DESC:INTRODUCTION

The drug compound having the adopted name “Milvexian” has chemical name: (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-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-1(18),2(6),4,14,16-pentaen-8-one as below.

The compound Milvexian was first described in PCT publication WO2015116886A1 and its use thereof as a selective factor XIa inhibitor or a dual inhibitor of FXIa and plasma kallikrein was also disclosed.
The PCT application WO2016053455A1 describes a method of preparing Milvexian.
Another PCT application WO2020210613A1 describes a method of preparing Milvexian using transaminase.
One more PCT application WO2022081473A1 also describes another method for the preparation of Milvexian.
The reported methods in the art are not feasible for commercial scale due to low yield, operational challenges and like.
Therefore, there is a need in the art for novel and improved methods for synthesizing Milvexian in commercially viable and cost-effective manner, which is suitable for large scale cGMP production for its pharmaceutical formulation manufacturing.
SUMMARY
In an aspect, the present application provides novel processes for preparation of Milvexian.
In another aspect, the present application also provides novel intermediates of formula IIb, IIc, IId, II, III, Ib.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1: 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, t-BuOK, BuLi, t-BuLi, LHMDS, imidazole and like. The inorganic base used in the present invention includes but not limited to NaH, Cs2CO3, K2CO3, NaHCO3, 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-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6 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, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-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, m-xylene, o-xylene, p-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, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-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, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 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 -(C=N) 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), ?,?-dimethylacetamide (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 dimethylsulfone, diethylsulfone, diisopropylsulfone, 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 t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 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 p-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 CoCl2.6H2O 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 NH4Cl or HCl or acetic acid; Zn in presence of NH4Cl or acetic acid; SnCl2; sodium dithionite; sodium sulfide; sodium hydrogen sulfide; boron reagents such as B2pin2 and B2(OH)4; HSiCl3 in combination with a tertiary amine such as TEA or DIPEA; LiAlH4/AlCl3 and like.
The “RCM catalyst” used in the present invention include but not limited to Hoveyda-Grubbs Catalyst 2nd generation, Grubbs Catalyst M207 (C827), Grubbs Catalyst 1st Generation, Grubbs Catalyst 2nd Generation, Grubbs Catalyst 3rd Generation, Schrock’s catalyst, Zhan Catalyst-1B 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), N,N'-disuccinimidyl carbonate, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, trichlorobenzoyl chloride, 4-nitobenzoyl chloride, diethyl cyanophosphonate (DEPC), (1-Cyano-2-ethoxy-2-oxoethyliden-aminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluoro-phosphate N-oxide (HATU) and the like.
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 Ib, 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 Ia to yield compound of formula Ib,
b) reaction of compound of formula Ib 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 HCl 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 2nd generation or Hoveyda-Grubbs catalyst 2nd 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 Ib, II and III.

Another aspect of the present application provides use of compounds of formula Ib, 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 Ia to yield compound of formula IIb,
b) reaction of compound of formula IIb with compound of formula Ic to yield compound of formula IIc,
c) reduction of nitro group in compound of formula IIc to yield compound of formula IId,
d) reaction of compound of formula IId with compound of formula IIe 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 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 HCl in dioxane as acid and methanol 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 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 2nd generation or Hoveyda-Grubbs catalyst 2nd 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 IIb, IIc, IId, Ib.

Another aspect of the present application provides use of compounds of formula IIb, IIc and IId 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 PF6– counterion impurities is quite efficiently achieved during the work-up itself. Traces of the PF6– 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.1. Fig.1 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 PF6– 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 PF6– 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 PF6– counterion impurities.
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 Ib

A solution of HCl in 1,4-dioxane (4M, 12 mL) was added slowly over a period to a solution of Ia (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 oC under reduced pressure to obtain a dark brown syrup to which ethyl acetate (50 mL), followed by saturated NaHCO3 solution (20 mL), was added. The obtained mixture was stirred for 10 minutes at 25 oC after which the layers were allowed to separate. The aqueous layer was separated from the organic layer which was washed with water (2?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 Ib 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 oC. Subsequently, a solution of Ib (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 oC. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure at <50 oC. Water (60 mL) and ethyl acetate (60 mL) were added to the obtained residue. The resulting mixture was stirred for 10 minutes at 28 oC 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 NaHCO3 solution (60 mL) and brine solution (3?60 mL), dried over anhydrous Na2SO4 and finally concentrated under reduced pressure at <50 oC. 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 IIb

A solution of HCl in 1,4-dioxane (4M, 24.4 mL) was added slowly over a period of 5-10 min to a solution of IIa (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 NaHCO3 solution until a pH of 8 was attained. The resulting mixture was extracted with ethyl acetate (2?20 mL). The EtOAc extracts were combined, washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield IIb as a dark red syrup [yield: 1.17 g].
1H NMR (DMSO-d6, 400 MHz): d 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-d6, 376 MHz): d -94.91, -94.92.
Mass (ESI+): m/z 310.2 [M + H]+

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

A 50 mL round-bottom flask (RBF) was charged with 4 Å 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 IIb (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?40 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?20 mL). The separated organic layers were combined, washed with a brine (3?60 mL), dried using anhydrous Na2SO4 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 IIc as a pale orange solid [yield: 0.420 g].

