DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application no IN 201841029980 filed on Aug 09, 2018.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Pibrentasvir or its pharmaceutically acceptable salts.
DESCRIPTION OF THE RELATED ART

Pibrentasvir is chemically named as Methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate and is represented by the following chemical structure:

Pibrentasvir
Pibrentasvir was disclosed in U.S Patent 8937150 B2 which is hereby incorporated by reference.
Pibrentasvir is an antiviral agent. In the United States and Europe, it is approved for the use with Glecaprevir as the combination drug Glecaprevir/Pibrentasvir under the brand name MAVYRET TM in USA and Maviret in the EU for the treatment of adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis. Mavyret is also approved for adult patients with HCV genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both.
According to product patent US8937150B2, Pibrentasvir was prepared by following the process as illustrated in scheme 1

Most of the intermediates of the above scheme were isolated as foam materials and purified by column chromatography. The inventors of the present invention developed an improved process for the preparation of Pibrentasvir isolating the intermediates as solids in desired isomeric forms. The process developed by the present inventors is easy to handle and produce Pibrentasvir in good yield and purity.

OBJECT OF THE INVENTION:
The main object of the present invention is to provide an improved process for the preparation of Pibrentasvir.

SUMMARY OF THE INVENTION.
The Principal aspect of the present invention is to provide an improved process for the preparation of Pibrentasvir or its pharmaceutically acceptable salts as shown in scheme below.

In one aspect, the compounds of formula IV, VI, VII, VIII, IX and X are isolated as solid in desired isomeric forms.
In yet another aspect, the Pibrentasvir obtained by the process according to the present invention is in amorphous form.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of Pibrentasvir with high yield and purity.

In one embodiment, the present invention relates to an improved process for the preparation of Pibrentasvir comprising the steps of:

a) Mesylating the compound of the formula (I) [(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)-1,4-butanediol] in the presence of suitable solvent and base to obtain compound of formula (II) [(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)-1,4-butanediol, 1,4-dimethanesulfonate].

b) condensing the compound of the formula (II) with compound of formula (III) [3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]benzenamine] in presence of suitable solvent to obtain compound of formula (IV) [1-[4-[(2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)-1-pyrrolidinyl]-2,6-difluorophenyl]-4-(4-fluorophenyl)piperidine]

c) coupling of the compound of the formula (IV) with compound of formula (V) [1-Boc-L-Prolinamide] in presence of catalyst, suitable solvent and base to obtain compound of formula (VI) [(2S,2'S) 2,2'-[[(2R,5R)-1-(3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]phenyl]-2,5-pyrrolidinediyl]bis[(5-fluoro-2-nitro-4,1-phenylene) iminocarbonyl]]bis-1-pyrrolidinecarboxylic acid, 1,1'-bis(1,1-dimethylethyl)ester].

d) reducing the compound of formula (VI) in the presence of catalyst, suitable reducing agent and a solvent to obtain compound of formula (VII) [2,2'-[[(2R,5R)-1-(3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]phenyl]-2,5-pyrrolidinediyl]bis[(5-fluoro-2-amino-4,1-phenylene) iminocarbonyl]]bis-(2S,2'S)-1-pyrrolidinecarboxylic acid, 1,1'-bis(1,1-dimethylethyl)ester]

e) cyclizing the compound of formula (VII) in the presence of suitable solvent to obtain compound of formula (VIII) [-(2S,2'S) 2,2'-[[(2R,5R)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)-1piperidinyl]phenyl]-2,5-pyrrolidinediyl)bis(6-fluoro-1H-benzimidazole-5,2-diyl)]bis-1-pyrrolidinecarboxylic acid, 1,1'-bis(1,1-dimethylethyl)ester].

f) deprotecting of the compound of formula (VIII) in the presence of suitable solvent and reagent to obtain compound of formula (IX) [5,5'-[(2R,5R)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]phenyl]-2,5-pyrrolidinediyl]bis[6-fluoro-2-(2S)-2-pyrrolidinyl-1H-benzimidazole hydro chloride]

g) neutralizing the compound of formula (IX) using aqueous ammonia in presence of suitable solvent or mixture of solvents to obtain free base of compound of the formula (X)

h) reacting the compound of the formula (X) with compound of formula XI [(2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid] in presence of coupling agent and suitable solvent to obtain Pibrentasvir

According to the present invention, mesylating the compound of the formula (I) may be carried out by using methane sulfonyl chloride in presence of suitable solvent such as dichloromethane, Ethylacetate, Tetrahydrofuran, Acetonitrile, Toluene, 2-Methyl-tetrahydrofuran and suitable base Triethylamine, Di-isopropyl ethyl amine, Sodium bicarbonate, Sodium Carbonate, Potassium carbonate, to get compound of formula (II).

According to the present invention, after the reaction is completed, monitored by TLC, purified water is added to the reaction mass and maintained for about an hour followed by filtration to obtain a wet cake which is again taken into water and filtered to obtain compound of formula (II). Isolation of the compound from water enable fast filtration.

According to the present invention, compound of the formula (II) is condensed with compound of formula (III) in presence of suitable solvent such as Acetonitrile, Dimethylformamide, N-Methyl-2-pyrrolidone, Dimethylacetamide, Toluene to obtain compound of formula (IV) which is purified in Toluene.

According to the present invention, the desired isomer of compound of formula (IV) may be obtained by purifying compound (IV) in Toluene avoiding column separation of the isomers. Further the compound of formula (IV) may be isolated as a solid with good yield which was otherwise reported to be a foam in prior art methods.

According to the present invention, reacting the compound of formula (IV) with formula (V) may be carried in the presence of a catalyst such as Xantphos, BINAP, Substituted XantPhos and metal catalyst such as Palladium acetate, Tris(dibenzillideneacetone)dipalladium, Tripheylphosphine Palladium, Bis(triphenylphosphine)palladium(II)chloride, and a suitable solvent such as Toluene, Ethyl acetate, Isopropyl acetate, 1,4-dioxane, THF, 1,2 Dimethoxy ethane, Dimethyl formamide and base such as Cesium carbonate, Sodium tert-butoxide, Potassium propionate, Sodium carbonate, potassium carbonate, alkoxides of metals from Group 1 & 2 of periodic table to obtain a compound of the formula (VI) which may be purified in ethanol and acetonitrile.

According to the present invention, the desired isomer of compound of formula (VI) may be obtained by purifying compound (VI) in Ethanol and Acetonitrile avoiding column separation of the isomers. Further the compound of formula (VI) may be isolated as a solid with good yield and purity which was otherwise reported to be a foam in prior art methods.

According to the present invention, reduction of the compound of the formula (VI) may be carried in the presence of suitable catalyst such as Raney Nickel, Palladium on carbon (Pd/C), Platinum on carbon, Iron, Zinc, Tin and solvent such as Tetrahydrofuran, Methanol, Ethanol, Isopropyl alcohol or mixture thereof to obtain compound of the formula (VII) as a solid. Reduction can be carried using Sodium dithionite, Hydrose in a solvent or mixture of solvents.
According to the present invention, cyclization of the compound of the formula (VII) may be carried by treating compound (VII) with an acid such as Acetic acid in the presence of suitable solvent such as Toluene. After completion of the reaction, the solvent may be removed and the residue is taken in a solvent such as Ethyl acetate and water and neutralized with a base. The organic layer may be separated and concentrated to obtain a residue which may be dissolved in Acetonitrile and cooled to obtain compound of the formula (VIII) as a solid.

According to the present invention, deprotection of the compound of the formula (VIII) may be carried by treating compound (VIII) with acetyl chloride, in the presence of suitable solvent such as methanol, deprotection can be carried out by Hydrochloric acid, Sulphuric acid, methanesulfonyl chloride, methanesulfonic acid, PTSA in a suitable solvent or mixture of solvents. After completion of the reaction, the solvent may be removed and the residue is taken in a solvent such as ethanol. The ethanol layer may be added to di-isopropyl ether taken in another flask and the obtained solid may be filtered to obtain compound of the formula (IX) as a solid. Compound of formula (IX) may be isolated as a hydrochloride salt.

According to the present invention, reacting the compound of the formula (IX) with aqueous ammonia in the presence of solvent such as Ethyl acetate, Methanol, Dichloromethane, water or mixtures thereof to obtain compound of the formula (X) as a solid.

