WO2025099743A1

WO2025099743A1 - Process for preparation of milvexian and solid-state forms thereof

Info

Publication number: WO2025099743A1
Application number: PCT/IN2024/052181
Authority: WO
Inventors: Sushrut Kulkarni; Ajay Kumar Handa; Ankur Bhargava; Sainath Digambar KADAM; Sainath Kalisetty; Vivek Kumar Ghosh; Nekkanti SATISH CHOWDARY; Srinivas ORUGANTI; Saikat Sen; Vishnu Vardhana Vema Reddy EDA; Romesh Jha; Sachin Arora; Saswati BHATTACHARYA
Original assignee: Dr Reddys Laboratories Ltd
Current assignee: Dr Reddys Laboratories Ltd
Priority date: 2023-11-07
Filing date: 2024-11-06
Publication date: 2025-05-15
Anticipated expiration: 2026-05-07

Abstract

The invention of the present application relates to process for preparation of Milvexian using new intermediates. The present application is further relating to the solid-state forms of Milvexian and process for their preparation.

Description

PROCESS FOR PREPARATION OF MILVEXIAN AND SOLID-STATE

FORMS THEREOF

CROSS REFERENCE

This application claims the priority of Indian provisional applications IN202341076040 filed on 07^th November, 2023 and IN202341081239 filed on 30^th November, 2023.

FIELD OF THE INVENTION

The present application relates to process for preparation of Milvexian using new intermediates. The present application is further relating to the solid-state forms of Milvexian and process for preparation thereof.

BACKGROUND ART

Milvexian, also known as (9R, 135)-13-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol- 1 -yl)phenyl]-6-oxo- 1 ,6-dihydropyrimidin- 1 -yl } -3 -difluoromethyl) -9-methyl-

3,4,7,15-tetraazatricyclo[12.3.1.02,6]octadeca-l(18),2(6),4,14,16-pentaen-8-one, is an inhibitor of FXIa that may be useful in the treatment of thromboembolic diseases. The effects of Milvexian has been studied in clinical trials in human volunteers for the treatment of Ischemic Stroke, Acute Coronary Syndrome and Atrial Fibrillation.

The compound Milvexian is first described in PCT publication WO2015116886A1 and its use thereof as selective factor Xia inhibitors or dual inhibitors of FXIa and plasma kallikrein. The PCT applications WO2016053455A1, W02020210613A1 and WO2022081473A1 describes processes for preparation of Milvexian.

Another application W02020210629A1 describes Amorphous solid dispersion composition of Milvexian with HPMC-AS.

The reported methods in the art are not feasible for commercial scale due to low yield due to requirement of repeated crystallization, operational challenges and the like.

Therefore, there is a need in the art for an improved process for preparation of Milvexian in commercially viable and cost-effective manner, which is suitable for large scale cGMP production.

New solid-state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid-state forms of Milvexian, that can be used readily in pharmaceutical compositions suitable for use as therapeutics.

SUMMARY OF INVENTION

An aspect of the present application provides a new process for preparation of Milvexian.

Another aspect of the present application provides new intermediates of formula lib, lie, lid, II, III, lb.

Yet another aspect of the present application provides an amorphous solid dispersion of Milvexian. Still another aspect of present application provides a process for the preparation of amorphous solid dispersion of Milvexian.

Another aspect of the present application provides a pharmaceutical composition comprising an amorphous solid dispersion of Milvexian and at least one pharmaceutically acceptable excipient.

Yet another aspect of the present application provides use of amorphous solid dispersion of Milvexian for treating a disease for which a selective factor Xia inhibitors or dual inhibitors of FXIa and plasma kallikrein is indicated.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 : PXRD pattern of amorphous solid dispersion of Milvexian with PVAP(Poly vinyl acetate pthalate) (1 :2 w/w)

Figure 2: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55 (1 :2 w/w)

Figure 3: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPMC Phthalate HP50:: 1 :1 (1:2 w/w)

Figure 4: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPC SSL::3: 1 (1 :2 w/w)

Figure 5: PXRD pattern of amorphous solid dispersion of Milvexian with (Eudragit L100 55: TPGS::9: 1) (1:2 w/w)

Figure 6: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55 (3:1 w/w)

Figure 7: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPC SSL::3: 1 (3: 1 w/w)

Figure 8: PXRD pattern of amorphous solid dispersion of Milvexian with (Eudragit L100 55: TPGS::9: 1) (3: 1 w/w)

Figure 9: PXRD pattern of amorphous solid dispersion of Milvexian with Eudragit L100 55: HPC SSL::3: 1 (4: 1 w/w)

Figure 10: An overlay of the ¹⁹F NMR spectra of two column purified Milvexian samples, one obtained by the prior art process and the other obtained by the process described in the instant application DETAILED DESCRIPTION

As used herein, the following definitions shall apply unless otherwise indicated.

Base used in the present invention refers to inorganic and organic base. The organic base used in the present invention includes but not limited to triethylamine, pyridine, DBU, DABCO, DIPEA, DMAP, NaOMe, NaOEt, Z-BuOK, BuLi, Z-BuLi, LHMDS, imidazole and like. The inorganic base used in the present invention includes but not limited to NaH, Cs₂CO₃, K2CO3, NaHCCh, NaOH, KOH, LiOH, Na₂CO₃ and like or mixture thereof.

Suitable solvent as used herein include, but are not limited to, alcohols, aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, nitriles, polar aprotic solvents, ketones, water or mixtures thereof. An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. "Alcoholic solvents" include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxy ethanol, 1 -butanol, 2-butanol, /-butyl alcohol, /-butyl alcohol, 2- ethoxy ethanol, di ethylene glycol, 1-, 2-, or 3 -pentanol, neo-pentyl alcohol, /-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Cl -6 alcohols, or mixtures thereof.

An "aliphatic or alicyclic hydrocarbon solvent" refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, //-pentane, isopentane, neopentane, //-hexane, isohexane, 3 -methylpentane, 2, 3 -dimethylbutane, neohexane, //-heptane, isoheptane, 3- methylhexane, neoheptane, 2,3 -dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3 -ethylpentane, 2,2, 3 -trimethylbutane, //-octane, isooctane, 3- methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.

"Aromatic hydrocarbon solvent" refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, ///-xylene, o-xylene, //-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, or mixtures thereof.

An "ester solvent" is an organic solvent containing a carboxyl group -(C=O)- O- bonded to two other carbon atoms. "Ester solvents" include, but are not limited to, ethyl acetate, //-propyl acetate, //-butyl acetate, isobutyl acetate, /-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or mixtures thereof.

A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" include, but are not limited to, di chloromethane, 1,2-di chloroethane, trichloroethylene, perchloroethylene, 1,1,1- tri chloroethane, 1,1,2-tri chloroethane, chloroform, carbon tetrachloride, or mixtures thereof.

A "ketone solvent" is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. "Ketone solvents" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, 4- methyl- pentane-2-one or mixtures thereof.