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

A solution of NH4Cl (0.231 g) in water (1.56 mL) was added to a mixture of IIc (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 NH4Cl solution (0.115 g of NH4Cl 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 NH4Cl solution (0.115 g of NH4Cl 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?10 mL). The filtrate and washings were combined and washed with saturated NaHCO3 solution (20 mL). The aqueous layer, thus separated from the organic layer, was extracted with ethyl acetate (2?10 mL). The separated organic layers were combined, washed with water (20 mL) followed by brine (20 mL), dried using anhydrous Na2SO4 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 IId as an orange color solid [0.110 g].

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

IIe (0.020 g, 0.0002 moles) and pyridine (0.050 g, 0.00063 mol) were added to a solution of IId (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?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 2nd 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 oC, heated to 70-75 oC and stirred at the same temperature for 2 h under argon atmosphere. Thereafter, the reaction mixture was concentrated under reduced pressure at <50 oC 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 oC under an oxygen atmosphere. The obtained reaction mixture was heated to 55-60 0C and stirred at the same temperature for 20 h. Thereafter, the reaction was quenched with saturated NaHCO3 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 Na2SO4 and concentrated under reduced pressure at <50 oC. 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 Ib
A solution of HCl in 1,4-dioxane (4M, 137.5 mL) was added slowly over a period of 5-10 min to a solution of Ia (25.0 g, 0.0541 moles) in DCM (300.0 mL) maintained at 0-5 oC 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 oC under reduced pressure to obtain a dark brown syrup. Saturated NaHCO3 solution (250 mL) was added to the residue followed by ethyl acetate (250 mL). The obtained mixture was stirred for 10 minutes at 25 oC 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?250 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain Ib as a greenish black sticky liquid [yield: 19.0 g (97%)].
1H NMR (DMSO-d6, 400 MHz): d 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-d6, 376 MHz): d -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 Å 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 Ib (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 NH4Cl solution (570 mL), water (380 mL), saturated NaHCO3 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%)].
1H NMR (DMSO-d6, 400 MHz): d 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-d6, 376 MHz): d -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 IIb
A solution of HCl in 1,4-dioxane (4M, 61.0 mL) was added slowly over a period of 5-10 min to a solution of IIa (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 NaHCO3 solution (20 mL) until a pH of 8 was attained. The resulting mixture was extracted with ethyl acetate (3?50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield IIb as a brown sticky liquid [yield: 4.6 g (crude)].

Example 12: A process for the preparation of compound of formula IIc
A 250 mL round-bottom flask (RBF) was charged with 4 Å 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 IIb (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 NH4Cl 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 Na2SO4 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 IIc as an off-white foamy solid [yield: 4.0 g (55% from IIa)].
1H NMR (CDCl3, 400 MHz): d 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 (CDCl3, 376 MHz): d -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 IId
A solution of NH4Cl (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 IIc (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 NH4Cl solution (1.78 g of NH4Cl 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 NaHCO3 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 Na2SO4 and finally concentrated under reduced pressure at a temperature below 40 °C to yield IId as a pale yellow color solid [yield: 3.43 g (90.4%)].
1H NMR (CDCl3, 400 MHz): d 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 (CDCl3, 376 MHz): d -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 IIe (0.73 g, 0.0073 moles) were added sequentially to a solution of IId (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%)].
1H NMR (DMSO-d6, 400 MHz): d 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-d6, 376 MHz): d -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 2nd 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 2nd 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 2nd 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 oC. The obtained residue was stirred in mixture of EtOAc (50 mL) and saturated NaHCO3 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%)].
1H NMR (DMSO-d6, 400 MHz): d 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-d6, 376 MHz): d -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 oC under an oxygen atmosphere. The obtained reaction mixture was heated to 55-60 oC 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 NH4Cl 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 NaHCO3 solution (35.0 mL) and brine (30.0 mL), and finally concentrated under reduced pressure below 50 oC. 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%)].
1H NMR (CD3OD, 400 MHz): d 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): d -90.8, -91.4, -96.4, -97.0.
Mass (ESI+): m/z 626.1 [M + H]+ ,CLAIMS:Claim 1: 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.

Claim 2. A process as claimed in claim 1, step a) is conducted in presence of Grubbs catalyst 2nd generation or Hoveyda-Grubbs catalyst 2nd generation in ethyl acetate as solvent.

Claim 3. A process as claimed in claim 1, step b) is conducted in presence of hydrazine hydrate, p-toluenesulfonic acid and acetonitrile as the solvent.

Claim 4. A Process for preparation of Milvexian comprising, olefin reduction in compound of formula III to yield Milvexian.

Claim 5. A process as claimed in claim 4, reaction is conducted in presence of hydrazine hydrate, p-toluenesulfonic acid and acetonitrile as the solvent.

Claim 6. A compound of formula II

Claim 7. A compound of formula III