PRIORITY
This application claims the benefit under Indian Provisional Application No. 201641011580 filed on 01 Apr, 2016 entitled "An improved process for the preparation of Velpatasvir", the contents of which is incorporated by reference herein.
FIELD OF THE INVENTION
The present invention generally relates to an improved process for preparation of velpatasvir or a pharmaceutically acceptable salt thereof of Formula I.
BACKGROUND OF THE INVENTION
Velpatasvir is chemically known as methyl {(2S)-l-[(2S,5S)-2-(9-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino- ]-2-phenylacety 1}-4-(methoxymethyl)pyrrolidin-2-yl]-lH-imidazol-5-yl}-l,ll-dihydroisochromeno[4',3':6,7]naphtho[l,2-d] imidazol -2-yl)-5-methylpyrroIi-din-l-yl]-3-methyI-l-oxobutan-2-yl}carbamate; represented by the following structure: H3co
H3CO—" OCH3
Velpatasvir (Formula I)
Velpatasvir is an investigational pan-genotypic NS5A inhibitor and presently under clinical trials in combination with nucleotide analog polymerase inhibitor sofosbuvir (SOF), approved as Sovaldi , for the treatment of chronic genotype 1-6 hepatitis C virus (HCV) infection.
U.S. Patent No (s). 8940718 ("the '718 patent"), 8575135 ("the '135 patent") and 8921341 ("the '341 patent") discloses new HCV therapeutic agents such as velpatasvir and its processes for preparation. The process disclosed in the '718 patent is schematically represented as follows:

The process disclosed in the '718 patent involves isolation of velpatasvir by involving tedious chromatographic purification by HPLC and isolated by lyophilization to obtain trifluoroacetate salt of velpatasvir. The obtained TFA salt was basified with saturated NaHCC>3 in ethylacetate and concentrated the organic phase to obtain velpatasvir free base. Then the free base was dissolved in acetonitrile/water and Iyophilizes to afford velpatasvir.
PCT publication No. 2015/191437 ("the '437 publication") discloses a process for preparation of velpatasvir. The process disclosed in the '437 publication is schematically represented as follows:

The process disclosed in the '437 publication involves use of expensive coupling reagent like F26-CDMT, which is commercially not readily available and highly expensive reagent. Also the process disclosed in the '437 publication does not discloses yields and purities in all stages including intermediates.
Further, CN patent publications (s) CN105294713A, CN105712969A, CN105732563A and CN105732765A discloses various processes for preparation of velpatasvir and its intermediates.
There is a need in the art to develop an improved process for the preparation of velpatasvir or a pharmaceutically acceptable salt thereof, which is readily amenable on large scale production.
The present invention provides an improved process for the preparation of velpatasvir or a pharmaceutically acceptable salt thereof with greater yield and high purity by using inexpensive reagents.
SUMMARY OF THE INVENTION
In accordance with one embodiment, the present invention provides an improved process for the preparation of velpatasvir or a pharmaceutically acceptable salt thereof of Formula I:

Formula I comprising: coupling a compound of Formula III or a salt thereof with a compound of Formula IV in presence of a suitable coupling agent and a suitable base to obtain velpatasvir or a pharmaceutical^ acceptable salt thereof; wherein the coupling agent is selected from the group comprising: 2-chIoro-4,6-dimethoxy-l,3,5-triazine (CDMT), Carbonyldiimidazole (CDI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-Aza-lH-benzotriazoM-yl)- N,N,N',N'-tetramethylaminium hexafluorophosphate) (HATU) and 2-(lH-Benzotriazol-l-yl) - N,N,N\NMetramemylaminium tetrafluoro borate (TBTU).
In accordance with another embodiment, the present invention provides an improved process for the preparation of velpatasvir, comprising:
a) coupling a compound of Formula III or a salt thereof with a compound of Formula IV in presence of a suitable coupling agent, suitable base and suitable solvent to obtain velpatasvir,
b) isolating the velpatasvir as phosphate salt,
c) neutralizing the velpatasvir phosphate salt in presence of a suitable base, water
. and water immiscible organic solvent selected from the group comprising
halogenated hydrocarbons, ethers, aromatic hydrocarbons, aliphatic hydrocarbons and alicyclic hydrocarbons,
d) separating the water immiscible organic layer and concentrating the solvent to obtain a residue,
e) dissolving the residue in an organic solvent to obtain a solution,
f) adding anti-solvent to the step e) solution or vice-versa, and
g) isolating the velpatasvir.