A "nitrile solvent" is an organic solvent containing a cyano -(ON) bonded to another carbon atom. "Nitrile solvents" include, but are not limited to, acetonitrile, propionitrile, C2-6 nitriles, or mixtures thereof.

A "polar aprotic solvent" has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N- dimethylformamide (DMF), M -di methyl acetamide (DMAc), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethyl sulfone, diethylsulfone, diisopropyl sulfone, 2-methylsulfolane, 3- methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO). An "ether solvent" is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. "Ether solvents" include, but are not limited to, diethyl ether, diisopropyl ether, methyl /-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, dibutyl ether, dimethylfuran, 2- methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.

The term “olefin reducing agent” referred to in the specification is any reagent, a combination of reagents or a combination of reagent(s) and catalyst(s) known in the literature which can be used for reduction of olefins. They include, but are not limited to hydrazine in presence of oxygen; hydrazine hydrate and oxygen in combination with an acid such as /?-toluenesulfonic acid; hydrogen in presence of Pd-C or Pt-C or Adams catalyst or Rh-C or Wilkinson’s catalyst or Crabtree's catalyst; hydrazine hydrate and air in combination with riboflavin or FeCl₃.6H₂O or CuSO₄.5H₂O; NaBH₄ in presence of COC1₂.6H₂O and CuSO₄.5H₂O; NaBH₄ in presence of NiCl₂.6H₂O and the like.

The “nitro group reducing agent” referred to in the specification are any reagent known in the literature which can be used for reduction of nitro group. They include but are not limited to Fe in presence of NH₄C1 or HC1 or acetic acid; Zn in presence of NH₄C1 or acetic acid; SnCl₂; sodium dithionite; sodium sulfide; sodium hydrogen sulfide; boron reagents such as B₂pin₂ and B₂(OH)₄; HSiCE in combination with a tertiary amine such as TEA or DIPEA; LiAlEU/AlCh and like.

The “RCM catalyst” used in the present invention include but not limited to Hoveyda-Grubbs Catalyst 2^nd generation, Grubbs Catalyst M207 (C827), Grubbs Catalyst 1^st Generation, Grubbs Catalyst 2^nd Generation, Grubbs Catalyst 3^rd Generation, Schrock’s catalyst, Zhan Catalyst- IB and the like.

Acid-Amine coupling agent used in the present invention include but not limited to propanephosphonic acid anhydride (PPAA, T3P), 1,1'- carbonyldiimidazole (CDI), A,A'-disuccinimidyl carbonate, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, tri chlorobenzoyl chloride, 4-nitobenzoyl chloride, diethyl cyanophosphonate (DEPC), (l-Cyano-2-ethoxy-2-oxoethyliden- aminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), Benzotriazole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), A,A,A', A'-Tetramethyl-(9-(lJ7-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), A-[(Dimethylamino)-lZ/-l,2,3-triazolo-[4,5-

Z>]pyridin-l-ylmethylene]-7V-methylmethanaminium hexafluoro-phosphate A-oxide (HATU) and the like.

As used herein the term "amorphous" refers to solid forms that consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.

As used herein "crystalline" refers to compounds or compositions where the structural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order. The structural units that constitute the crystal structure can be atoms, molecules, or ions. Crystalline solids show definite melting points.

As used herein, a "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase).

The term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a drug and polymer, optionally containing other components such as surfactants or other pharmaceutical excipients, where drug is either amorphous, and the physical stability and/or dissolution and/or solubility of the amorphous drug is enhanced by the other components.

The term “polymer” used herein may comprise hydrophobic regions and hydrophilic regions. In some embodiments, the polymer is selected from cellulose esters; cellulose ethers; polyalkylene oxides; polyvinyl chlorides; polyvinyl alcohols; polyacrylates; polymethacrylates; homopolymers and copolymers of N- vinyl lactams, polyacrylamides, and vinyl acetates; graft copolymers of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; oligosaccharides; polysaccharides; and mixtures thereof.

In some embodiments polymer from polyethylene glycol (PEG) glyceride include but not limited to PEG-6 caprylic/capric glyceride, palm glycerides and like.

In some embodiments polymer from polyethylene glycol (PEG) include but not limited to poly(ethylene glycol) methyl ether, poly-ethylene glycol vinyl acetate vinylcaprolactam (Soluplus), polyethylene glycol 6000 (PEG 6000), D-a-tocopheryl polyethylene glycol succinate (TPGS) and like.

In some embodiments polymer from Vinyl Acetate include but not limited to Polyvinyl Acetate phthalate, Soluplus and like.

In some embodiments polymer from cellulose esters, cellulose ethers include but not limited to Hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS) and like.

In some embodiments polymer from methyl acrylic acid /ethyl acrylate copolymer is selected from Eudragit S 100, Eudragit RS 100, Eudragit L 100-55, EUDRAGIT L 30 D-55, Kollicoat, Aery coat, MAE 100P, LI 00 and like.

In some embodiments, the polymer is selected from but not limited to methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, Hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), poly(ethylene glycol) methyl, poly-ethylene glycol vinyl acetate vinylcaprolactam (Soluplus), polyethylene glycol 6000 (PEG 6000), D-a-tocopheryl polyethylene glycol succinate (TPGS), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), Polyvinyl acetate phthalate (PVAP), blended polyvinyl acetate phthalate (e.g., Sureteric), Poly(ethyl acrylate-co-methyl methacrylate-co- trimethylammonioethyl methacrylate chloride) 1 :2:0.1 (e.g., Eudragit RS 100), methyacrylic acid copolymer type B (e.g., Eudragit S 100), methacrylic acid-ethyl acrylate copolymer (1 : 1) (e.g. Eudragit L 100-55); methyacrylic acid copolymer type B, polyoxyethylene-polyoxypropylene block copolymer (e.g., Pluronic F-68) and polyoxyethylene (20) sorbitan monooleate (Tween 80) and like and mixture thereof.

As used herein, 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.

One aspect of the present application relates to new processes for the preparation of Milvexian via new intermediates.

Another aspect of the present application provides a process of preparation of Milvexian via new intermediates of formula lb, II and III.

Yet another aspect of the present application provides a process for preparation of Milvexian comprising the steps of, olefin reduction in compound of formula III to prepare Milvexian.

Still another aspect of the present application provides a process for preparation of Milvexian comprising: a) ring closing metathesis (RCM) in compound of formula II to yield compound of formula III b) olefin reduction in compound of formula III to yield Milvexian.

Still another aspect of the present application provides a process for preparation of Milvexian comprising: a) Boc deprotection in compound of formula la to yield compound of formula lb, b) reaction of compound of formula lb with a compound of formula Ic to yield compound of formula II, c) ring closing metathesis (RCM) in compound of formula II to yield compound of formula III, d) olefin reduction in compound of formula III to yield Milvexian.

In an embodiment, the reaction of step a) is conducted in presence of a suitable acid and a suitable solvent.

In a particular embodiment, the reaction of step a) is conducted in presence of HC1 in dioxane as acid and dichloromethane as solvent.

