DESC:FORM 2

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

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

“IMPROVED PROCESS FOR THE PREPARATION OF NIRMATRELVIR”

We, ZYDUS LIFESCIENCES LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Corporate Park, Scheme No. 63, Survey No. 536, Khoraj (Gandhinagar), Nr. Vaishnodevi Circle, Sarkhej – Gandhinagar Highway, Ahmedabad – 382481, Gujarat, India,

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION

Present invention relates to an improved process for the preparation of Nirmatrelvir. The present invention also relates to a novel amorphous form of the Nirmatrelvir and process for the preparation thereof. The invention also relates to pharmaceutical compositions that include novel amorphous form of Nirmatrelvir.
BACKGROUND OF THE INVENTION
Nirmatrelvir (PF-07321332), is an irreversible inhibitor of SARS-CoV-2 Mpro that is co-formulated with ritonavir allowing an oral route of administration marketed as Paxlovid). Nirmatrelvir is chemically known as (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and has the following structural of Formula (I).

(I)

WO 2021250648 disclosed novel peptidomimetic nitriles novel heterocyclic compounds, their preparation, pharmaceutical composition containing them and their methods for the treatment of COVID-19. Nirmatrelvir, its hydrate and solvate form and process for the preparation is also disclosed in WO 2021250648.
The different physical properties exhibited by polymorphs affect important pharmaceutical parameters selected from storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favoured crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency are toxic. In addition, the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing. For example, an amorphous form may provide better bioavailability than the crystalline form.
Therefore, it may be desirable to have an amorphous form of drugs with high purity to meet the regulatory requirements and also highly reproducible processes for their preparation.
In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of Nirmatrelvir and its novel amorphous form and preparation thereof.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Nirmatrelvir. The present invention also relates to an amorphous form of Nirmatrelvir and process for the preparation thereof.

EMBODIMENT OF THE INVENTION
In one embodiment, there is provided an improved process for the preparation of Nirmatrelvir.
In a further embodiment there is provided a novel amorphous form of Nirmatrelvir.
In a further another embodiment, there is provided a process for the preparation of the amorphous form of Nirmatrelvir. The above and other embodiments are further described in the following paragraphs.

Instrument details
XRD : Model : D8 Advance, Make : Bruker.
DSC : Model : Q20, Make : TA instruments
IR : Model : IRAffinity-1S, Make : Shimazdu

DESCRIPTION OF THE DRAWINGS
FIG. 1 is a powder X-ray diffraction (PXRD) pattern of the amorphous Nirmatrelvir polymorphic Form.

DETAIL DESCRIPTION OF THE INVENTION
As used herein, the term “DIPE” refers to Diisopropyl ether; as used herein the term “DMSO” refers to Dimethyl sulfoxide; as used herein, the term “MTBE” refers to Methyl-tert Butyl Ether; as used herein, the term “THF” refers to Tetrahydrofuran; as used herein, the term “DMF” refers to N,N-Dimethyl formamide; as used herein, the term “DMA” refers to N,N-Dimethylacetamide; as used herein, the term “MIBK” refers to Methyl Isobutyl Ketone; as used herein, the term “MEK” refers to Methyl ethyl ketone.
In an embodiment, the term alcohols used anywhere in the specification, unless otherwise specified means suitable (C1-C6) linear or branched chain alcohols, more preferably those that are selected from methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol, ethylene glycol or suitable mixtures thereof.
In an embodiment, the term halogenated hydrocarbon solvents used anywhere in the specification, unless otherwise specified may be selected from chloroform, dichloromethane, dichloroethane or suitable mixtures thereof.
In an embodiment, the term esters used anywhere in the specification, unless otherwise specified may be selected from ethyl acetate, isopropyl acetate, butyl acetate or suitable mixtures thereof.
In an embodiment, the term hydrocarbons used anywhere in the specification, unless otherwise specified may be selected from benzene, toluene, xylene, ethyl benzene, trimethyl benzene, cyclohexane or suitable mixtures thereof.
In an embodiment, the term ketone used anywhere in the specification, unless otherwise specified may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or suitable mixtures thereof.
In an embodiment, the term nitriles used anywhere in the specification, unless otherwise specified may be selected from acetonitrile and the likes.
In an embodiment, the term aprotic polar solvents used anywhere in the specification, unless otherwise specified may be selected from DMF, DMSO, DMA, N-methyl pyrrolidone or suitable mixtures thereof.
In an embodiment, the term ethers used anywhere in the specification, unless otherwise specified may be selected from diethyl ether, 1,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF, methyl THF or suitable mixtures thereof.
The main objective of the present invention is to provide an improved process for the preparation of Nirmatrelvir as formula (I). The process comprises the following steps:
(i) reacting compound of formula II with compound of formula III