In accordance with another embodiment, the present invention provides an improved process for the preparation of velpatasvir or a pharmaceutically acceptable salt thereof of Formula I, comprising:
a) coupling a compound of Formula III or a salt thereof with a compound of Formula rV in presence of a suitable coupling agent and a suitable base to obtain velpatasvir or a pharmaceutical ly acceptable salt thereof; wherein the coupling agent is selected from the. group comprising 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), Carbonyldiimidazole (CDI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluoro phosphate (PyBOP), benzotriazol-1-yloxy-tris (dimethyl amino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-Aza-lH-benzotriazol-1-yl)- N,N,N',N'-tetramethylaminium hexafluorophosphate) (HATU) and 2-(lH-Benzotriazol-l-yl) - N,N,N',N'- tetramethylaminium tetrafluoroborate (TBTU),
b) isolating the velpatasvir as an intermediate salt, and
c) neutralizing the velpatasvir salt in presence of methylene chloride, water and sodium bicarbonate to obtain velpatasvir.
In accordance another embodiment, the present invention provides an improved process for the preparation of velpatasvir, comprising:
a) coupling a compound of Formula III or a salt thereof with a compound of Formula IV in presence of 2-Chloro-4,6-dimethoxy-l,3,5-triazine (CDMT) and N-methyl morpholine to obtain velpatasvir,
b) isolating the velpatasvir as phosphate salt,
c) neutralizing the velpatasvir phosphate salt in presence of methylene chloride, water and sodium bicarbonate,
d) separating the methylene chloride layer and concentrating the solvent to obtain a residue,
e) dissolving the residue in an organic solvent to obtain a solution, '
f) adding anti-solvent to the step e) solution or vice-versa, and
g) isolating the velpatasvir.
In accordance another embodiment, the present invention provides a process for the preparation of amorphous form of velpatasvir, comprising:
a) dissolving velpatasvir in an organic solvent to obtain a solution,
b) adding anti-solvent to the step a) solution or vice-versa, and
c) isolating the amorphous velpatasvir.

wherein the organic solvent is selected from the group comprising: alcohols selected from methanol, ethanol, n-propanol, isopropanol; esters selected from methyl acetate, ethyl acetate, isopropyl acetate and mixture thereof; and the anti-solvent is selected from the group comprising: ethers selected from tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane; aliphatic hydrocarbons selected from hexane, heptane, propane; alicyclic hydrocarbons selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane; water and mixture thereof.
In accordance with another embodiment, the present invention provides a velpatasvir or a pharmaceutical^ acceptable salt thereof obtained by the process described herein, having a purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC.
In accordance with another embodiment, the present invention provides an amorphous Form of velpatasvir characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1.
In accordance with another embodiment, the present invention provides an amorphous Form of velpatasvir characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.
In accordance with another embodiment, the present invention provides an amorphous Form of velpatasvir characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.
In accordance with another embodiment, the present invention provides a pharmaceutical composition, comprising velpatasvir of Formula I prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous velpatasvir prepared according to ExampIe-3.

Figure 2 is the characteristic Differential scanning calorimetry (DSC) thermogram of amorphous velpatasvir prepared according to Example-3.
Figure 3 is the characteristic Thermogravimetric analysis (TGA) of amorphous velpatasvir prepared according to Exampte-3.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of velpatasvir of Formula I with greater yield and high purity by using inexpensive reagents.
In accordance with one embodiment, the present invention provides an improved process for the preparation of velpatasvir or a pharmaceutically acceptable salt thereof of Formula I:
H3CO
V-^ V-1 HN^O
HjCO--" OCH3
Formula I comprising: coupling a compound of Formula III or a salt thereof with a compound of Formula IV in presence of a suitable coupling agent and a suitable base to obtain velpatasvir or a pharmaceutically acceptable salt thereof; wherein the coupling agent is selected from the group comprising: 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), Carbonyldiimidazole (CDI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), benzotriazol-l-yloxy-tris (dimetnylamino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-Aza-1 H-benzotriazol-1 -yl)- N,N,N' ,N' -tetramethylaminium hexafluorophosphate) (HATU) and 2-(lH-Benzotriazol-l-yl) - N3N,N',N'-tetramethylaminium tetrafluoroborate (TBTU).

The starting materials of compound of Formula III and Formula rv are known in the art and can be prepared by any known method, for example compound of Formula II may be synthesized as disclosed in US Patent No. 8940718 or PCT publication No. 2015/191437 or may be by the process described in the present application, and compound of Formula IV is known in the art and may be available from commercial source.
Unless otherwise specified the term "pharmaceutical acceptable salts" include acid addition salts formed with inorganic acids or with organic acids. The inorganic acids may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, and the like; organic acids may be selected from acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid and the like.
Unless otherwise specified the term 'PC represents a suitable amine protecting group, includes but is not limited to carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenyImethyloxycarbonyl (FMOC), acetyl, benzoyl (Bz), benzyl (Bn), a carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), a succinimide, tosyl (Ts), and other sulfonamides such as Nosyl; preferably the amine protecting group is tert-butyloxycarbonyl.
The starting compound of Formula III of the present invention may be prepared from the compound of Formula II by deprotecting a compound of Formula II, wherein 'PG' represents a suitable amine protecting group as process described in the. following embodiment.
MeO"^ O
Formula II
In another embodiment, the present invention provides a process for the preparation of compound of Formula III, comprising; deprotecting a compound of Formula II in presence of a suitable deprotecting agent to obtain a compound of Formula III or a salt thereof, wherein 'PG' represents a suitable amine protecting group; preferably tert-butyloxycarbonyl.

In a preferred embodiment the compound of Formula II can be specifically represented as follows:
Formula II
The suitable deprotecting agent for deprotection of amine protecting group of compound of Formula II includes, but is not limited to hydrochloric acid, hydrochloric acid is generated from acetyl chloride, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichJoro acetic acid, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, 4-bromo benzenesulfonic acid, thionyl chloride, p-toluenesulfonic acid, trimethylsilyl chloride and the like and mixture thereof; preferably hydrochloric acid is generated from acetyl chloride.
The source of acid may be in the form of an aqueous, anhydrous or gas form, for example aqueous hydrochloric acid or solvent containing hydrochloric acid or hydrochloric acid gas,
The deprotection of amine protecting group of compound of Formula II may be carried out in a suitable solvent. The suitable solvent includes, but is not limited to alcohols, ketones, nitriles, ethers, halogenated hydrocarbons, and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but arc not limited to acetonitrile, propionitrile, benzonitrile and the like; ethers include, but are not limited to tetrahydrofuran, 2-methyI tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; preferably methanol, ethanol, acetone, tetrahydrofuran and methylene chloride; more preferably methanol.
The deprotection of Formula II is carried out at a temperature of about 25°C to reflux temperature; preferably at below 70°C.
After completion of the deprotection reaction, reaction mass may be neutralized with a suitable base and then the compound of Formula HI may by isolated as its acid addition salt by adding a suitable acid.

The suitable base for neutralizing the reaction mass includes, but is not limited to inorganic bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, pyridine and the like and mixtures thereof; preferably sodium methoxide.
The suitable acid for isolating the compound of Formula III as its acid addition salt includes, but is not limited to hydrochloric acid, hydrobromic acid, trifluoro acetic acid, sulfuric acid, ethane sulfonic acid, benzenesulfonic acid, 4-bromo benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid and the like; preferably phosphoric acid.
The acid addition salt of compound of Formula III may be isolated by optionally adding seed crystals to the reaction soltuon to initiate the salt crystallization; preferably the acid addition salt of compound of Formula III may be isolated by with out adding any seed to the reaction mass.
, The resultant compound of Formula III or a salt thereof by the processes described above can be used for the preparation of velpatasvir.
In another embodiment, the present invention provides an improved process for the preparation of velpatasvir or a pharmaceutically acceptable salt thereof of Formula I, comprising: coupling a compound of Formula III or a salt thereof with a compound of Formula IV in presence of a suitable coupling agent and a suitable base to obtain velpatasvir or a pharmaceutically acceptable salt thereof; wherein the coupling agent is selected from the group comprising: 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), Carbonyldiimidazole (CDI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol-1-yl-oxytripyrrolidmo phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-Aza-lH-benzotriazoI-1-yl)- N,N,N^NMetramethylamiruum hexafluorophosphate) (HATU) and 2-(lH-Benzotriazol-l-yl) - N,N,N',N'- tetramethylaminium tetrafluoroborate (TBTU); preferably 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT),