In an embodiment, the reaction of step b) is conducted in presence of an acid-amine coupling agent and a suitable solvent.

In an embodiment, the reaction of step b) is conducted in presence of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) and HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) in a suitable solvent.

In a particular embodiment, the reaction of step b) is conducted in presence of acetonitrile as a solvent.

In an embodiment, the reaction of step c) is conducted in presence of a suitable RCM catalyst in a suitable solvent.

In a particular embodiment, the reaction of step c) is conducted in presence of Grubbs catalyst 2^nd generation or Hoveyda-Grubbs catalyst 2^nd generation in ethyl acetate as solvent.

In an embodiment, the reaction of step d) is conducted in presence of a suitable olefin reducing agent in a suitable solvent optionally in presence of a suitable catalyst.

In a particular embodiment, the reaction of step d) is conducted with a combination of hydrazine hydrate and oxygen serving as the reducing agent, p- toluenesulfonic acid serving as the catalyst and acetonitrile serving as the solvent.

The summary of the specific embodiment is given below in Scheme 1.

Scheme -1

Another aspect of the present application provides new intermediates of formula lb, II and III.

Another aspect of the present application provides use of compounds of formula lb, II and III for preparation of Milvexian.

Yet Another aspect of the present application provides a process of preparation of Milvexian comprising, a) Boc deprotection in compound of formula la to yield compound of formula lib, b) reaction of compound of formula lib with compound of formula Ic to yield compound of formula lie, c) reduction of nitro group in compound of formula lie to yield compound of formula lid, d) reaction of compound of formula lid with compound of formula He to yield compound of formula II, e) ring closing metathesis (RCM) in compound of formula II to yield compound of formula III, f) olefin reduction in compound of formula III to yield Milvexian.

In a particular embodiment, the reaction of step a) is conducted in presence of HC1 in dioxane as acid and methanol as solvent.

In an embodiment, the reaction of step c) is conducted with a suitable nitro group reducing agent in presence of a suitable solvent.

In a particular embodiment, the reaction of step c) is conducted with a combination of iron and ammonium chloride serving as the reducing agent and a mixture of methanol and water serving as the solvent.

In an embodiment, the reaction of step d) is conducted using a suitable acid- amine coupling reagent and a suitable base in a suitable solvent.

In a particular embodiment, the acid-amine coupling agent and base used in step d) are propanephosphonic acid anhydride (PPAA, T3P) and pyridine respectively.

In an embodiment, the reaction of step e) is conducted in presence of a suitable RCM catalyst in a suitable solvent.

In a particular embodiment, the reaction of step e) is conducted in presence of Grubbs catalyst 2^nd generation or Hoveyda-Grubbs catalyst 2^nd generation in ethyl acetate as solvent. In an embodiment, the reaction of step f) is conducted in presence of a suitable olefin reducing agent in a suitable solvent optionally in presence of a suitable catalyst.

In a particular embodiment, the reaction of step f) is conducted with a combination of hydrazine hydrate and oxygen serving as the reducing agent, p- toluenesulfonic acid serving as the catalyst and acetonitrile serving as the solvent.

The summary of the specific embodiment is given below in Scheme 2.

Scheme-2

Another aspect of the present application provides new intermediates of formula lib, lie, lid, lb.

Another aspect of the present application provides use of compounds of formula lib, lie and lid for preparation of Milvexian.

In embodiments, starting materials used in this aspect for preparing Milvexian may be obtained by any methods known in the art.

Processes described in the prior arts employ HATU in the final step of the synthetic sequence. This inevitably lead to isolation of an API that is contaminated with a significant quantity of HATU derived PF6-counterion impurity. Presence of this undesirable PF6-counterion impurity at various stages of API isolation and purification was detected not only by 19F NMR, but by ion chromatography as well. Removal of these impurities is laborious and requires multiple steps of washing and re-crystallization. This inevitably leads to a highly undesirable erosion of product yield in the final step of the API synthesis. This makes the prior art processes economically unsuitable for preparation of an active pharmaceutical ingredient.

In the processes of the instant application, HATU mediated coupling is carried out at an early stage in the synthesis and removal of the PFe” counterion impurities is quite efficiently achieved during the work-up itself. Traces of the PFe” counterion impurities, which may get carried over, can easily be managed during work-up or purification down-steam.

The above advantage can be shown unambiguously by Fig.10. Fig.10 shows an overlay of the ¹⁹F NMR spectra of two column purified Milvexian samples, one obtained by the prior art process (shown in Grey color) and the other obtained by the process described in the instant application (shown in Black color). The ¹⁹F signals of the PFe” counterion appear at around -75 ppm, while the ¹⁹F signals of Milvexian appear at around -91 ppm and -96 ppm. The ¹⁹F signals of the PFe” counterion impurities dominate over the ¹⁹F signals of Milvexian prepared by the prior art process. On the other hand, ¹⁹F signals of Milvexian prepared by the process of the instant application dominate over ¹⁹F signals of PFe” counterion impurities.

Yet another aspect of the present application relates to solid form of Milvexian and the pharmaceutical compositions thereof. Specific aspect of present application relate to the amorphous solid dispersions (ASD) of Milvexian and their preparative processes.

Another aspect of the present application provides an amorphous solid dispersion of Milvexian with pharmaceutically acceptable polymers.

An embodiment of the present application provides an amorphous solid dispersion of Milvexian with pharmaceutically acceptable polymers selected from Methacrylic acid/ethyl acrylate copolymer, polyethylene glycol (PEG) glycerides, Polyethylene Glycols, Carbopol copolymers, Capryl ocaproyl polyoxyl-8 glycerides and the like.

Another embodiment of the present application provides an amorphous solid dispersion of Milvexian with pharmaceutically acceptable polymers selected from but not limited to Gelucire, Poloxamer, Sodium Alginate, Labrasol ALF, Eudragit, Kollicoat MAE, Polyvinyl Acetate phthalate, Soluplus, HPMC phthalate, Ethyl cellulose, Methyl cellulose and the like; and mixture thereof.

One embodiment of the present application provides an amorphous solid dispersion of Milvexian with Methacrylic acid/ethyl acrylate copolymer optionally in presence of one or more polymer.

One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit.

Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit, wherein the ratio of API: polymer is 1:2.

Yet another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit, wherein the ratio of API: polymer is 3: 1.

Another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit, optionally with one more pharmaceutically acceptable polymer. Specifically, the optional polymer may be selected from a group of a cellulose ester polymer, cellulose ether polymer and polyethylene glycol polymer. More specifically, the optional polymer may be selected from a group of HPMC phthalate, HPC and TPGS.

Still another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPMC phthalate.

One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPMC phthalate in a APE polymer ratio of 1:2, wherein the ratio of Eudragit and HPMC phthalate is 1: 1.

Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC.

One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC in a API: polymer ratio of 1 :2, wherein the ratio of Eudragit and HPC is 3 : 1.

Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC in a API: polymer ratio of 3:1, wherein the ratio of Eudragit and HPC is 3: 1.

Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and HPC in a API: polymer ratio of 4:1, wherein the ratio of Eudragit and HPC is 3: 1.

Another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and TPGS.

One specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and TPGS in a API: polymer ratio of 1 :2, wherein the ratio of Eudragit and TPGS is 9: 1.

Another specific embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit and TPGS in a API: polymer ratio of 3: 1, wherein the ratio of Eudragit and TPGS is 9: 1.

Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Poly vinyl acetate pthalate, optionally with one more pharmaceutically acceptable polymer.

Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Poly vinyl acetate phthalate (in a API: polymer ratio of 1 :2), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 1.

Still another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit (in a API: polymer ratio of 1:2), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 2.

Yet another embodiment of the present application provides an amorphous solid dispersion of Milvexian with Eudragit (in a API : polymer ratio of 3: 1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 6.

One embodiment of the present application provides ASD of Milvexian with Eudragit and hydroxypropyl methylcellulose phthalate (HPMC phthalate) (in a API: polymer ratio of 1:2 and Eudragit and HPMC phthalate in a ratio of 3: 1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 3.

Another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and Hydroxypropylcellulose (HPC) (in a API: polymer ratio of 1 :2 and Eudragit and HPC in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 4.

Another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and Hydroxypropylcellulose (HPC) (in a API : polymer ratio of 3: 1 and Eudragit and HPC in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 7.

Another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and Hydroxypropylcellulose (HPC) (in a API : polymer ratio of 4: 1 and Eudragit and HPC in a ratio of 3:1), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 9.

Yet another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and D-a-Tocopherol polyethylene glycol succinate (TPGS) (in a API : polymer ratio of 1 :2 and Eudragit and TPGS in a ratio of 1 :9), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 5.

Yet another embodiment of the present application provides amorphous solid dispersion of Milvexian with Eudragit and D-a-Tocopherol polyethylene glycol succinate (TPGS) (in a API : polymer ratio of 3: 1 and Eudragit and HPC in a ratio of 1 :9), characterized by a powder X-ray diffraction pattern, as illustrated by Figure 8. One embodiment of the present application provides Milvexian in an amount from 1% to 90% by weight of the amorphous solid dispersion.

One specific embodiment of the present application provides Milvexian in an amount from 10% to 85% by weight of the amorphous solid dispersion.

Another specific embodiment of the present application provides Milvexian in an amount from 20% to 80% by weight of the amorphous solid dispersion.

Yet another specific embodiment of the present application provides Milvexian in an amount of 33% by weight of the amorphous solid dispersion.

Yet another specific embodiment of the present application provides Milvexian in an amount of 75% by weight of the amorphous solid dispersion.

Yet another specific embodiment of the present application provides Milvexian in an amount of 80% by weight of the amorphous solid dispersion.

In another aspect, the present application provides a process for the preparation of amorphous solid dispersion of Milvexian comprising: a) Dissolving Milvexian and one or more polymer in an organic solvent, and b) Isolating the solid.

One embodiment of the present application provides isolation of amorphous solid dispersion by distillation, lyophilization or spray-drying. Another embodiment of the present application provides isolation of amorphous solid dispersion by melting technique, Co-precipitation process, simple physical mixing and like.

Yet another aspect of the present application provides use of amorphous solid dispersion of Milvexian for treating a disease for which a selective factor Xia inhibitors or dual inhibitors of FXIa and plasma kallikrein is indicated. Specifically, the disease may be selected from a group of Ischemic Stroke, Acute Coronary Syndrome and Atrial Fibrillation. In all the embodiments, the isolated solid are optionally dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25°C or above.

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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Examples

Example 1: A process for the preparation of compound of formula lb

A solution of HC1 in 1,4-dioxane (4M, 12 mL) was added slowly over a period to a solution of la (2.2 g, 0.00476 moles) in DCM (26 mL) maintained at 0-5 °C under nitrogen atmosphere. The resulting reaction mixture was warmed to RT and allowed to stir at the same temperature under N2-atmosphere for 1 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated at 25 °C under reduced pressure to obtain a dark brown syrup to which ethyl acetate (50 mL), followed by saturated NaHCCL solution (20 mL), was added. The obtained mixture was stirred for 10 minutes at 25 °C after which the layers were allowed to separate. The aqueous layer was separated from the organic layer which was washed with water (2 X 100 mL). The separated aqueous layers were combined and extracted with ethyl acetate (50 mL). The separated organic layers were combined, washed with brine (26 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain lb as a dark brown sticky liquid [yield: 1.6 g]. Example 2: A process for the preparation of compound of formula II

HATU (1.73 g, 0.0045 moles) and DBU (0.82 g, 0.00539 moles) were added to a solution of Ic (1.082 g, 0.00352 moles) in CH3CN (60.0 mL) maintained RT under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes at 28 °C. Subsequently, a solution of lb (1.5 g, 0.0041 moles) in CH3CN (15.0 mL) was added to the reaction mixture which was then stirred for 2 h under nitrogen atmosphere at 28 °C. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure at <50 °C. Water (60 mL) and ethyl acetate (60 mL) were added to the obtained residue. The resulting mixture was stirred for 10 minutes at 28 °C after which the layers were allowed to separate. The organic layer was separated from the aqueous layer which was then extracted with ethyl acetate (60 mL). The separated organic layers were combined, washed successively with water (60 mL), saturated NaHCCL solution (60 mL) and brine solution (3 X 60 mL), dried over anhydrous ISfeSCU and finally concentrated under reduced pressure at <50 °C. The crude product thus obtained was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (5:95^50:50) to obtain II as a pale-yellow solid [yield: 1.1 g].

Example 3: A process for the preparation of compound of formula lib

("a) (lib)

A solution of HC1 in 1,4-di oxane (4M, 24.4 mL) was added slowly over a period of 5- 10 min to a solution of Ila (2.0 g, 0.0048 moles) in methanol (6 mL) maintained under nitrogen atmosphere at RT. The resulting reaction mixture was stirred under nitrogen for 2 h. Upon completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure at 25 °C. The residue obtained was treated with saturated NaHCOs solution until a pH of 8 was attained. The resulting mixture was extracted with ethyl acetate (2 X20 mL). The EtOAc extracts were combined, washed with brine (20 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure to yield lib as a dark red syrup [yield: 1.17 g],

'H NMR (DMSO 400 MHz): 3 8.73 (s, 1H), 8.72 (dd, J =4.7, 0.55 Hz, 1H), 7.68 (t, J= 56.4 Hz, 1H), 7.66 (s, 1H), 7.48 (dd, J = 5.2, 1.6 Hz, 1H), 5.80-5.71 (m, 1H), 5.03-4.96 (m, 2H), 4.03 (t, J= 6.4 Hz, 1H), 2.54-2.47 (m, 1H), 2.39-2.32 (m, 1H), 2.18 (br s, 2H).

¹⁹F NMR (DMSO 376 MHz): 3 -94.91, -94.92.