in one or more organic solvent in presence of a base and coupling reagent to obtain compound of formula (IV);
(i1) dissolving compound of formula IV in one or more organic solvent in presence of a base to obtain compound of formula V;

(iii) reacting compound of formula V with trifluoroacetic acid in one or more organic solvent in presence of a base to obtain compound of formula VI;

(iv) dissolving compound of formula VI in one or more organic solvent in presence of ethyl trifluoroacetate and coupling reagent to obtain compound of formula VII;

(v) reacting compound of formula VII with compound of formula VIII in one or more organic solvent in presence of suitable reagent to obtain compound of formula IX;

(vi) reacting compound of formula IX with imidazole in one or more organic solvent in presence of a base to obtain compound of formula (I).

In general, suitable bases which can be used at step (i) may include one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine and the like. In particular, N,N-diisopropylethylamine may be used.

In general, the organic solvent used in step (i) may be selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in dimethylformamide and acetonitrile.
In general suitable coupling reagents can be used at step (i) may include one or more of N,N’-dicyclohexylcarbodiimide (DCC) , N,N’-diisopropylcarbodiimide (DIC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC HCl) , 1-hydroxybenzotriazole (HOBt) , 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) , O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, Hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium, Tetrafluoroborate (TATU), O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium,
Tetrafluoroborate (TBTU)and the like. In particular, HATU may be used.

In general, the organic solvent used in step (ii) may be selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in tetrahydrofuran.

In general, base which can be used in step (ii) may be selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide. In particular, sodium hydroxide may be used.

In general, the organic solvent used in step (iii) may be selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in dichloromethane.

In general, suitable bases which can be used in step (iii) may include one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine and the like. In particular, triethylamine may be used.

In general, the organic solvent used in step (iv) may be selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in ethyl acetate, diisopropyl ether and hexane.

In general suitable coupling reagents can be used in step (iv) may include one or more of N,N’-dicyclohexylcarbodiimide (DCC) , N,N’-diisopropylcarbodiimide (DIC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC HCl) , 1-hydroxybenzotriazole (HOBt) , 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) , O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumHexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumTetrafluoroborate (TATU) , O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium
Tetrafluoroborate (TBTU) and the like. In particular, HOBt may be used.

In general, the organic solvent used in step (v) may be selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in ethyl acetate , dimethylformamide and methyl tert-butyl ether.
In general suitable base which can be used at step (v) may include one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine and the like. In particular, N-methyl morpholine may be used.

In general, the organic solvent used in step (vi) may be selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. In particular, the reaction may be carried out in dichloromethane.
In general suitable base which can be used at step (vi) may include one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine, morpholine, piperidine, pyrollidine, imidazole, DBU, DBN, 1,4-diazabicyclo[2,2,2]octane, dimethylamino pyridine and pyridine and the like. In particular pyridine may be used.

In one of the embodiments, the present invention provides an amorphous form of Nirmatrelvir.

In a further embodiment, the present invention provides an amorphous form of Nirmatrelvir characterized by an XPRD pattern substantially in accordance with the pattern as in Fig. 1.

In a further embodiment, the present invention provides a process for preparing amorphous form of Nirmatrelvir. The process includes obtaining a solution of Nirmatrelvir in one or more solvents; adding an anti-solvent to the solution; and isolating the amorphous form of Nirmatrelvir by removing the solvents.

In general suitable solvent used may be selected from one or more of ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate or mixture thereof. In particular, ethyl acetate may be used.

In general anti-solvent used may be selected from one or more of chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether or mixture thereof. In particular, hexane may be used.