The process disclosed in the '437 publication for coupling the compound of Formula III with a compound of Formula IV involve use of coupling reagent like F26-CDMT, which is commercially not readily available and highly expensive reagent. To overcome the difficulties associated with the processes described in the prior-art, the inventors of the present invention have replaced inexpensive and readily available coupling reagent for the coupling of compound of Formula III or a salt thereof with a compound of Formula IV.
Optionally,, prior to coupling step the compound of Formula III may be neutralized with a suitable base in a suitable solvent at a temperature of about 0°C to reflux temperature; preferably at below 30°C. The suitable base herein used includes, but is not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixture thereof; preferably ammonium hydroxide. The suitable solvent used herein, includes but is not limited halogenated hydrocarbons, aromatic hydrocarbons, esters, water and mixtures thereof. The halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; esters include, but are not limited to ethyl acetate, isopropyl acetate and the like; water and mixture thereof; preferably a mixture of methylene chloride and water.
After completion of neutralization, the free base of compound of Formula III may be isolated by separating the organic and aqueous layers and followed by concentrating the organic layer under vacuum to obtain free base of compound of Formula III as a solid. The obtained free base solid may be used for the coupling step.
The suitable coupling agent for coupling of compound of Formula III with a
compound of Formula IV includes, but is not limited to 2-chloro-4,6-dimethoxy-
1,3,5-triazine (CDMT), Carbonyldiimidazole (CDI), N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic
acid cyclic anhydride (PPA), benzotriazol-1-yl-oxytripyrrolidino phosphonium
hexafluorophosphate (PyBOP), benzotriazol-1-yloxy-tris (dimethylamino)-
phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-
Aza-1 H-benzotriazol-1-yl)- N,N,N\NMetramethylaminium hexafluorophosphate)
(HATU) and 2-(lH-Benzotriazol-l-yl) . - N,N,N',N'- tetramethylaminium
tetrafluoroborate (TBTU); preferably 2-chloro-4,6-dimethoxy-l,3,5-triazine, N-(3-
dimemylarmnopropyI)-N'-ethylcarbodiimide,benzotriazol-l-yI-oxytripyiTolidino
phosphonium hexafluorophosphate, N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide, dicyclohexylcarbodiimide or 2-(7-aza-lH-benzotriazol-l-yl)-N,N,N\NMetramemylaminiumhexafluorophosphate) and mixtures thereof.

Exemplary bases used herein for coupling of compound of Formula III or a salt thereof with a compound of Formula rv, include but is not limited to triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like and mixtures thereof; preferably N-methyl morpholine and diisopropyl ethylamine.
Optionally the coupling of compound of Formula III with a compound of Formula IV
can be carried out in presence of an additive. The additive used herein may be
selected from the group comprising hydroxy benzotriazole (HOBt), l-hydroxy-7-
azabenzotriazole (HO At), 6-chloro-l-hydroxy-lH-benzotriazole (Cl-HOBt),
hydroxy pyridines (HOPy), imidazole or its salts, l,8-diazabicyclo[5A0] undec-7-en (DBU), tertiary amines or its salts and the like; preferably hydroxy benzotriazole.
The coupling of compound of Formula III with a compound of Formula IV may be carried out in a suitable organic solvent. The organic solvent includes but is not limited to alcohols, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide and the like; nitriles include, but are not limited to acetonitrile, propionitrile, benzonitrile and the like; ethers include, but are not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether and the like; halogenated hydrocarbons include, but are not. limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture threof; preferably methanol, methylene chloride, dimethyl formamide, 2-methyl tetrahydrofuran and mixture thereof; more preferably a mixture of methanol and methylene chloride.
The coupling of compound of Formula III with a compound of Formula IV is carried out at a temperature of about 0°C to 50°C; preferably at below 10°C.
After completion of the reaction, the reaction mass may be treated with a suitable aqueous base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like and then separated the organic and aqueous layers. Then the product containing organic layer may be washed with a suitable aqueous acid such as hydrochloric acid, acetic acid and the like and then separated the organic and aqueous layers. Again the product containing organic layer further washed with a suitable aqueous base, for example potassium bicarbonate and the product containing organic layer may be separated and concentrated under vacuum to obtain velpatasvir as crude.

The resulting velpatasvir of Formula I, obtained by the aforementioned process, may have a chemical purity of at least about 98%, as measured by HPLC.
In another embodiment, the crude velpatasvir obtained as above may be purified to get pure product. The purification step includes forming velpatasvir as an intermediate salt in presence of a suitable salt forming agent and followed by neutralizing the intermediate salt with a suitable neutralizing agent to obtain a pure velpatasvir which is having chemical purity of at least about 99.5%, as measured by HPLC.
The suitable salt forming agent includes, but is not limited to hydrochloric acid, hydrobromic acid, trifluoro acetic acid, sulfuric acid, ethane sulfonic acid, benzenesulfonic acid, 4-bromo benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, tartaric acid, maleic acid, malonic acid and the like; preferably phosphoric acid.
The velpatasvir intermediate salt formation step may be carried out in a suitable organic solvent includes but is not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like, water and mixture thereof; preferably a mixture of ethanol and water.
The salt formation step is carried out at a temperature of about 0°C to 70°C; , preferably at below 30°C.
After completion of salt formation reaction, the velpatasvir intermediate salt, preferably phosphate salt can be recovered by any conventional techniques known in the art, for example filtration.
The velpatasvir intermediate salt obtained according to process described herein above, preferably phosphate salt may be neutralized by using a suitable base such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate and the like and mixture thereof; preferably sodium bicarbonate. The neutralization of velpatasvir intermediate salt step is carried out at a temperature of about 0°C to 50°C; preferably at below 30°C.
The neutralization of velpatasvir salt step may be carried out in a water immiscible organic solvents includes, but is not limited to halogenated hydrocarbons, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, and water and mixture thereof. The halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; ethers include, but are not limited to methyl tertiary

butyl ether, diethyl ether and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane; alicyclic hydrocarbons selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like and mixture thereof; preferably a mixture of methylene chloride and water.
The process disclosed in the '437 publication involves use of ethyl acetate as a solvent and potassium bicarbonate as a base in the neutralization step, which process yields gummy material and difficult to handle for further processing steps. In order to overcome the difficulties, the present inventors have found that a mixture of methylene chloride and water in sodium bicarbonate yields clear layer separation. Thereby the product containing organic layer can be easily separated for the product isolation.
Then the product containing organic layer may be concentrated under vacuum at
below 50°C to obtain velpatasvir as a residue. The isolation of product may be carried
out by crystallizing the product by a suitable organic solvent or by a solvent -
antisolvent system. ' .
. In a preferred embodiment, the product may be isolated by one or more of the steps, comprising: dissolving the residue obtained as. above in an organic solvent to obtain a solution, adding anti-solvent to the solution or vice-versa, and isolating the velpatasvir.
The dissolution step is carried out at a temperature of about 0°C to 80°C; preferably at below 50°C.
The suitable organic solvent includes, but is not limited to alcohols, esters and the like and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, . n-propanol, isopropanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like and mixture thereof; preferably methanol, ethanol, ethyl acetate or isopropyl acetate. The velpatasvir can be isolated by adding the above obtained solution to anti-solvent or vice-versa at a temperature of about below 30°C to precipitation. Then the velpatasvir can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about 10°C to about 30°C, preferably at about 20°C to about 25°C.