Mass (ESI+): m/z 310.2 [M + H]⁺

Example 4: A process for the preparation of compound of formula lie

A 50 mL round-bottom flask (RBF) was charged with 4 A molecular sieve powder (-400 mg) and flushed with nitrogen. Subsequently Ic (0.792 g, 0.0025 moles), acetonitrile (10.60 mL), DBU (0.490 mL, 0.0033 moles) and HATU (1.042 g, 0.0027 moles) were charged sequentially in to the same RBF maintained under nitrogen atmosphere. The reaction mixture thus obtained was stirred for 30 minutes at room temperature. Thereupon a solution of lib (0.530 g, 0.0017 moles) in dry acetonitrile (12.2 mL) was introduced slowly in to the reaction mixture at RT which was then stirred for 3 h at the same temperature. Upon completion of the reaction as indicated by TLC, the reaction mixture was filtered on a celite bed which was washed with ethyl acetate (3 X40 mL). The filtrate and washings were combined and washed with water (15 mL). The aqueous layer, thus separated from the organic layer, was extracted with ethyl acetate (3 X20 mL). The separated organic layers were combined, washed with a brine (3 X60 mL), dried using anhydrous ISfeSCU and concentrated under reduced pressure (<40 °C). The crude product obtained was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (5:95^50:50) to isolate lie as a pale orange solid [yield: 0.420 g].

Example 5: A process for the preparation of compound of formula lid

A solution of NH4CI (0.231 g) in water (1.56 mL) was added to a mixture of lie (0.260 g, 0.0004 moles) and iron powder (0.096 g, 0.0017 moles) in MeOH (3.64 mL) at RT. The reaction mixture was then heated to 70-75°C and stirred at the same temperature for 4 h. Progress of the reaction was monitored using TLC which showed incomplete consumption of the starting material (SM) after 4 h. At this stage, a second lot of iron powder (0.048 g, 0.0008 moles) and aqueous NH4CI solution (0.115 g of NH4CI dissolved in 0.8 mL of water) were introduced into the reaction mixture. The reaction was continued at 80-85 °C for 1 h after which a third lot of iron powder (0.048 g, 0.0008 mol) and aqueous NH4CI solution (0.115 g of NH4CI dissolved in 1.56 mL of water) were added. The reaction was allowed to continue at 80-85 °C for 3 h whereupon TLC analysis showed complete consumption of the SM. The reaction mixture was filtered through a celite bed which was washed with EtOAc (2 X 10 mL). The filtrate and washings were combined and washed with saturated NaHCOs solution (20 mL). The aqueous layer, thus separated from the organic layer, was extracted with ethyl acetate (2 X 10 mL). The separated organic layers were combined, washed with water (20 mL) followed by brine (20 mL), dried using anhydrous ISfeSCU and concentrated under reduced pressure at a temperature below 40°C. The crude product thus obtained was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (10:90^60:40) to yield lid as an orange color solid [0.110 g].

Example 6: A process for the preparation of compound of formula II

He (0.020 g, 0.0002 moles) and pyridine (0.050 g, 0.00063 mol) were added to a solution of lid (0.090 g, 0.00015 moles) in EtOAc (0.9 mL) at -10°C under nitrogen atmosphere. Thereafter T3P (50% solution in EtOAc, 0.301 mL, 0.00047 moles) was added slowly into the reaction mixture maintained at -10°C. The reaction mixture was then warmed to room temperature and stirred at the same temperature for 18 h under nitrogen. After completion of the reaction as indicated by TLC, water (10 mL) was added to the reaction mixture at room temperature which was then stirred for 5 min. The organic layer was separated from the aqueous layer which was extracted with ethyl acetate (2 X 10 mL). The separated organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure at temperatures below 40°C. The crude product thus obtained was purified by column chromatography using silica gel and EtOAc-hexanes (30:70^80:20) to isolate a pale yellowish sticky material. This was triturated with hexanes (10 mL) at room temperature for 20 min. The resulting suspension was filtered and the obtained solid was washed with hexanes (2 mL) and dried to obtain II as a pale yellow solid [yield: 0.040 g].

Example 7: A process for the preparation of compound of formula III

A solution of II (1.0 g, 0.00154 moles) in ethyl acetate (433.0 mL) was sparged with argon for 30 min. Grubbs catalyst 2^nd generation (0.326 g, 0.000385 moles) was charged under argon atmosphere into the resulting degassed solution. The obtained reaction mixture was sparged with argon for 10-20 min at 26 °C, heated to 70-75 °C and stirred at the same temperature for 2 h under argon atmosphere. Thereafter, the reaction mixture was concentrated under reduced pressure at <50 °C and the obtained crude product was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (10:90^60:40). The fractions, containing the pure product, were combined, treated with charcoal and filtered. The obtained filtrate was concentrated to obtain III as a pale brown solid [yield: 0.6 g].

Example 8: A process for the preparation of Milvexian

A solution of PTSA.H2O (3.04 mg, 0.02 mmol) in CH3CN (0.16 mL), followed by hydrazine monohydrate (16 mg, 0.32 mmol), were added to a solution of III (0.05 g, 0.08 mmol) in CH3CN (1.50 mL) maintained at 28 °C under an oxygen atmosphere. The obtained reaction mixture was heated to 55-60 °C and stirred at the same temperature for 20 h. Thereafter, the reaction was quenched with saturated NaHCOs solution (1.5 mL) at RT. Water (10.0 mL) and ethyl acetate (10.0 mL) were added to the obtained reaction mixture which was then stirred for 10 min. The aqueous layer was separated from the organic layer which was then washed with brine (10 mL), dried over anhydrous ISfeSC and concentrated under reduced pressure at <50 °C. The crude product thus obtained was purified by column chromatography using silica gel and EtOAc-hexanes (30:70^80:20) to obtain a pale yellowish-brown sticky liquid. This was triturated with hexanes (10 mL) at RT for 20 min. The resulting suspension was filtered and the solid thus obtained was washed with hexanes (2 mL) and dried to obtain Milvexian as a pale green solid [yield: 0.02 g].

Example 9: A process for the preparation of compound of formula lb

A solution of HC1 in 1,4-dioxane (4M, 137.5 mL) was added slowly over a period of 5-10 min to a solution of la (25.0 g, 0.0541 moles) in DCM (300.0 mL) maintained at 0-5 °C under nitrogen atmosphere. The resulting reaction mixture was warmed to RT and allowed to stir at the same temperature under N2 atmosphere for 1 h. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated at 25 °C under reduced pressure to obtain a dark brown syrup. Saturated NaHCOs solution (250 mL) was added to the residue followed by ethyl acetate (250 mL). The obtained mixture was stirred for 10 minutes at 25 °C after which the layers were allowed to separate. The aqueous layer was separated and further extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (2 X250 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure to obtain lb as a greenish black sticky liquid [yield: 19.0 g (97%)].