Nirmatrelvir to be used as the starting material can be prepared by any process known in the literature for example, International (PCT) Publication No. WO 2021250648 or may be obtained by the process of the present invention. The so-obtained Nirmatrelvir is suspended in an organic solvent and a solution of Nirmatrelvir is obtained. The solution may be obtained by heating the Nirmatrelvir in an organic solvent. The resultant solution can be clarified to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities. The solution so obtained may be concentrated to reduce the amount of solvent. The solution may be concentrated by removing the solvent completely to get a residue. The solvent may be removed under reduced pressure. To the residue so obtained an anti-solvent is added. The anti-solvent is characterized by the fact that Nirmatrelvir is insoluble, practically insoluble or very slightly soluble in the anti-solvent. The terms insoluble, practically insoluble and very slightly soluble have their ordinary meanings as defined in United States Pharmacopoeia 2002.

In general, any solvent can be used as an anti-solvent in which Nirmatrelvir is insoluble, practically insoluble or very slightly soluble. The terms insoluble, practically insoluble and very slightly soluble have their ordinary meanings as defined in United States Pharmacopoeia 2002.

Another aspect of the invention provides a pharmaceutical composition comprising amorphous form of Nirmatrelvir and optionally one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may include one or more of diluents, carriers, lubricants, binders, colorants, and disintegrants.

The invention is further illustrated by the following examples, which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Example – 1
Synthesis of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (V)
(S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (III) (80 g, 344 mmol) was added in the solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (II) (65.0 g, 316 mmol), acetonitrile (1105 mL) and dimethylformamide (123.5 mL) at 25 oC. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (131 g, 344 mmol) and N,N-diisopropylethylamine (166 ml, 948 mmol) was added to the above reaction mixture at 0 to 10 oC in portion wise over 30 min and stirred for 16 h at 25 to 30 oC. Concentrated the reaction mixture, 500 mL of water added and extracted with ethyl acetate (500 mL X 3). The combined organic layer were washed by water (380 mL) and organic layer concentrated to get oily compound (IV). Oily compound (IV) was dissolved in tetrahydrofuran (720 mL) and added a solution of NaOH (37.6 g, 941 mmol) in water (384 mL) in 30 min at 0 to 10 oC and stirred for 18 h at 25 to 30 oC. Concentrated the reaction mixture and to it added water (970 mL), followed by 10% aq. HCl solution (600 mL) at 0 to 10 oC to get pH 2-3, filtered the solid and dried at 35 to 40 oC for 12 h, to get (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (V) as a white solid 111g, in 95 % yield.
1H NMR (400 MHz, DMSO-d6): 12.64 (s, 1H), 6.70 (d, J = 9.2 Hz, 1H), 4.13 (s, 1H), 4.04 (d, J=9.6 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 3.77 (dd, J = 10.4, 5.2 Hz, 1H), 1.52 – 1.48 (m, 1H), 1.40 (s, 1H), 1.35 (s, 9H), 1.01 (s, 3H), 0.94 (s, 9H), 0.84 (s, 3H). ESI MS m/z 369.22 [M+H]+.

Example – 2
(1R,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 (VII)
Trifluoroacetic acid (230 mL, 2985 mmol) was added to the solution of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (V) (110 g, 299 mmol) in dichloromethane (1100 mL) and stirred for 2 h at 25-30 oC. Reaction mixture was concentrated. Resulting oily residue was treated with DIPE (500 mL X 3). Ethyl trifluoroacetate (550 mL, 4603 mmol) was added in oily residue, followed by TEA (100 mL, 716 mmol) at 0 to 10 oC and the reaction mixture was stirred at 60 to 65 oC for 3h. The reaction mixture was concentrated and added water (1000 mL), followed by 10% aq. HCl solution (125 mL) at 10 to 15 oC and aqueous layer was extracted with ethyl acetate (550 mL X 3). The combined organic layer was concentrated and oily residue was treated with DIPE (515 mL X 2) and hexane (515 mL X 2) and dried it at 45 to 50 oC for 2 h to get (1R,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 (VII) as a white solid 87g, in 80% yield.
1H NMR (400 MHz, DMSO-d6): 12.75 (s, 1H), 9.45 (d, J = 8.4 Hz, 1H), 4.44 (d, J = 8.4 Hz, 1H), 4.15 (s, 1H), 3.85 (dd, J = 10.4, 5.2 Hz, 1H), 3.72 (d, J = 10.4 Hz, 1H), 1.53 (dd, J = 7.6, 5.2 Hz, 1H), 1.43 (d, J = 7.6 Hz, 1H), 1.01 (d, J = 3.2 Hz, 12H), 0.83 (s, 3H). ESIMS m/z 365.16 [M+H]+.

