acetate) (14.0 mL) and diisopropylethylamine (4.8 mL) were added. This mixture was pumped through an agitated flow reactor maintained at 60 °C for a residence time of about 40 minutes. The homogeneous reaction mixture obtained was pumped into another tubular reactor maintained at 100 °C for a residence time of 30 minutes under 4.0 bar pressure. The reaction mixture exiting from the reactor was collected after attainment of steady state. The collected mixture was treated with water (10 mL) and extracted with ethyl acetate (2X 10 mL). The combined organic layer was washed successively with 3N HC1 (2X 5 mL), saturated aqueous NaHCCh (10 mL), water (2 X 5 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound I (300 mg from 438 mg of VI input at steady state, purity by HPLC: 91.44 %).

Claims

THE CLAIMS:

1. A process for preparing the Nirmatrelvir compound of Formula I,

(R1R2R3N) and coupling agent to provide compound of Formula VII,

wherein Ri, R2 and R3 are alkyl, aryl or arylalkyl group, or a part of a saturated heterocyclic ring. 2. The process as claimed in claim 1, wherein the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof.

3. The process as claimed in claim 2, wherein the solvent is preferably THF.

4. The process as claimed in claim 1, wherein amine base (R1R2R3N) of step (a) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

5. The process as claimed in claim 4, wherein the amine base of step (a) is preferably DIPEA.

6. The process as claimed in claim 1, wherein coupling agent is selected from carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), propanephosphonic acid anhydride (T3P), O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-CI), 2-chloro-4,6-dimethoxy-l,3,5- triazine (CDMT), N-(dimethylaminopropyl)-N'-ethyl-carbodiimide and the like and mixtures thereof .

7. The process as claimed in claim 6, wherein the coupling agent is preferably

T3P.

8. The process as claimed in claim 1, wherein the reaction of step (a) is carried out at a temperature range of 0 °C to 150 °C.

9. The process as claimed in claim 1, wherein the isolated compound of Formula VII in step (b) is purified by column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization.

10. The process as claimed in claim 1, wherein the suitable solvent of step (c) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

11. The process as claimed in claim 10, wherein the solvent is preferably THF.

12. The process as claimed in claim 1, wherein the amine base of step (c) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

13. The process as claimed in claim 1, wherein the amine base of step (c) is preferably DIPEA.

14. The process as claimed in claim 1, wherein dehydrating agent of step (c) is T3P.

15. The process as claimed in claim 1, wherein the reaction of step (c) is carried out at a temperature range of 40 °C to 150 °C.

16. A process for preparing Nirmatrelvir compound of Formula I in a continuous flow,

17. The process as claimed in claim 16, wherein the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof.

18. The process as claimed in claim 17, wherein the solvent is preferably THF. The process as claimed in claim 16, wherein the amine base of step (a) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof. The process as claimed in claim 19, wherein the amine base of step (a) is preferably DIPEA. The process as claimed in claim 16, wherein the solutions in step (a) are passed through individual tubing in to flow reactor with defined flow rates ranging from 0.1 mL/min to 50 mL/min. The process as claimed in claim 16, wherein the formation of compound of Formula VII in step (a) is carried out at system back pressure ranging from 0.5 to 40 bar in the flow reactor. The process as claimed in claim 16, wherein the formation of compound of Formula VII in step (a) is carried out at a temperature ranging from 0 °C to 120 °C. The process as claimed in claim 16, wherein the isolated crude compound of Formula VII in step (b) is purified by column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization. The process as claimed in claim 16, wherein the solvent in step (c) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof. . The process as claimed in claim 25, wherein the solvent is preferably THF. . The process as claimed in claim 16, wherein the suitable amine base in step (c) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof. . The process as claimed in claim 27, wherein the amine base of step (c) is preferably DIPEA. . The process as claimed in claim 16, wherein the solutions in step (c) are passed through individual tubing in to flow reactor with defined flow rates ranging from 0.1 mL/min to 50 mL/min. . The process as claimed in claim 16, wherein formation of compound of Formula I in step (c) is carried out at system back pressures ranging from 0.5 to 40 bar in the flow reactor. . The process as claimed in claim 16, wherein formation of compound of Formula I in step (c) is carried out at a temperature range of 40 °C to 120 °C. . A process for preparing the Nirmatrelvir compound of Formula I in continuous flow, wherein the process comprising the steps of: a) reacting a solution, containing compound of Formula VI and T3P in a suitable solvent, with another solution, containing compound of Formula IV and an amine base (R1R2R3N) in a suitable solvent, by passing through individual tubings in to flow reactor at an appropriate temperature to provide product stream having compound of Formula VII. b) passing the product stream obtained in step (a) in to a second flow reactor at an appropriate temperature to provide a compound of Formula I.

33. The process as claimed in claim 32, wherein the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

34. The process as claimed in claim 33, wherein the solvent is preferably THF.

35. The process as claimed in claim 32, wherein the amine base of step (a) is selected from triethylamine, diisopropylethylamine (DIPEA) and the like and mixtures thereof.

36. The process as claimed in claim 35, wherein the amine base is preferably DIPEA.

37. The process as claimed in claim 32, wherein the solutions and product stream from step (a) are passed through individual tubing in to flow reactor with defined flow rates ranging from 0.1 mL/min to 50 mL/min.

38. The process as claimed in claim 32, wherein formation of compound of Formula VII in step (a) and formation of compound of Formula I in step (b) are carried out at system back pressures ranging from 0.5 to 40 bar in flow reactor.

39. The process as claimed in claim 32, wherein formation of compound of

Formula VII in step (a) is carried out at a temperature range of 0 °C to 120

40. The process as claimed in claim 32, wherein formation of compound of

Formula I in step (b) is carried out at a temperature range of 40 °C to 120

41. The process as claimed in claims 1 to 40, wherein the reactor in Steps (a) and (c) of Claim 16 and Steps (a) and (b) of claim 32 is a continuous flow reactor, semi-batch reactor or a combination of either.

42. The process as claimed in claim 41, wherein continuous flow reactor is a plug flow reactor, mixed flow reactor or a combination of both.

43. The process as claimed in claim 42, wherein continuous flow reactor has a static mixing element.

44. The process as claimed in claim 43, wherein the static mixing element is passive, active or both.

45. A process for preparing Nirmatrelvir intermediate of Formula II, wherein the process comprising the steps of:

b) optionally, isolating compound of Formula V of step (a), c) converting compound of Formula V of step (b) to compound of Formula II at an appropriate temperature in presence of a solvent, an amine base and a dehydrating agent.

wherein Pi is a suitable nitrogen protecting group. 6. The process as claimed in claim 45, wherein the solvent of step (a) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform, and the like and mixtures thereof. 7. The process as claimed in claim 46, wherein the solvent is preferably THF.

48. The process as claimed in claim 45, wherein the amine base of step (a) is selected from group comprising triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like and mixtures thereof.

49. The process as claimed in claim 48, wherein the amine base is preferably DIPEA.

50. The process as claimed in claim 45, wherein the coupling agent is selected from a group comprising carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), propylphosphonic anhydride (T3P), O- (benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-CI), 2- chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), N-(dimethylaminopropyl)- N'-ethyl-carbodiimide and the like and mixtures thereof.

51. The process as claimed in claim 50, wherein the coupling agent is preferably T3P.

52. The process as claimed in claim 45, wherein the reaction of step (a) is carried out at a temperature range of 0 °C to 150 °C.

53. The process as claimed in claim 45, wherein isolated crude compound of Formula V in step (b) is purified by column chromatography, fractional distillation, acid base treatment, slurrying or recrystallization.

54. The process as claimed in claim 45, wherein the solvent of step (c) is selected from aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; polar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran (THF) and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; and mixtures thereof.

55. The process as claimed in claim 54, wherein the solvent is preferably THF.

56. The process as claimed in claim 45, wherein the amine base is selected from a group comprising triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and the like and mixtures thereof.

57. The process as claimed in claim 56, wherein the amine base is preferably DIPEA.

58. The process as claimed in claim 45, wherein the dehydrating agent is selected from a group comprising of propanephosphonic acid anhydride (T3P), A1CE, P2O5, (COC1)2, cyanuric chloride, l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC), methanesulfonyl chloride, 2- chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), l-chloro-N,N,2-trimethyl-l- propenylamine, hexamethylphosphoric triamide (HMPT), trifluoroacetic anhydride, ethyl dichlorophosphate, dimethoxymethylsilane and N-methyl- N-(trimethylsilyl) trifluoroacetamide and the like and mixtures thereof.

59. The process as claimed in claim 58, wherein the dehydrating agent is preferably T3P.

60. The process as claimed in claim 45, wherein the reaction of step (c) is carried out at a temperature range of 40 °C to 150 °C.

61. The process as claimed in claim 45, wherein the reaction of compound of Formula III with compound of Formula IV to obtain compound of Formula V is carried out in batch or preferably, in continuous flow.

62. A process for preparing Nirmatrelvir intermediate of Formula II, wherein the process comprising the steps of: a) reacting compound of Formula Illa with compound of Formula IV to provide compound of Formula Va in presence of propanephosphonic acid anhydride (T3P),

The process as claimed in claim 62, wherein the process is carried out in batch or preferably, in continuous flow. A process for preparing Nirmatrelvir compound of Formula I in a continuous flow, wherein the process comprises the step of converting compound of Formula VII to compound of Formula I by passing a solution, containing compound of Formula VII, T3P and DIPEA amine base (R1R2R3N) in THF solvent, through a flow reactor to obtain a compound of Formula I. The process as claimed in claims 1 to 64, wherein the processes do not specifically involve reagents which require special handling, storage conditions and are difficult to procure commercially.