'H NMR (DMSO 400 MHz): 3 9.47 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.05 (s, 1H), 7.68 (t, J = 58.0 Hz, 1H), 7.49 (s, 1H), 7.28 (dd, J = 4.8, 0.8 Hz, 1H), 5.90- 5.74 (m, 2H), 5.11-4.98 (m, 4H), 4.04-3.98 (m, 1H), 3.22-3.15 (m, 1H), 2.55-2.50 (m, 2H), 2.38-2.31 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H).

¹⁹F NMR (DMSO 376 MHz): 3 -92.54, -92.57.

Mass (ESI+): m/z 362.2 [M + H]⁺

Example 10: A process for the preparation of compound of formula II

HATU (21.98 g, 0.0578 moles) and DBU (10.39 g, 0.0683 moles) were added to a mixture of Ic (13.71 g, 0.044 moles) and 4 A molecular sieves (-38.0 g) in CH3CN (570.0 mL) maintained at RT under nitrogen atmosphere. The reaction mixture was stirred for 15 minutes at 28 °C. Subsequently, a solution of lb (19.0 g, 0.052 moles) in CH3CN (190.0 mL) was added to the reaction mixture which was then stirred for 2 h under nitrogen atmosphere at 28 °C. Upon completion of the reaction as indicated by TLC, the reaction mixture was filtered on a Celite bed, which was then washed with ethyl acetate (950.0 mL). The filtrate and washings were combined and washed successively with saturated NH4CI solution (570 mL), water (380 mL), saturated NaHCCL solution (380.0 mL) and brine (380.0 mL). It was then dried over anhydrous Na2SO4 and finally concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (10:90->50:50) to obtain II as an off-white solid [yield: 18.0 g (52.47%)].

'H NMR (DMSO 400 MHz): 3 9.51 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.08 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.82 (dd, J = 8.8, 2.4 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.69 (t, J = 57.2 Hz, 1H), 7.56 (s, 1H), 7.40 (dd, J = 5.2, 1.2 Hz, 1H), 6.47 (s, 1H), 6.07 (dd, J = 8.8, 6.8 Hz, 1H), 5.90-5.81 (m, 1H), 5.77-5.66 (m, 1H), 5.12-5.02 (m, 4H), 3.21-3.14 (m, 1H), 3.08-2.98 (m, 2H), 1.12 (d, J = 6.8 Hz, 3H).

¹⁹F NMR (DMSO 376 MHz): 3 -91.69, -92.29, -92.66, -93.26.

Mass (ESI+): m/z 652.1 [M + H]⁺

Example 11: A process for the preparation of compound of formula lib

A solution of HC1 in 1,4-di oxane (4M, 61.0 mL) was added slowly over a period of 5- 10 min to a solution of Ila (5.0 g, 0.0122 moles) in methanol (15.0 mL) maintained under nitrogen atmosphere at RT. The resulting reaction mixture was stirred under nitrogen for 1-2 h. Upon completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure at 45 °C. The residue obtained was treated with saturated NaHCOs solution (20 mL) until a pH of 8 was attained. The resulting mixture was extracted with ethyl acetate (3 X 50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to yield lib as a brown sticky liquid [yield: 4.6 g (crude)].

Example 12: A process for the preparation of compound of formula lie

A 250 mL round-bottom flask (RBF) was charged with 4 A molecular sieves (~4.0 g) and flushed with nitrogen. Subsequently Ic (5.37 g, 0.0175 moles), acetonitrile (74.0 mL), DBU (3.51 g, 0.023 moles) and HATU (7.1 g, 0.0188 moles) were charged sequentially in to the same RBF maintained under nitrogen atmosphere. The reaction mixture thus obtained was stirred for 30 minutes at room temperature. Thereupon a solution of lib (3.7 g, 0.0119 moles;) in dry acetonitrile (85.1 mL) was introduced slowly in to the reaction mixture at RT which was then stirred for 2-3 h at the same temperature. Upon completion of the reaction as indicated by TLC, the reaction mixture was filtered on a Celite bed which was washed with ethyl acetate (111.0 mL). The filtrate and washings were combined and washed with saturated NH4CI solution (37.0 mL). The aqueous layer, thus separated from the organic layer, was extracted with ethyl acetate (111.0 mL). The separated organic layers were combined, washed with brine (37.0 mL), dried using anhydrous ISfeSCU and concentrated under reduced pressure at 40 °C. The crude product obtained was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (5:95-^50:50) to isolate lie as an off-white foamy solid [yield: 4.0 g (55% from Ila)].

'H NMR (CDCL, 400 MHz): 3 8.80 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.68 (d, J= 2.4 Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J= 8.8, 2.4 Hz, 1H), 7.50-7.48 (m, 2H), 7.37 (dd, J= 4.8, 1.2 Hz, 1H), 7.13 (t, J= 58 Hz, 1H), 6.40 (s, 1H), 6.17 (dd, J = 8.4, 7.2 Hz, 1H), 5.76-5.65 (m, 1H), 5.17-5.09 (m, 2H), 3.13-3.06 (m, 1H), 3.02-2.93 (m, 1H).

¹⁹F NMR (CDCL, 376 MHz): <5 -91.14, -91.75, -92.16, -92.77.

Mass (ESI+): m/z 600.0 [M + H]⁺

Example 13: A process for the preparation of compound of formula lid

A solution of NH4CI (1.78 g; 0.0333 moles) in water (8.0 mL) and iron powder (1.30 g, 0.0233 moles) were added sequentially to a solution of lie (4.0 g, 0.0066 moles) in MeOH (48.0 mL) maintained at RT. The reaction mixture was then heated to 70-75 °C and stirred at the same temperature for 24-29 h. Thereafter, a second lot of iron powder (1.30 g, 0.0233 moles) and aqueous NH4CI solution (1.78 g of NH4CI dissolved in 8.0 mL of water) were added into the reaction mixture. The reaction was continued at 70-75 °C for an additional 10-12 h. The reaction mixture was filtered through a Celite bed, which was then washed with EtOAc (40.0 mL). The filtrate and washings were combined and washed with saturated NaHCCh solution (40 mL). The aqueous layer, thus separated from the organic layer, was extracted with ethyl acetate (40.0 mL). The separated organic layers were combined, washed with water (20 mL) followed by brine (20 mL), dried using anhydrous ISfeSCU and finally concentrated under reduced pressure at a temperature below 40 °C to yield lid as a pale yellow color solid [yield: 3.43 g (90.4%)].

¹ H NMR (CDCh, 400 MHz): 3 8.67 (d, J = 5.2 Hz, 1H), 8.48 (s, 1H), 7.70-7.54 (m, 5H), 7.51-7.39 (m, 3H), 7.15 (t, J= 59.2 Hz, 1H), 6.36 (s, 1H), 6.12 (t, J= 7.6 Hz, 1H), 5.77-5.62 (m, 1H), 5.17-5.10 (m, 2H), 3.10-2.96 (m, 3H).

¹⁹F NMR (CDCh, 376 MHz): 3 -90.24.