Example – 3
(1R,2S,5S)-N-((S)-1-amino-1-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 (IX)
(S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (47 g, 226 mmol) (VIII) was added to a solution of (1R,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 (VII) (75 g, 206 mmol) in ethyl acetate (600 mL) and DMF (150 mL). Cooled the reaction mixture to 0 to 5 oC , EDC (47.4 g, 247 mmol), HOBT (6.30 g, 41.2 mmol) and N-methylmorpholine (56.6 ml, 515 mmol) was added at 0 to 10 oC under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 25 to 30 oC. Reaction mixture was dumped into water (750 mL) and organic layer was separated, aqueous layer was again extracted with ethyl acetate (750 mL X 4). The combined organic layer was washed by 10% sodium chloride solution (325 mL) then mixture of 10% aqueous HCl (250 mL) and saturated aqueous sodium chloride solution (125 mL), followed by the mixture of 5% sodium bicarbonate solution (300 mL) and saturated sodium chloride solution (150 mL). Finally the organic layer was washed with saturated aqueous sodium chloride solution (250 mL) then concentrated organic layer to get oily residue. The oily residue was stirred in the mixture of ethyl acetate (100 mL) and tert-butyl methyl ether (1000 mL) for 1 h at 55 to 60 °C and 2 h at 25 to 30 oC. Solid was filtered and dried at 35 to 40 oC for 5 h to get (1R,2S,5S)-N-((S)-1-amino-1-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 (IX) as an off-white solid 92 g, in 86% yield.
1H NMR (400 MHz, DMSO-d6): 9.42 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.05 (s, 1H), 4.43 (d, J = 8.4 Hz, 1H), 4.30 – 4.28 (m, 2H), 3.91 – 3.87 (m, 1H), 3.67 (d, J = 10.4 Hz, 1H), 3.13 (t, J = 8.8 Hz, 1H), 3.06 – 3.02 (m, 1H), 2.42 – 2.39 (m, 1H), 2.15 – 2.12(m,1H), 1.95 – 1.94 (m, 1H), 1.67 – 1.64 (m, 1H), 1.53 – 1.47 (m, 2H), 1.39 – 1.37 (d, J = 7.6 Hz, 1H), 1.11 (s, 3H), 1.08 (s, 9H), 0.84 (s, 3H). ESI MS m/z 518.26 [M+H]+.

Example – 4
(1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I).
Imidazole (0.700 g, 10.28 mmol) was added to the solution of (1R,2S,5S)-N-((S)-1-amino-1-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 (IX) (2.0 g, 3.86 mmol) in DCM (12 mL) and pyridine (12 mL, 148 mmol and the reaction mixture was cooled to -25 to -30 oC and POCl3 (2.064 mL, 22.14 mmol) was added. The reaction mixture was stirred at -25 to -30 oC for 1.5 h, after that quenched with 10% aqueous HCl (128 mL) and stirred for 1h at 25-30 oC and extracted by DCM ( 120 mL X 3 ). The combined organic layer was concentrated and the residue was crystalized with a mixture of ethyl acetate and hexane (1:9 ratio) to get (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (I) as an off-white amorphous solid 1.36 g, in 71 % yield.
1H NMR (400 MHz, DMSO-d6): d 9.42 (d, J = 8.4 Hz, 1H), 9.03 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 4.97 (ddd, J = 10.4, 8.4, 5.2 Hz, 1H), 4.41 (d, J = 8.4 Hz, 1H), 4.16 (s, 1H), 3.91 (dd, J = 10.4, 5.6 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.17 – 3.12 (m, 1H), 3.07 – 3.01 (m, 1H), 2.45 – 2.37 (m, 2H), 2.18 – 2.05 (m 2H), 1.76 – 1.67 (m, 2H), 1.57 (dd, J = 7.6, 5.6 Hz, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.03 (s, 3H), 0.98 (s, 9H), 0.85 (s, 3H). ESI MS m/z 522.1954 [M+Na]+.

The amorphous polymorph form may be used to obtain Nirmatrelvir in a pure form.