According to the present invention, compound of the formula (X) may be coupled with compound of the formula (XI) in the presence of coupling agents such as 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or (EDAC.HCl) and 1-Hydroxy benzotriazole (HOBt), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-Hydroxy-7-azabenzotriazole (HOAt), NMM:CDMT (2-chloro-4,6-dimethoxy-1,3,5-triazine)complex and suitable solvent such as Dichloromethane, N,N-dimethyl formamide, Ethylacetate, Dimethyl sulfoxide to obtain crude Pibrentasvir. The crude Pibrentasvir may be crystallized with n-Butylamine. The solid thus obtained may be taken in Dichloromethane and water and neutralized the solution using an acid such as acetic acid. The organic layer may be separated and concentrated to obtain a solid. The obtained solid may be slurried in Di-isopropyl ether and filtered to obtain pure Pibrentasvir in amorphous form.

The major advantage of the present invention is isolating all the intermediates in desired isomeric forms as solids without use of column chromatography which were otherwise reported as foam materials and isolated by column chromatography. The compound of formula IV obtained during reaction without base gives more yield and less formation of unwanted isomers.

The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the invention.

Experimental procedure:

Example 1: Process for the preparation of compound of formula II

Compound of formula I (250 g) was charged into methylene dichloride (2500 ml) under Nitrogen atmosphere. The reaction mixture was cooled to -10±2oC and charged Triethyl amine at -10±2oC. Slowly Methane sulfonyl chloride (164.45 g) was added at -10±2oC. Reaction mass was stirred for 30 min at -10±2oC and slowly raised the temperature to 25±3oC. Reaction mass was maintained for 30 min at 25±3oC, reaction was monitored by TLC. Added purified water (1250 ml) to the reaction mass at 25±3oC and stirred the reaction mass for 30 min at 25±3oC. Reaction mass was filtered and washed with methylene dichloride (250 ml). The obtained wet cake was taken into separate RB flask and charged purified water (1250 ml) at 25±3oC and stirred for 30 min at 25±3oC. Reaction mass was filtered and washed with purified water (250 ml). Suck dried and dried under hot air oven at 55°C for 12 hours to obtain compound of formula II.

Example 2: Process for the preparation of compound of formula IV.

Compound of formula II (400 g), Compound of formula III (825 g) and Di-isopropyl ethyl amine (435 g) were taken into Acetonitrile (2000 ml) at 25±3oC and raised the reaction mass temperature to 82±2oC. Maintained the reaction mass for 16 hours at 82±2oC. Distilled out volatiles under vacuum at below 60°C to get residue. Residue was stripped off with toluene (3x800 ml) at below 60°C. Charged Toluene (2000 ml) to the residue at below 60°C and raised the temperature to 95±5°C. Reaction mass was stirred till dissolution and then cooled to 37±2°C. Material was filtered and washed with Toluene (100 ml). The obtained wet solids taken into separate RB flask and charged Toluene at 25±3oC. Raised the temperature to 65±3°C, stirred for 60 min and cooled to 35±3°C. Material was filtered and washed with Toluene (100 ml). Wet material was dried under hot air oven at 55±3°C to obtain the compound of formula IV.

Example 3: Process for the preparation of compound of formula IV.

Compound of formula II (400 g), Compound of formula III (825 g) were taken into Acetonitrile (2000 ml) at 25±3oC and raised the reaction mass temperature to 65±5oC. Maintained the reaction mass for 72 hours at 65±5oC. Distilled out volatiles under vacuum at below 60°C to get residue. Residue was stripped off with toluene (3x800 ml) at below 60°C. Charged Toluene (2000 ml) to the residue at below 60°C and raised the temperature to 95±5°C. Reaction mass was stirred till dissolution and then cooled to 37±2°C. Material was filtered and washed with Toluene (100 ml). The obtained wet solids taken into separate RB flask and charged Toluene at 25±3oC. Raised the temperature to 65±3°C, stirred for 60 min and cooled to 35±3°C. Material was filtered and washed with Toluene (100 ml). Wet material was dried under hot air oven at 55±3°C to obtain the compound of formula IV.

Example 4: Process for the preparation compound of formula VI.

Compound of formula IV (250 g), compound of formula V (166.68 g), Xantphos (24.55 g), potassium carbonate (107.35 g) and palladium acetate (4.76 g) were charged in Toluene (2500 ml) at 25±3°C under nitrogen atmosphere. Temperature was raised to 107±3°C and maintained for 90 min. After reaction completion, reaction mass was distilled out under vacuum and residue was cooled to 35±3°C. Ethyl acetate (2500 ml) and purified water (2500 ml) was charged at 35±3°C and stirred for 30 min at 35±3oC. Organic layer was separated and washed with 10 % aqueous sodium chloride solution (3x 1250 ml). N-acetyl-L-cystine (38 g) was charged to the organic layer at 35±3°C and stirred the reaction mass for 12 hours. Aqueous sodium hydroxide solution (38 g NaOH in 1250 ml) was added to the reaction mass at 35±3°C and stirred for 2 hours. Organic layer was separated and washed with 10 % aqueous sodium chloride solution (3x 1250 ml). Organic layer was concentrated completely under vacuum at below 60°C. Residue was stripped off with Ethanol (3 x 250 ml) at below 60°C. Ethanol (1000 ml) and Acetonitrile (125 ml) was charged to the residue at below 60°C and raised the temperature to 82±3°C and maintained for 30 minutes. Reaction mass was cooled to 25±3°C and stirred for 2 hours. Material was filtered off and washed with Ethanol (2 x100 ml). Wet material was dried in hot air oven at 55°C to obtain compound of formula VI as yellow colored solid.

Example 5: Process for the preparation of compound of formula VII.

Compound of formula VI (190 g) was charged to the autoclave followed by Raney-nickel (115 g) using tetrahydrofuran (1000 ml). Applied Hydrogen pressure (2 kg/cm2) at 30±2°C and stirred the reaction mass for 6 hours at 30±2°C under hydrogen pressure (2 kg/cm2). After completion of reaction, catalyst was filtered under nitrogen atmosphere and washed bed using ethyl acetate (2x100 ml). Filtrate was distilled out completely under vacuum at below 60°C and Ethyl acetate (190 ml) was charged to the residue at below 60°C. Reaction mass was cooled to 30±5°C, Hexanes (950ml) was added to it and maintained for 60 min at 30±5°C. Material was filtered off and washed with Hexanes (100 ml). wet material was dried under hot air oven at 55°C for 12 hours to obtain Compound of formula VII as a solid.

Example 6: Process for the preparation of Compound of formula VIII

Compound of formula VII (130 g) and Acetic acid (78 g) in Toluene (1300 ml) was charged to the flask at 30±5°C. Temperature was raised to 50±2°C and stirred for 8 hours at 50±2. After completion of reaction, distilled out solvent completely under vacuum at below 60°C. Cooled the residue to 30 ± 5°C and Charged Ethyl acetate (1300 ml) and water (750 ml). pH of the reaction mass was adjusted to 7-7.5 using 7% aqueous sodium bi carbonate solution (650 ml). Organic layer was separated and washed with 10% aqueous sodium chloride solution (2 x 650 ml). Organic layer was distilled out completely under vacuum at below 60°C. Residue was stripped off with Acetonitrile (2 x130 ml) at below 60°C under vacuum. Charged Acetonitrile (650 ml) to the residue at below 60°C and raised the temperature to 75±3°C and stirred for 60 min. Cooled the reaction mass to 30±5°C and stirred for 60 min. Material was filtered and washed with Acetonitrile (2x60 ml). Wet material was dried under vacuum oven at 50°C for 12 hours to obtain Compound of formula VIII as a yellow color solid.

Example 7: Process for the preparation of compound of formula IX.