Mass (ESI+): m/z 570.0 [M + H]⁺

Example 14: A process for the preparation of compound of formula II

Pyridine (1.77 g, 0.0224 moles) and He (0.73 g, 0.0073 moles) were added sequentially to a solution of lid (3.2 g, 0.00562 moles) in EtOAc (32.0 mL) maintained at -10 to -15 °C under nitrogen atmosphere. Thereafter T3P (50% solution in EtOAc, 10.7 mL, 0.0168 moles) was added slowly into the reaction mixture maintained at -10 to -15 °C. The reaction mixture was then warmed to room temperature and stirred at the same temperature for 20-21 h under nitrogen. After completion of the reaction as indicated by TLC, water (16.0 mL) and ethyl acetate (32.0 mL) were added at room temperature to the reaction mixture, which was then stirred for 5-10 min. The organic layer was separated from the aqueous layer, which was extracted with ethyl acetate (32.0 mL). The separated organic layers were combined, washed with brine (16.0 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure at temperatures below 40 °C. The crude product thus obtained was purified by column chromatography using silica gel and EtOAc- hexanes (10:90->50:50) to obtain II as a pale yellow solid [yield: 2.5 g (68.2%)].

'H NMR (DMSO-de, 400 MHz): 3 9.51 (s, 1H), 8.70 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.69 (t, J = 57.6 Hz, 1H), 7.56 (s, 1H), 7.40 (dd, J = 4.8, 1.2 Hz, 1H), 6.47 (s, 1H), 6.07 (dd, J = 9.2, 7.2 Hz, 1H), 5.90-5.81 (m, 1H), 5.76-5.66 (m, 1H), 5.12-5.02 (m, 4H), 3.21-3.14 (m, 1H), 3.08-2.98 (m, 2H), 1.12 (d, J = 6.8 Hz, 3H).

¹⁹F NMR (DMSO-de, 376 MHz): 3 -91.69, -92.30, -92.66, -93.27.

Mass (ESI+): m/z 652.1 [M + H]⁺

Example 15: A process for the preparation of compound of formula III

A solution of II (5.0 g, 7.663 mmol) in ethyl acetate (1.25 L) was sparged with argon for 30 min. Hoveyda-Grubbs catalyst 2^nd generation (0.35 g, 0.5594 mmol) was charged under argon atmosphere into the resulting degassed solution. The obtained reaction mixture was sparged with argon for 20-25 min at 29 °C, heated to 65-70 °C and stirred at the same temperature for 2.5-3.0 h under argon atmosphere. Thereafter, a second lot of Hoveyda-Grubbs catalyst 2^nd generation (0.83 g, 1.32 mmol) was added into the reaction mixture. The reaction was continued at 65-70 °C for 3 h after which a third lot of Hoveyda-Grubbs catalyst 2^nd generation (0.624 g, 0.996 mmol) was added. The reaction was allowed to continue at 65-70 °C for an additional 16-17 h whereupon TLC analysis showed 80-85% consumption of the SM. Thereafter, the reaction mixture was concentrated under reduced pressure at <50 °C to a volume of about 50- 70 mL to which activated carbon (1.8 g) was added. The obtained mixture was stirred for 20-30 min at room temperature and filtered through a Celite bed, which was then washed with EtOAc (300 mL). The filtrate and washings were combined and concentrated under reduced pressure at a temperature below 50 °C. The obtained crude product was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (40:60->80:20). The fractions, containing the pure product, were combined and concentrated under reduced pressure below 50 °C. The obtained residue was stirred in mixture of EtOAc (50 mL) and saturated NaHCOs solution (100.0 mL) for 12-14 h at room temperature. Thereafter, the aqueous and organic layers were separated. The separated aqueous layer was further extracted with EtOAc (25.0 mL). The separated organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure below 50 °C. The obtained residue was mixed with hexane (100 mL) and concentrated under reduced pressure below 50 °C to obtain III as a blackish to brown solid [yield: 2.72 g (57.02%)].

'H NMR (DMSO-de, 400 MHz): 3 9.27 (s, 1H), 8.72 (s, 1H), 8.71 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.95-7.94 (m, 2H), 7.87 (t, J = 57.6 Hz, 1H), 7.83 (dd, J= 8.4, 2.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.28 (s, 1H), 6.34 (s, 1H), 5.88-5.77 (m, 2H), 4.49 (dd, J = 15.2, 9.6 Hz, 1H), 3.19-3.12 (m, 1H), 2.77- 2.63 (m, 2H), 0.97 (d, J= 6.4 Hz, 3H).

¹⁹F NMR (DMSO-de, 376 MHz): 3 -89.7, -90.3, -95.2, -95.8.

Mass (ESI+): m/z 624.0 [M + H]⁺

Example 16: A process for the preparation of Milvexian

PTSA.H2O (190.8 mg, 1.00 mmol) and hydrazine monohydrate (75% aqueous solution, 0.68 mL, 16.04 mmol) were added to a solution of III (2.5 g, 4.01 mmol) in CH3CN (75.0 mL) maintained at 28 °C under an oxygen atmosphere. The obtained reaction mixture was heated to 55-60 °C and stirred at the same temperature for 2-3 h. Thereafter, a second lot of PTSA.H2O (190.8 mg, 1.00 mmol) and hydrazine monohydrate (75% aqueous solution, 0.68 mL, 16.04 mmol) were added into the reaction mixture. The reaction was continued at 55-60 °C for 14-15 h under an oxygen atmosphere after which a third lot of PTSA.H2O (190.8 mg, 1.00 mmol) and hydrazine monohydrate (75% aqueous solution, 0.68 mL, 16.04 mmol) were added. The reaction was allowed to continue at 55-60 °C for 2-3 h under an oxygen atmosphere. Thereafter, a fourth lot of PTSA.H2O (95.4 mg, 0.50 mmol) and hydrazine monohydrate (75% aqueous solution, 0.34 mL, 8.02 mmol) were added, and the reaction mixture was stirred for 8 h at 55-60 °C under an oxygen atmosphere. The reaction mixture was then mixed with EtOAc (50.0 mL) and saturated NH4CI solution (35.0 mL), and stirred for 5-10 min. The organic layer was separated from the aqueous layer, which was then extracted with EtOAc (20.0 mL). The separated organic layers were combined, washed sequentially with saturated NaHCCf solution (35.0 mL) and brine (30.0 mL), and finally concentrated under reduced pressure below 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (100-200 mesh) and EtOAc-hexanes (30:70-^80:20) to obtain 1.8 g of a pale yellow solid. This was triturated with MTBE (20 mL) at RT for 10-15 min. The resulting suspension was filtered; the solid thus obtained was washed with MTBE (5.0 mL) and dried to obtain Milvexian as a white solid [yield: 1.53 g (61%)].