,CLAIMS:We claim:

1. A process for preparation of compound of formula (I) comprising of the following steps:

(I)
(i) reacting compound of formula II with compound of formula III

in one or more organic solvent in presence of a base and coupling reagent to obtain compound of formula (IV);
(ii) dissolving compound of formula IV in one or more organic solvent in presence of a base to obtain compound of formula V;

(iii) reacting compound of formula V with trifluoroacetic acid in one or more organic solvent in presence of a base to obtain compound of formula VI;

(iv) dissolving compound of formula VI in one or more organic solvent in presence of ethyl trifluoroacetate and coupling reagent to obtain compound of formula VII;

(v) reacting compound of formula VII with compound of formula VIII in one or more organic solvent in presence of suitable reagent to obtain compound of formula IX;

(vi) reacting compound of formula IX with imidazole in one or more organic solvent in presence of a base to obtain compound of formula (I).

2. The process as claimed in claim 1, wherein base in step (i) is selected from one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine and the like. Preferably the base is N,N-diisopropylethylamine.

3. The process as claimed in claim 1, wherein solvent in step (i) is selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. Preferably the solvent is dimethylformamide and acetonitrile.

4. The process as claimed in claim 1, wherein coupling reagents in step (i) and step (iv) is selected from one or more of N,N’-dicyclohexylcarbodiimide (DCC) , N,N’-diisopropylcarbodiimide (DIC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC HCl) , 1-hydroxybenzotriazole (HOBt) , 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, Hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium, Tetrafluoroborate (TATU), O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium, Tetrafluoroborate (TBTU)and the like. Preferably coupling reagent used in step (i) is hexafluorophosphate N-oxide (HATU) and in step (iv) is 1-hydroxybenzotriazole (HOBt).

5. The process as claimed in claim 1, wherein solvent in step (ii), is selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. Preferably the solvent is tetrahydrofuran.
6. The process as claimed in claim 1, wherein base in step (ii) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide. Preferably the base is sodium hydroxide.

7. The process as claimed in claim 1, wherein solvent in step (iii) and step (vi) is selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. Preferably, the solvent is dichloromethane.

8. The process as claimed in claim 1, wherein base in step (iii) is selected from one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine and the like. Preferably, the base is trimethylamine.

9. The process as claimed in claim 1, wherein solvent in step (iv) is selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. Preferably, the solvent are selected from ethyl acetate, diisopropylether and hexane.

10. The process as claimed in claim 1, wherein base in step (v) is selected from one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine and the like. Preferably, the base is N-methyl morpholine.

11. The process as claimed in claim 1, wherein solvent in step (v) is selected from one or more of alcohols selected from methanol, rectified spirit, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether , other solvents like dimethylformamide, diemthylsulfoxide and acetonitrile or mixture thereof. Preferably, the solvent is ethyl acetate , dimethylformamide and methyl tert-butyl ether.

12. The process as claimed in claim 1, wherein base used in step (vi) is selected from one or more of morpholine, N-methyl morpholine, triethylamine, diethylamine, isopropyl amine, N,N-diisopropylethylamine, morpholine, piperidine, pyrollidine, imidazole, DBU, DBN, 1,4-diazabicyclo[2,2,2]octane, dimethylaminopyridine and pyridine and the like. Preferably the base is pyridine.

13. Amorphous form of Nirmatrelvir.

14. The amorphous form of Nirmatrelvir as claimed in claim 13 characterized by a PXRD pattern as depicted in Figure 1.

15. The process for the preparation of amorphous form of Nirmatrelvir as claimed in claim 13 comprising:
(a) obtaining a solution of Nirmatrelvir in one or more solvents;
(b) adding an anti-solvent to the solution;
(c) isolating the amorphous form of Nirmatrelvir by removing the solvents.
16. The process as claimed in claim 15, wherein solvent in step (a) is selected from one or more of ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate or mixture thereof.
17. The process as claimed in claim 15, wherein anti-solvent in step (b) is selected from one or more of chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1 ,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether or mixture thereof.
18. A pharmaceutical composition comprising amorphous form of Nirmatrelvir as claimed in claim 13 and optionally one or more pharmaceutically acceptable excipients selected from one or more of diluents, carriers, lubricants, binders, colorants, and disintegrants.

Dated this 10th day of February 2023.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS