DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202041008564 filed on February 28, 2020.
FIELD OF THE INVENTION

The present invention relates to a process for the preparation of pure Pibrentasvir.
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

The process developed by the present inventors is cost effective, easy to handle and produce pure Pibrentasvir in good yield and purity.

FIELD OF THE INVENTION
The main object of the present invention is to provide a cost-effective process for the preparation of pure Pibrentasvir.

SUMMARY OF THE INVENTION

The Main aspect of the present invention is to provide a process for the preparation of pure Pibrentasvir comprising the steps of:
a) treating Pibrentasvir with an organic solvent, and
b) isolating pure Pibrentasvir.

Another aspect of the present invention is to provide a process for the preparation of Pibrentasvir as shown in scheme below.

In one aspect, the present invention is to provide a process for the preparation of Pibrentasvir wherein the Di-Boc-Benzimidazole is de-protected and in-situ reacted with O-Methyl-N-moc-L-Threonine to give pure Pibrentasvir.

In yet one aspect, the present invention is to provide a process for the preparation of Pibrentasvir wherein the Di-Boc-Benzimidazole is de-protected and then reacted with O-Methyl-N-moc-L-Threonine to give pure Pibrentasvir.

In yet another aspect, the present invention is to provide a process for the preparation of Pibrentasvir with or without using Hydroxybenzotriazole.

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

In one embodiment, the present invention relates to a process for the preparation of pure Pibrentasvir comprising the steps of:
a) treating Pibrentasvir with an organic solvent, and
b) isolating pure Pibrentasvir

According to the present invention, Pibrentasvir may be treated with an organic solvent selected from isopropyl ether or diethyl ether and filtered to obtain pure Pibrentasvir.

In another embodiment, the present invention relates to a process for the preparation of Pibrentasvir as shown in scheme below.

In yet another embodiment, the present invention relates a process for the preparation of Pibrentasvir wherein the Di-Boc-Benzimidazole is de-protected and in-situ reacted with O-Methyl-N-moc-L-Threonine to give Pibrentasvir.

In yet another embodiment, the present invention relates to a process for the preparation of Pibrentasvir wherein the Di-Boc-Benzimidazole is de-protected and then reacted with O-Methyl-N-moc-L-Threonine to give Pibrentasvir.

In yet another embodiment, the present invention relates to a process for the preparation of Pibrentasvir with or without using Hydroxybenzotriazole.

In yet another embodiment, the present invention relates to a process for the preparation of Pibrentasvir with or without using dipotassium hydrogen phosphate.

In yet one embodiment, the present invention relates to a process for the preparation of Pibrentasvir comprising the steps of:
a. deprotecting the di-Boc-Benzimidazole,
b. adding O-Methyl-N-moc-L-Threonine,
c. isolating Pibrentasvir

According to the present invention, Di-Boc-Benzimidazole may be taken in a solvent such as methylene dichloride, cooled to about 8°C and added hydrochloric acid followed by addition of water and methanol. The reaction mixture may be maintained at reflux temperature till completion of the reaction and the layers may be separated. The benzimidazole in aqueous layer may be preserved.

Separately, N-Moc-O-Methyl-L-threonine, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl), and hydroxy benzotriazole may be taken in methylene dichloride, cooled to about 15°C and maintained for about 5 to 6 hours followed by further cooling to about 8°C. To this reaction mixture, dipotassium hydrogen phosphate aqueous solution may be added. The above prepared and preserved aqueous layer of benzimidazole solution may be slowly added to this reaction mass and raised the temperature to about 30 to 35°C. Layers may be separated, and the organic layer may be distilled out completely under vacuum. Mixture of n-butylamine and methyl tertiary butyl ether may be added to the reaction mass and maintained for about 14 hrs. The obtained slurry may be filtered and washed with methyl tertiary butyl ether and dried.

The dried solid may be dissolved in methylene dichloride and added water. The reaction mass may be maintained at about 20 to 30°C for about 30-45 minutes and organic layer may be separated and washed with aqueous acetic acid and water. The organic layer may be optionally washed with dipotassium hydrogen phosphate and water and concentrated under vacuum and the obtained residue may be treated with Isopropyl ether to obtain Pibrentasvir with 99.7% purity.

According to the present invention, the treatment with Isopropyl ether involves addition of isopropyl ether to the residue and the reaction mixture was maintained for about 24 hours at 45±2°C, followed by cooling to about 25±3°C. The solid obtained may be filtered and washed with Isopropyl ether to obtain crystalline Pibrentasvir.

According to the present invention, the treatment with Isopropyl ether involves addition of isopropyl ether to the residue and the reaction mixture was maintained for an hour at 25±3°C. The solid obtained may be filtered, washed with Isopropyl ether and dried under vacuum at 50°C to obtain amorphous form of Pibrentasvir.

In yet another embodiment, the preparation of Pibrentasvir from benzimidazole base is represented in the scheme below:

According to the present invention, benzimidazole base may be taken in methylene dichloride and cooled to -15±2°C. To this reaction mass, N-Moc-O-Methyl-L-threonine taken in methylene dichloride may be added and the reaction mass may be maintained at about-15±3°C. To this reaction mixture, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) may be added at about -15±3°C and stirred for an hour. Temperature of the reaction mass may be raised to 25°C and added aqueous solution of dipotassium hydrogen phosphate. Layers may be separated, and the organic layer may be distilled out completely under vacuum. To this reaction mass, mixture of n-butylamine and methyl tertiary butyl ether may be added and maintained for about an hour. The obtained slurry may be filtered and dried.

The dried solid may added with water and maintained at about 25±3°C for about 5-10 minutes. To this slurry, aqueous acetic acid may be added and maintained about an hour. The resultant solid may be filtered and washed with water and dried under vacuum to obtain Pibrentasvir.

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: Preparation of Pibrentasvir in single stage from Di-Boc-Benzimidazole.
In a RB flask Di-Boc-Benzimidazole (20.0g) and Methylene dichloride (100 ml) are added and the clear solution is cooled to 5±3°C. 21g of HCl is added followed by 8 ml water and 8 ml methanol. Reaction mass is stirred at reflux temperature for 6 hours and cooled to 25°C, layers are separated and Benzimidazole solution of aqueous layer is preserved. Simultaneously when the deprotection is started, in another flask, N-Moc-O-Methyl-L-threonine (12g), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) (12g) and hydroxy benzotriazole (9.5g) is charged along with Methylene dichloride (180ml), cooled to 15°C and stirred for 5 hours. It is further cooled to 5±3°C and Dipotassium hydrogen phosphate aqueous solution (45g in 225 ml water) is added to it at 5-8°C. Preserved aqueous layer of Benzimidazole solution is slowly added to the reaction mass and raised the temperature to 32°C. Reaction mass is stirred for 6-8 hrs and cooled to 25°C. Layers are separated and Organic layer is washed twice with water (2 x 40ml). Organic layer is distilled out completely under vacuum. Mixture of n-Butylamine (40ml) and MTBE (200ml) is charged to the reaction mass and stirred for 14 hrs. slurry is filtered and washed with MTBE (40ml). On drying at 50-55°C, 22.4g material is obtained. Obtained solid is dissolved in Methylene dichloride (100ml) and water (100ml) is charged to it. Reaction mass is stirred at 25±3°C for 30-45 minutes and Organic layer is separated followed by aqueous acetic acid washings (0.21g in 100ml water) and water (100ml). Organic layer is concentrated under vacuum and residue is treated with Isopropyl ether (100ml) to obtain Pibrentasvir with 99.7% purity.

Example 2: Preparation of Pibrentasvir without using HOBT catalyst.
In a RF flask Benzimidazole base (3g) and Methylene dichloride (60ml) are added and cooled to -15±2°C. N-Moc-O-Methyl-L-threonine (2.99g) is dissolved in Methylene dichloride (20ml) and charged to the above reaction mass at -15±3°C and stirred for 10-15 minutes. EDC-HCl (2.99g) is charged to the reaction mass at -15±3°C and stirred for 60 minutes. Temperature is raised to 25°C and Dipotassium hydrogen phosphate aqueous solution (3g in 45 ml water) is charged to the reaction mass and stirred for 15 minutes. Layers are separated and Organic layer is washed twice with water (2 x 20ml). Organic layer is distilled out completely under vacuum. Mixture of n-Butylamine (10ml) and MTBE (40ml) is charged to the reaction mass and stirred for 1 hr. Slurry is filtered and washed with MTBE (10ml). On drying at 50-55°C, 3.8g material is obtained. Obtained solid (2g) is charged to the flask along with water (20ml) and stirred at 25±3°C for 5-10 minutes. Aqueous acetic acid (0.2g in 2 ml water) is added to the slurry and stirred for 1 hour. It is then filtered off and washed with water (20ml) and dried under vacuum to obtain 1.87 g of Pibrentasvir with 99.48% purity.

