DESC:RELATED APPLICATIONS
This application claims the benefit of priority of our Indian patent application numbers 201621035526 filed on 18th October 2016; 201721000751 filed on 9th January 2017 and 201721009019 filed on 16th March 2017 which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION
The present invention relates to process for preparation of Ledipasvir of formula-I. The present invention further relates to novel polymorphic forms of Ledipasvir, pharmaceutical compositions containing them, and method of treatment using the same.


BACKGROUND OF THE INVENTION
Ledipasvir is an inhibitor of the hepatitis C virus NS5A protein. Ledipasvir, a drug developed by Gilead Science that is used to treat hepatitis C. Ledipasvir/Sofosbuvir fixed dose combination tablet for genotype I hepatitis C was approved recently by the USFDA under brand name Harvoni. The combination is direct acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotype Ia or Ib without PEG-interferon or ribavirin.
Ledipasvir chemically known as Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7¬ {2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2¬ azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5¬ azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate known to be an effective anti-HCV agent. It has the following structural formula:

Ledipasvir and its pharmaceutical acceptable salts were first disclosed in US8088368B2 (Indian family equivalent- IN9313/DELNP/2011).
Patent applications WO2013184698 (Indian family equivalent- IN2644/MUMNP/2014), WO2016078505, WO2016103232 (Indian family equivalent-IN6558/CHE/2014), WO2016145269, WO2016145990, WO2016199049 (Indian family equivalent-IN2865/CHE/2015), WO2016207915, IN208581, CN104530016, CN104829599, CN104926796, CN105237516, WO2017072596, CN106632275, CN106892905, WO2017134548 and WO2017145028 disclose process for the preparation of Ledipasvir.
Patent applications WO2013184698 (Indian family equivalent-IN2644/MUMNP/2014), CN105237517, WO2016145269, WO2016193919 (Indian family equivalent-IN2181/MUM/2015) and WO2017005104 disclose various solid state forms of Ledipasvir.
The major disadvantage with the above prior art processes is that it uses catalysts and solvents are very expensive. Also, the Ledipasvir obtained by the prior art processes has poor yield with higher amount of by-products and impurities. Therefore prior art processes for preparing Ledipasvir is not optimal for industrial scale production.
The present inventors have surprisingly found out a novel process for preparation of Ledipasvir. Ledipasvir prepared according to present invention process not only provides an economically and commercially viable process but also provides better purity and yields thereby overcoming drawbacks associated with prior art process. The present process also discloses novel polymorphic forms of Ledipasvir and the process for preparing the same.

OBJECT OF THE INVENTION
In one aspect, the present invention relates to a process for preparation of Ledipasvir with improved yields making it reliable for large scale production.
In one aspect, the present invention relates to process for the preparation of intermediates useful in preparation of Ledipasvir.
In another aspect, the present invention relates to oxalic acid salt of 3-[6-(9,9-Difiuoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-azaspiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-gH-fluoren-2-yl)-lH-benzo
imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptmle-2-carboxylic tert-butyl ester (Compound III-a) useful in preparation of Ledipasvir and process for the preparation thereof.
In one aspect, present invention relates to iso-butyl acetate solvate of Ledipasvir.
In another aspect, the present invention relates to solid state form of iso-butyl acetate solvate of Ledipasvir characterized by X-ray diffraction pattern having characteristic peaks at about 3.1o, 6.2o, 7.0o, 8.6o, 15.6o, 17.2o and 18.2o + 0.2o 2?.
In another aspect, the present invention relates to process for the preparation of iso-butyl acetate solvate of Ledipasvir comprising steps of:
i) dissolving Ledipasvir in iso-butyl acetate;
ii) optionally, adding one or more of suitable solvent(s);
iii) isolating of iso-butyl acetate solvate of Ledipasvir by conventional techniques.
In one aspect, the present invention relates to a process for preparing stable amorphous form of Ledipasvir comprising steps of:
i) dissolving iso-butyl acetate solvate of Ledipasvir in one or more of suitable organic solvent(s);
ii) optionally, adding anti-solvent;
iii) isolating amorphous form of Ledipasvir by conventional techniques.
In another aspect, the present invention relates to acid addition salts of Ledipasvir and polymorphic forms thereof.
In another aspect, the present invention relates to process for the purification of Ledipasvir comprising steps of:
i) treating Ledipasvir with suitable acid to obtain acid addition
salt of Ledipasvir;
ii) optionally, isolating acid addition salt of Ledipasvir;
iii) converting acid addition salt of Ledipasvir to Ledipasvir base by conventional techniques.
In yet one aspect, the present invention provides amorphous form of Ledipasvir having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.
In one aspect, the present invention provides pharmaceutical compositions comprising Ledipasvir.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of amorphous form of Ledipasvir
Figure 2 is an illustration of a PXRD pattern of solid state form of iso-butyl acetate solvate of Ledipasvir
Figure 3 is an illustration of a PXRD pattern of solid state form of iso-butyl acetate solvate of Ledipasvir

DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting
In one embodiment, the present invention relates to a process for preparation of Ledipasvir with improved yields making it reliable for large scale production as described in scheme-1.
Compound -I and compound-II are reacted in presence of palladium catalyst to obtain compound III, preferably in presence of trans-dichlorobis(di-tert-butylphosphine)palladium(II) PdCl2[P(tBu)2Ph]2 or [1,1'-Bis(diphenylphosphino)ferrocene]dichloro palladium(II) Pd(dppf)Cl2 or the like.
Compound III is optionally, treated with an acid to obtain compound III-a, which is an acid addition salt of compound III.
Compound III-a is treated with acid in presence of suitable solvents to produce compound IV which is optionally isolated. Compound IV is treated with base in presence of suitable solvents to produce compound IV-a.
Ledipasvir is produced by reacting compound IV-a with N-(Methoxycarbonyl)-L-valine (Compound V) in presence of coupling agent, using suitable reagents and solvents. Preferred coupling agents include O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU) or 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) or acid halide or the like. A preferred acyl halide is pivaloyl chloride.

In one embodiment, the present invention relates to process for the preparation of intermediates useful in preparation of Ledipasvir.
In another embodiment, the present invention also relates to a process for preparation compound III-a as described below:

Compound-I and compound-II are reacted in presence of palladium catalyst to obtain compound III, preferably in presence of trans-dichlorobis(di-tert-butylphosphine)palladium(II) PdCl2[P(tBu)2Ph]2 or [1,1'-Bis(diphenylphosphino)ferrocene]dichloro palladium(II) Pd(dppf)Cl2 or the like. Compound III is optionally, treated with an acid to obtain compound III-a which is an acid addition salt of compound III.
In one embodiment, the present invention relates to oxalic acid salt of 3-[6-(9,9-Difiuoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-azaspiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-gH-fluoren-2-yl)-lH-benzo
imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptmle-2-carboxylic tert-butyl ester (Compound III-a) useful in preparation of Ledipasvir and process for the preparation thereof.

In one embodiment, the present invention also relates to process for the preparation of oxalic acid salt of compound-III (compound III-a).