'H NMR (CD₃OD, 400 MHz): 3 8.87 (s, 1H), 8.74 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 7.87 (d, J= 2.4 Hz, 1H), 7.74-7.71 (m, 2H), 7.68 (s, 1H), 7.65 (t, J = 57.2 Hz, 1H), 7.64 (d, J= 8.4, Hz, 1H), 7.51 (d, J= 6.0 Hz, 1H), 6.36 (s, 1H), 6.00 (dd, J = 12.4, 4.4 Hz, 1H), 2.71 (td, J = 6.8, 3.2 Hz, 1H), 2.29 (tt, J = 12.8, 4.4 Hz, 1H), 2.08-1.95 (m, 2H), 1.64-1.40 (m, 2H), 0.99 (d, J= 7.2 Hz, 3H).

¹⁹F NMR (CD3OD, 376 MHz): 3 -90.8, -91.4, -96.4, -97.0.

Mass (ESI+): m/z 626.1 [M + H]⁺

Example-17: Amorphous solid dispersion with PVAP (Poly vinyl acetate phthalate) (API : Polymer:: 1:2 w/w)

In a round bottomed flask, Milvexian (1.5 g) was dissolved together with PVAP (3 g; 1 :2 w/w) in Methanol-Acetone(l: l) solvent mixture at ambient temperature and subjected to dry distillation over rotavapor under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig.1.

Example-18: Amorphous solid dispersion with Eudragit L100 55

(API : Polymer:: 1:2 w/w)

Dissolved Milvexian (1.5 g) and Eudragit L100 55 (3 g; 1 :2 w/w) in Methanol- Acetone(l : l) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig.2.

Example-19: Amorphous solid dispersion with Eudragit L100 55: HPMC phthalate HP50::l:l) (API : Polymer:: 1:2 w/w) In a round bottomed flask, Milvexian (1 g) was dissolved together with polymer (Eudragit L100 55 (1 g): HPMC phthalate HP50 (1 g):: l : l) (1:2 w/w) in Methanol- Acetone(l : l) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig.3.

Example-20: Amorphous solid dispersion with Eudragit L100 55: HPC SSL::3:1 (API : Polymer:: 1:2 w/w)

Dissolved Milvexian (1 g) and polymer (Eudragit L100 55 (750 mg): HPC SSL (250 mg) : :3 : 1) (1 :2 w/w) in methanol at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig.4.

Example-21: Amorphous solid dispersion with (Eudragit L100 55: TPGS::9:1) (API : Polymer:: 1:2 w/w).

Milvexian (1 g) was dissolved in Polymer (Eudragit L100 55 (1.8 mg): TPGS (0.2 g) ::9: 1) (1:2 w/w) in Methanol-Acetone(l: l) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C The PXRD of the resultant solid material is given in Fig.5.

Example-22: Amorphous solid dispersion with Eudragit L100 55 (API : Polymer: :3:1 w/w)

Dissolved Milvexian (3 g) and polymer (Eudragit L100 55) (990 mg) (3: 1 w/w) in methanol and acetone in a ratio of 1 : 1 (160 mL) at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig. 6.

Example-23: Amorphous solid dispersion with Eudragit L100 55: HPC SSL::3:1 (API : Polymer: :3:1 w/w)

Dissolved Milvexian (3 g) and polymer (Eudragit L100 55 (742.5 mg): HPC SSL (247.5 mg) in methanol and acetone in a ratio of 1 : 1 (180 mL) at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig. 7.

Example-24: Amorphous solid dispersion with (Eudragit L100 55: TPGS::9:1) (API : Polymer: :3:1 w/w).

Milvexian (1 g) was dissolved in Polymer (Eudragit LI 00 55 (297 mg): TPGS (33 mg) in Methanol -Acetone (1: 1) (60 mL) solvent mixture at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig. 8.

Example-25: Amorphous solid dispersion with Eudragit L100 55: HPC SSL::3:1 (API : Polymer ::4:1 w/w)

Dissolved Milvexian (1 g) and polymer (Eudragit L100 55 (187.5 mg): HPC SSL (62.5 mg) in methanol and acetone in a ratio of 1 : 1 (60 mL) at ambient temperature and subjected to dry distillation over rotavapour under vacuum at 50°C.

The PXRD of the resultant solid material is given in Fig. 9.

Example-26: Solubility Studies of Amorphous solid dispersions of the present application:

Kinetic solubility of the ASDs were compared with the Milvrexian ASD with HPMC- AS MG (As known in W02020210629A1) in pH 1.2 chloride buffer, pH 4.5 acetate buffer and pH 6.8 phosphate buffer as shown in table-1. Approximately 2 mg of API or API equivalent ASD suspended in 1 mL of the above said buffers and maintained at 37°C and collected aliquots at stated intervals, centrifuged to collect the supernatant and analyzed by HPLC.

Table 1:

Example-27: Stability Studies of Amorphous solid dispersions of the present application:

The ASDs were kept at 40°C/75%RH at open condition for 7 days and the chemical purities were checked by HPLC method and physical nature of the samples were checked by XRD. The results are tabulated in Table-2.

Table-2

Claims

1. An amorphous solid dispersion of Milvexian and at least one polymer, wherein the polymer is selected from the group comprising of Methacrylic acid/ethyl acrylate copolymer, polyethylene glycol (PEG) glycerides, Polyethylene Glycols, Carbopol copolymers, Caprylocaproyl polyoxyl-8 glycerides.

2. The amorphous solid dispersion of Milvexian, as claimed in claim 1, comprising a methyl acrylic acid /ethyl acrylate copolymer.

3. The amorphous solid dispersion of Milvexian, as claimed in claim 2, comprising Eudragit.

4. The amorphous solid dispersion of Milvexian, as claimed in claim 1, optionally with an additional polymer.

5. The amorphous solid dispersion, as claimed in claim 4, wherein the additional polymer is selected from cellulose esters and cellulose ethers.

6. An amorphous solid dispersion of Milvexian comprising Eudragit.

7. The amorphous solid dispersion, as claimed in claim 6, optionally with an additional polymer.

8. The amorphous solid dispersion, as claimed in claim 7, wherein the additional polymer is selected from a group of HPC, HPMC and TPGS.

9. A process for the preparation of amorphous solid dispersion of Milvexian comprising: a) Dissolving Milvexian and one or more polymer in an organic solvent, and b) Isolating the solid.

10. The process, as claimed in Claim 9, wherein the polymer is selected from methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, Hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), poly(ethylene glycol) methyl, poly-ethylene glycol vinyl acetate vinylcaprolactam (Soluplus), polyethylene glycol 6000 (PEG 6000), D-a-tocopheryl polyethylene glycol succinate (TPGS), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), Polyvinyl acetate phthalate (PVAP), Sureteric, Eudragit RS 100, Eudragit S 100, Eudragit L 100-55, Pluronic F-68 and mixture thereof.

11. A Pharmaceutical composition comprising amorphous solid dispersions as claimed in claim 1 to 8.

12. A process for preparation of Milvexian comprising, a) ring closing metathesis (RCM) in compound of formula II to yield compound of formula III

b) olefin reduction in compound of formula III to yield Milvexian.

13. A Process for preparation of Milvexian comprising, olefin reduction in compound of formula III to yield Milvexian.

14. A compound of formula II

15. A compound of formula III