I
The suitable anti-solvent includes, but is not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably water, heptane and cyclohexane.
The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash . dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 40°C. The drying can be carried out for any desired time until the required product purity is achieved, e.g., a time period ranging from about 1 hour to about 10 hours.
The present invention provides a velpatasvir or a pharmaceutically acceptable salt thereof obtained by the process described herein, having a purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC.
Velpatasvir recovered using the process of the present invention is in substantially amorphous form.
Amorphous Form of velpatasvir characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1.
Amorphous Form of velpatasvir characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2.
Amorphous Form of velpatasvir characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.
Amorphous Form of velpatasvir characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 1, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 3.
In another embodiment, the present invention provides a pharmaceutical composition, comprising velpatasvir of Formula I prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

The X-Ray powder diffraction can be measured using PANalytical X'per3pro X-ray powder Diffractometer equipped with a Cu-anode ([X] =1.54 Angstrom), X-ray source operated at 45kV, 40 tnA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°26; step size=0.01°; and Time per step=43 sec.
All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.
All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about 30°C to about 250°C.
EXAMPLES
The following non limiting examples illustrate specific embodiments of the present . invention. They are not intended to be limiting the scope of the present invention in any way.
EXAMPLE-1:
Preparation of methyl((S> 1 -((25355)-2-((2S,)45}-4-(methoxymethyl)pyrrolidin-2-yl)-l//-imidazol-5-yl)-l,ll-dihydroisochromeno [4',3':6,7] naptho[l,2-rf] irrudazol-2-yl)-5-methylpyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl) carbamate triphosphate
Methanol (250 mL) was charged in a 500-mL reaction flask and cooled to 20-25nC. To the reaction mass acetyl chloride (49.5 g) was added slowly at 20-25°C and stirred for 15-30 min at same temperature, tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-l-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-l,l.l-dihydroisochromeno [4', 3':6,7] naphtho[l,2-d] imidazol-9-yl)-lH-imidazol-2-yl]-4- (methoxy methyl) pyrrolidine-1-carboxylate (100 g) and methanol (250 mL) were combined in another 2-L reaction flask and reaction mass was heated to 60-65°C. To the reaction mass the above mixture of methanol and acetyl chloride was added slowly at 60-65°C and stirred at same temperature. After completion of the reaction, reaction mass was cooled to 15-20°C and pH of the reaction mass was adjusted to 7-8 with sodium methoxide (120 mL, 25% methanol). To the reaction mass Orthophosphoric acid (8.7 mL) was added at 15-20°C and filtered through hyflo bed. To the filterate Orthophosphoric acid (34.6 mL) was slowly added at 15-20°C and the reaction mass was heated to 60-65°C and stirred for 4 hx at same temperature. The reaction mass

was allowed to cool to 20-25°C slowly over a period of 3-4 hr and stirred for 1-1.5 hr at same temperature. Precipitated solid was filtered and washed with methanol (200 mL) and dried at 50-55°C under vacuum for 12 hrs to get the title compound. Yield: 120 g; HPLC purity: 98.8%.
EXAMPLE-2:
Preparation of Velpatasvir phosphate
methyl((S)-1 -((25,55)-2-((25,45)-4-(methoxymethyl)pyrrolidin-2-yl)- l//-imidazol-5-yl)-l,ll-dihydroisochromeno [4\3':6,7] naptho[l,2- 1 -((2S,5S)-2-((2S,4S)-4-(methoxymethy l)pyrrolidin-2-yl)-1 //-imidazol-5-yl)-l,ll-dihydroisochromeno (4',3':6,7] naptho[l,2-(i] imidazol-2-yl)-5-methylpyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl) carbamate triphosphate (0.5 g), water (5 mL) and methylene chloride (5 mL) were combined in a 25-mL reaction flask and stirred at 20-25°C. To the reaction mass ammonium hydroxide (0.36 mL). was added at 20-25°C. The reaction mass was filtered through hyflo and separated the organic and aqueous layers, the organic layer was washed with water (2.5 mL) and distilled out solvent completely under vacuum at below 35°C to obtain residue. The obtained solid mass was dissolved in dimethylformamide (1 mL) at 25-30°C. Dimethylformamide (2.5 mL), Moc-phenyl glycine (0.14 g) was combined in another 10-mL.reaction flask at 25-30°C and cooled the reaction mass to 0°C. To the reaction mass hydroxy benzotriazole (HOBT) (10 mg), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP) (0.32 g) was charged at same temperature and stirred for 15 min. To the reaction mass above dimethylformamide solution and diisopropylethylamine (0.2 g) was charged at 0-5°C and stirred for 1 hr at same temperature. After completion of the reaction, to the reaction mass water (12.5 mL) was added at 20-25°C and stirred for 1 hr at same temperature. Precipitated solid was filtered and washed with water (2.5 mL) and hexane (2.5 mL) to get the title compound. Yield: 0.3 g.
EXAMPLE-9:
Preparation of Velpatasvir (coupling agent: DCC/HOBt)