Example 3: Preparation of Crystalline Pibrentasvir from Di-Boc-Benzimidazole.
In a RB flask Di-Boc-Benzimidazole (60.0g), Methylene dichloride (300 ml), 24 ml of water and 24 ml of methanol were added and the clear solution is cooled to 10±2°C. 60 g of HCl is added. Reaction mass is stirred at reflux temperature for 6 hours and cooled to 25°C, layers are separated, and aqueous layer is preserved. Simultaneously, in another flask, N-Moc-O-Methyl-L-threonine (36g) and methylene dichloride (1200 ml) are charged and cooled to 2±3°C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) (36g) and hydroxy benzotriazole (28.5g) is charged and stirred for 2.5 hours at 2±3°C. Dipotassium hydrogen phosphate aqueous solution (108g in 900 ml water) is added to it by maintaining temperature 2±3°C. Preserved aqueous layer is slowly added to the reaction mass and raised the temperature to 27±3°C. Reaction mass is stirred for 4 hrs. Layers are separated and Organic layer is washed with Dipotassium hydrogen phosphate solution (54 g in 600 ml water). Organic layer is washed with water (300 ml) followed by sodium chloride solution (30 g in 300 ml water). Organic layer is distilled out completely under vacuum. Mixture of n-Butylamine (180ml) and MTBE (600ml) is charged to the reaction mass and stirred for 12 hrs. slurry is filtered and washed with MTBE (3x60ml) and suck dried properly. Obtained wet solid is dissolved in Methylene dichloride (300ml) and water (300ml) is charged to it. Reaction mass is stirred at 25±3°C for 10-15 minutes. pH of reaction mass is adjusted to 5±0.3 with acetic acid (~17.5g Acetic acid). Reaction mass is stirred for 30 minutes and layers separated. Organic layer is washed with Dipotassium hydrogen phosphate solution (15g in 300 ml water) followed by water (300 ml). Organic layer is concentrated under vacuum and Isopropyl ether (600 ml) is charged to the residue and stirred for 24 hrs at 45±2°C. Cooled the reaction mass to 25±3°C and stirred for 1 hour, filtered and washed with Isopropyl ether to obtain crystalline Pibrentasvir with 99.6% purity.

Example 4: Preparation of Amorphous Pibrentasvir from Di-Boc-Benzimidazole.
In RB flask Di-Boc-Benzimidazole (10.0g), Methylene dichloride (50 ml), 4 ml of water and 4 ml of methanol were added, and the clear solution is cooled to 10±2°C. 10 g of Hydrochloric acid is added to it. Reaction mass is stirred at reflux temperature for 6 hours and cooled to 25°C, layers are separated and Benzimidazole solution of aqueous layer is preserved. Simultaneously, in another flask, N-Moc-O-Methyl-L-threonine (6.0g) and methylene dichloride (200 ml) are charged and cooled to 2±2°C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) (6.0g) and hydroxy benzotriazole (4.75g) is charged and stirred for 2.5 hours. Dipotassium hydrogen phosphate aqueous solution (18g in 150 ml water) is added to it at 2±2°C and preserved aqueous layer of Benzimidazole solution is added to the reaction mass and raised the temperature to 27±3°C. Reaction mass is stirred for 4 hours. Layers are separated and organic layer is washed with Dipotassium hydrogen phosphate solution (9 g in 100 ml water). Organic layer is washed with water (50 ml) followed by sodium chloride solution (5 g in 50 ml water). Organic layer is distilled out completely under vacuum. Mixture of n-Butylamine (30ml) and MTBE (100ml) is charged to the reaction mass and stirred for 12 hours. Reaction slurry is filtered and washed with MTBE (3x10ml). Obtained wet solid is dissolved in Methylene dichloride (50ml), water (50ml) is charged to it. Reaction mass is stirred at 25±3°C for 10-15 minutes. pH of the reaction mass is adjusted to 5±0.3 with acetic acid (~2.0g Acetic acid). Reaction mass is stirred for 30 minutes and layers are separated. Organic layer is washed with Dipotassium hydrogen phosphate solution (2.5g in 50ml water) followed by water (50 ml). Organic layer is concentrated under vacuum and Isopropyl ether (50 ml) charged to the residue and stirred the reaction mass at 25±3°C for 1 hour and filtered followed by washing with Isopropyl ether. The wet material is duck dried properly and then dried under vacuum oven at 50°C to obtain Amorphous form of Pibrentasvir with 99.67% purity.
,CLAIMS:A process for the preparation of pure Pibrentasvir comprising the steps of:
a) treating Pibrentasvir with an organic solvent, and
b) isolating pure Pibrentasvir

2. The process as claimed in claim 1, wherein the organic solvent is selected from the isopropyl ether or diethyl ether

3. The process as claimed in claim 2, wherein the organic solvent is isopropyl ether.

4. The process as claimed in claim 1, wherein the isolation is by filtration.

5.The Pibrentasvir as claimed in claim 1, is prepared comprising the steps of:
a) deprotecting di-Boc-Benzimidazole,
b) optionally isolating deprotected benzimidazole,
c) adding O-Methyl-N-moc-L-Threonine, and
d) isolating Pibrentasvir

6. The process as claimed in claim 5, wherein the deprotection is carried out using an acid selected from hydrochloric acid, sulphuric acid, methanesulfonyl chloride, methane sulfonic acid, para toluene sulfonic acid in presence of suitable solvent selected from methylene dichloride, methanol, water, acetonitrile or mixtures thereof.

7. The process as claimed in claim 5, further comprises addition of a coupling agent selected from 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC.HCl), N,N-Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide(DIC), carbonyldiimidizole(CDI) using an organic solvent selected from methylene dichloride or THF.

8. The process as claimed in claim 5, further comprises addition of hydroxy benzotriazole.

9. The process as claimed in claim 5, further comprises addition of dipotassium hydrogen phosphate.

10. The process as claimed in claim 5, wherein the isolation is by distillation.