Charged methanol (800 ml) into a RB flask and cooled to -10±2°C. Added acetyl chloride slowly at -10±2°C followed by compound of formula VIII (80 g) at -10±2°C. Stirred the reaction mass for 30 min at -10±2°C and raised the reaction mass temperature to 30±2°C. Reaction mass was stirred for 4 hours at 30±2°C. After reaction completion, reaction mass was concentrated under vacuum at below 50°C and stripped off with Ethanol (2 x 80 ml). Ethanol (160 ml) was charged to residue at below 50°C and cooled to 30±2°C. In another flask Di-isopropyl ether (800 ml) was taken and above Ethanol solution was added at 30±2°C. Stirred the reaction mass for 120 min at 30±2°C and filtered. Bed washed with Di-isopropyl ether (2x40 ml). suck dried solids till ML’s expelled out completely and dried under vacuum oven at 45°C for 12 hours to obtain compound of formula IX as off-white solid.
Deprotection in CAN HCl
Example 8: Process for the preparation of compound of formula X.

Compound of formula IX (70 g) was charged into purified water (350 ml) at 30±2°C and stirred till dissolution is observed. Methylene dichloride and Methanol mixture (560 ml :140 ml) was charged to it. 25% Aqueous ammonia solution (53 g) at 30±2°C was charged to it and stirred for 60 min at 30±2°C. Organic layer was separated and washed with water (70 ml). Distilled out Organic layer completely under vacuum at below 50°C and Di-isopropyl ether (350ml) was charged to the residue at below 50°C and cooled the reaction mass to 30±2°C. Stirred the reaction mass for 2 hours at 30±2°C and filtered off. washed the bed with Di-isopropyl ether (70 ml) and suck dried. Wet material was dried under vacuum oven at at 50°C for 12 hours to obtain compound of formula X as off white colored solid.

Example 9: Process for the preparation of Pibrentasvir amorphous.

Charged EDAC.HCl (55 g,) and 1-Hydroxy Benzotriazole monohydrate (44 g) in Methylene dichloride (550 ml) at 27±8°C. Stirred the reaction mass for 15 min at 30±2°C. Cooled the reaction mass to -10±2°C. Charged compound of formula XI (i.e. N-Moc-O-methyl-L-Threonine, 55 g) at -10±2°C. Stirred the reaction mass for 60 min at -10±2°C. Compound of formula X (55 g) was added lot wise at -10±2°C in 60 min. Stirred the reaction mass for 60 min at -10±2°C and raised the reaction mass temperature to 27±3°C. Stirred the reaction mass for 5 hours at 27±3°C, charged purified water (33 ml) to the reaction mass at 27±3°C and stirred the reaction mass for 15 hours at 27±3°C. pH of reaction mass was adjusted to 5.0 – 5.5 by adding 25% aqueous di potassium hydrogen phosphate solution. Organic layer was separated and washed with 8% aqueous di potassium hydrogen phosphate solution (2 x550 ml). Organic layer was washed with water (550 ml). Organic layer was distilled out completely under vacuum at below 50°C. n-butyl amine (165 ml) was charged to it at 27±3°C and stirred for 12 hours. filtered and washed bed using n-butyl amine (25 ml) and Di-isopropyl ether (55 ml). Obtained wet solids charged into separate RB flask. Charged n-butyl amine (180 ml) at 27±3°C and stirred the reaction mass for 12 hours at 27±3°C. Filtered reaction mass and washed bed using n-butyl amine (25 ml) and Di-isopropyl ether (50 ml). Suck dried solids till ML’s expelled out completely under vacuum. Obtained wet solid was taken into separate RB flask and charged Methylene dichloride (250 ml) along with purified water (550 ml) at 27±3°C and stirred for 12 hours. Organic layer was separated and charged water (265ml) to the Organic layer and pH adjusted to 7.0 -7.5 using acetic acid. Stirred the reaction mass for 30 min. Separated both the organic and aqueous layer. Organic layer was concentrated under vacuum at below 50°C. Di- isopropyl ether (100 ml) was charged to the above solids and stirred the reaction mass for 60 min at 27±3°C. Filtered the solids and washed with Di-isopropyl ether (25 ml). Suck dried the solids till ML’s expelled out completely. Filtered solid material was dried under vacuum oven at 55°C for 24 hours to obtain Pibrentasvir as amorphous solid.

,CLAIMS:1. An improved and industrially viable process for the preparation of high pure Pibrentasvir by isolation of pure intermediates.