methyl(OS)-1 -((25)55)-2-((25,4S)-4-(methoxymethyl)pyrrolidin-2-yI)-1 //-imidazol-5-yl)-l,ll-dihydroisochromeno [4',3':6,7] naptho[l,2-cf] imidazol-2-yl)-5-methylpyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl) carbamate triphosphate (1 g), water. (10 mL) and methylene chloride (10 mL) were combined in a 25-mL reaction flask and stirred at 20-25°C. To the reaction mass ammonium hydroxide (0.72 g) was added at 20-25°C and stirred for 1 hr at same temperature. The reaction mass was filtered through hyflo and separated the organic and aqueous layers, the organic layer was washed with water (5 mL) and distilled out solvent completely under vacuum at below 35°C to obtain residue. The obtained solid mass was dissolved in methylene chloride (13 mL) at 25-30°C. Methylene chloride (5 mL), Moc-phenyl glycine (0.28 g) was combined in another 10-mL reaction flask at 25-30°C and cooled the reaction mass to 0°C. To the reaction mass hydroxy benzotriazole (HOBT) (14 mg), dicyclohexyl carbodiimide (DCC) (0.25 g) was charged at same temperature and stirred for 2 hrs at same temperature. To the reaction mass above methylene chloride solution was charged at 0-5°C and stirred for 1 hr at same temperature. After completion of the reaction, reaction mass was filtered and washed the salt with methylene chloride (2 mL), then the filterate was washed with 10% potassium bicarbonate solution (0.4 g dissolved in 4 mL water), 3% hydrochloric acid solution (8 mL) and followed by 10% potassium bicarbonate solution (8 mL). Then the resultant organic layer was distilled under vacuum at below 40°C to get the title compound. Yield: 0.85 g; HPLC purity: 98.5%.
EXAMPLE-10:
Preparation of Velpatasvir (coupling agent: HATU)
methyl((5)-l-((25,55)-2-((25,45)-4-(methoxymethyl)pyrrolidin-2-yl)-l//-imidazol-5-yl)-l,ll-dihydroisochromeno [4',3':6,7] naptho[\,2-d] imidazol-2-yl)-5-methylpyrTolidin-l-yl)-3-methyl-l-oxobutan-2-yl) carbamate triphosphate (0.5 g), water (5 mL) and methylene chloride (5 mL) were combined in a 25-mL reaction flask and stirred at 20-25°C. To the reaction mass ammonium hydroxide (0.36 g) was added at 20-25°C and stirred for 45 min at same temperature. The reaction mass was filtered through hyflo and separated the organic and aqueous layers, the organic layer was washed with water (2.5 mL) and distilled out solvent completely under vacuum at below 35°C to obtain residue. The obtained solid mass was dissolved in dimethylformamide (2.5 mL) at 25-30°C. Dimethylformamide (2.5 mL), Moc-phenyl glycine (0.14 g) was combined in another 10-mL reaction flask at 25-30°C and cooled the reaction mass to 0°C. To the reaction mass 2-(7-Aza-lH-benzotriazol-l-yl)- N,N,NSN'-tetramethylaminium hexafluorophosphate) (HATU) (0.23 g) was charged at same temperature and stirred for 10 min at same temperature. To the

reaction mass above dimethylformamide solution was charged at 0-5°C and stirred for 1 hr at 25-30°C. After completion of the reaction, to the reaction mass water (12.5 mL) and ethyl acetate (5 mL) was added at 20-25°C and stirred for 15 min at same temperature and separated the organic and aqueous layers were separated, then the organic layer was washed with 10% potassium bicarbonate (2 mL), water (2 mL). Then the resultant organic layer was distilled under vacuum at below 40°C to get the title compound. Yield: 0.4 g.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.