2. The process as claimed in claim 1, wherein process for the preparation of Pibrentasvir comprises the steps of:
a) Mesylating the compound of the formula (I) [(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)-1,4-butanediol] in the presence of suitable solvent and base to obtain compound of formula (II) [(1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)-1,4-butanediol, 1,4-dimethanesulfonate].

b) condensing the compound of the formula (II) with compound of formula (III) [3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]benzenamine] in presence of suitable solvent and an optional base to obtain compound of formula (IV) [1-[4-[(2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)-1-pyrrolidinyl]-2,6-difluorophenyl]-4-(4-fluorophenyl)piperidine]

c) coupling of the compound of the formula (IV) with compound of formula (V) [1-Boc-L-Prolinamide] in presence of a catalyst, suitable solvent and base to obtain compound of formula (VI) [(2S,2'S) 2,2'-[[(2R,5R)-1-(3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]phenyl]-2,5-pyrrolidinediyl]bis[(5-fluoro-2-nitro-4,1-phenylene) iminocarbonyl]]bis-1-pyrrolidinecarboxylic acid, 1,1'-bis(1,1-dimethylethyl)ester].

d) reducing the compound of formula (VI) in the presence of catalyst, suitable reducing agent and a solvent to obtain compound of formula (VII) [2,2'-[[(2R,5R)-1-(3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]phenyl]-2,5-pyrrolidinediyl]bis[(5-fluoro-2-amino-4,1-phenylene) iminocarbonyl]]bis-(2S,2'S)-1-pyrrolidinecarboxylic acid, 1,1'-bis(1,1-dimethylethyl)ester]

e) cyclizing the compound of formula (VII) in the presence of suitable solvent to obtain compound of formula (VIII) [-(2S,2'S) 2,2'-[[(2R,5R)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)-1piperidinyl]phenyl]-2,5-pyrrolidinediyl)bis(6-fluoro-1H-benzimidazole-5,2-diyl)]bis-1-pyrrolidinecarboxylic acid, 1,1'-bis(1,1-dimethylethyl)ester].

f) deprotecting of the compound of formula (VIII) in the presence of suitable solvent and reagent to obtain compound of formula (IX) [5,5'-[(2R,5R)-1-[3,5-difluoro-4-[4-(4-fluorophenyl)-1-piperidinyl]phenyl]-2,5-pyrrolidinediyl]bis[6-fluoro-2-(2S)-2-pyrrolidinyl-1H-benzimidazole hydro chloride]

g) neutralizing the compound of formula (IX) using aqueous ammonia in presence of suitable solvent or mixture of solvents to obtain free base of compound of the formula (X)

h) reacting the compound of the formula (X) with compound of formula XI [(2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid] in presence of a coupling agent and suitable solvent to obtain Pibrentasvir

which can be recrystallized to obtain the pure Pibrentasvir compound.

3. The process as claimed in claim 2, wherein the catalyst in step (c) is selected from Xantphos, BINAP, Substituted XantPhos and metal catalyst such as Palladium acetate, Tris(dibenzillideneacetone)dipalladium, Tripheylphosphine Palladium, Bis(triphenylphosphine)palladium(II)chloride; solvents is selected from toluene, ethyl acetate, Isopropyl acetate, 1,4-dioxane, THF, 1,2 dimethoxy ethane, dimethyl formamide, acetonitrile and the like preferably toluene; base is selected from Cesium carbonate, Sodium tert-butoxide, Potassium propionate, Sodium carbonate, potassium carbonate and the like preferably Cesium carbonate.

4. The process as claimed in claim 2, wherein the deprotection in step (f) is carried out using acetyl chloride, hydrochloric acid, sulphuric acid, methanesulfonyl chloride, methane sulfonic acid, para tolu sulfonic acid in the presence of suitable solvent such as methanol or acetonitrile.

5. The process as claimed in claim 2, wherein the intermediates at each step are isolated as solids in their isomeric forms.

6. The isolation as claimed in claim 1 and 2, the obtained intermediates of compound of the formula (II) isolated from water; compound of formula (IV) isolated from Toluene; compound of formula (VI) isolated from ethanol and acetonitrile; compound of the formula (VIII) isolated from Acetonitrile and compound of the formula (IX) isolated from ethanol and di-isopropyl ether.

7. The pure Pibrentasvir as claimed in claim 1 is isolated as amorphous form.