Compound III is treated with oxalic acid in presence of suitable solvents to produce Compound III-a.
In one embodiment,, the present invention relates to solid state form of oxalic acid salt of 3-[6-(9,9-Difiuoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-azaspiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-gH-fluoren-2-yl)-lH-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptmle-2-carboxylic tert-butyl ester (Compound III-a) characterized by X-ray diffraction pattern having characteristic peaks at about 6.4o, 6.7o, 7.3o, 8.9o, 10.4o, 13.7, 14.7, 15.5o, 16.4o, 17.4o, 18.1o, 18.7o, 20.1o, 22.7o and 23.4o + 0.2o 2?.
In one embodiment, the present invention relates to solid state form of hemi-hydrate of Carbamic acid, N-[(1S)-1-[[6-[5-[7-[2--2-azabicyclo[2.2.1]hept-3-yl-1H-benzimidazol-6-yl]-9,9-difluoro-9H-fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl]carbonyl]-2-methylpropyl]-, methyl ester (Compound IV-a) characterized by X-ray diffraction pattern having characteristic peaks at about 4.7o, 7.2o, 9.3o, 16.7o and 18.4o + 0.2o 2?.
In one embodiment, the present invention relates to hemi ethyl acetate solvate of Carbamic acid, N-[(1S)-1-[[6-[5-[7-[2--2-azabicyclo[2.2.1]hept-3-yl-1H-benzimidazol-6-yl]-9,9-difluoro-9H-fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl]carbonyl]-2-methylpropyl]-, methyl ester (Compound IV-a).
In another embodiment, the present invention relates to solid state form of hemi ethyl acetate solvate of Carbamic acid, N-[(1S)-1-[[6-[5-[7-[2--2-azabicyclo[2.2.1]hept-3-yl-1H-benzimidazol-6-yl]-9,9-difluoro-9H-fluoren-2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl]carbonyl]-2-methylpropyl]-, methyl ester (Compound IV-a) characterized by X-ray diffraction pattern having characteristic peaks at about 6.4o, 8.2o, 9.4o, 10.0o, 11.4o, 13.6, 14.1, 15.1o, 16.5o, 17.4o, 17.9o, 18.4o, 18.9o, 19.3o, 19.8o, 22.9o, 23.9o and 26.1o + 0.2o 2?.
In one embodiment, present invention relates to iso-butyl acetate solvate of Ledipasvir.
In another embodiment, the present invention relates to solid state form of iso-butyl acetate solvate of Ledipasvir characterized by X-ray diffraction pattern having characteristic peaks at about 3.1o, 6.2o, 7.0o, 8.6o, 15.6o, 17.2o and 18.2o + 0.2o 2?.
In another embodiment, the present invention relates to process for the preparation of iso-butyl acetate solvate of Ledipasvir comprising steps of:
i) dissolving Ledipasvir in iso-butyl acetate;
ii) optionally, adding one or more of suitable solvent(s);
iii) isolating of iso-butyl acetate solvate of Ledipasvir by conventional techniques.
In one embodiment, the present invention relates to a process for preparing stable amorphous form of Ledipasvir comprising of following steps:
i) dissolving iso-butyl acetate solvate of Ledipasvir in one or more of suitable organic solvent(s);
ii) optionally, adding anti-solvent;
iii) isolating amorphous form of Ledipasvir by conventional techniques.
In another embodiment, the present invention relates to acid addition salts of Ledipasvir and polymorphic forms thereof.
In another embodiment, the present invention relates to process for the purification of Ledipasvir comprising steps of:
i) treating Ledipasvir with suitable acid to obtain acid addition
salt of Ledipasvir;
ii) optionally, isolating acid addition salt of Ledipasvir;
iii) converting acid addition salt of Ledipasvir to Ledipasvir base by conventional techniques.
In one embodiment, the present invention further relates to process for the preparation of polymorphic form of acid addition salts of Ledipasvir, process comprising:
i) dissolving acid addition salts of Ledipasvir in a suitable organic solvent(s) or water or mixture thereof;
ii) optionally, adding anti-solvent;
isolating polymorphic form of acid addition salts of Ledipasvir by conventional techniques.
In yet one embodiment, the present invention provides amorphous form of Ledipasvir having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.
In another embodiment, the present invention provides pharmaceutical compositions comprising Ledipasvir alone or in combination with other drugs.
Further the present invention provides a process of preparing a pharmaceutical composition comprising Ledipasvir alone or in combination with other drugs. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.
Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol. The said polymers/agents are used to facilitate the presence of Ledipasvir.
The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuum, evaporation, solvent-antisolvent, spray drying, lyophilization or freeze drying.
The “acid addition salts” as used herein can be prepared from the free base forms of the compounds by reaction of the latter with pharmaceutically acceptable acid, followed by isolation of salt by conventional techniques, if required. A salt can be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
Suitable acids for forming acid addition salts of the compounds used in the present invention include, but are not limited to, acetic, benzoic, benzenesulfonic, hydrobromic, hydrochloric, citric, gluconic, glucuronic, glutamic, lactic, malic, maleic, oxalic, camphorsulphonic, methanesulfonic, palmoic, salicylic, stearic, succinic, sulfuric, and the like. The class of acids suitable for formation of pharmaceutically acceptable salts is well known to person having ordinary skills in the art, and are described, for example in Stahl, P. H., et al., “Handbook of Pharmaceutical Salts”, Wiley-VCH, Weinheim: Germany (2002), the contents of which are hereby incorporated herein by reference.
Representative salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, camphor-sulphonate, naphthylate, mesylate, glucoheptonate, lactiobionate, laurylsulphonate salts, and the like. Pharmaceutically acceptable salts are well known to person having ordinary skills in the art, and are described, for example in Berge S. M., et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19, 1977, the contents of which are hereby incorporated herein by reference.
The tem “base” as used herein includes but not limited to ingorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine. The base may be chosen as appropriate depending on various reaction conditions known to those skilled in the art.
The term “coupling agent” as used herein includes but not limited to O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), acid halide, 1-hydroxybenzotriazole (HOBt), 1-Hydroxy-7-aza-1H-benzotriazole (HOAt), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 2-(6-Chloro-1H-benzotriazol-1-yl)- N,N,N’,N’-tetramethylaminium hexafluorophosphate (HCTU), 1-[1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino]- uronium hexafluorophosphate (COMU) and the like.
The term “acid halide” as used herein includes but not limited to pivaloyl chloride, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride and the like.
The term “palladium catalyst” as used herein includes but not limited to trans-dichlorobis(di-tert-butylphosphine)palladium(II) PdCl2[P(tBu)2Ph]2, [1,1'-Bis(diphenylphosphino)ferrocene]dichloro palladium(II) Pd(dppf)Cl2, Bis[di-(tert-butyl)(4-trifluoromethylphenyl)
phosphine]palladium(II) chloride, Tetrakis(triphenylphosphine)
palladium(0) Pd(PPh3)4, Bis(di-tert-butyl(4-dimethylaminophenyl)
phosphine)dichloropalladium(II) Pd(amphos)Cl2 and the like.
The term “stable amorphous form of Ledipasvir” as used herein refers to amorphous form of Ledipasvir which is stable and does not show any change in the PXRD pattern after storage for three months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity. The term “stable amorphous form of Ledipasvir” as used herein further refers to amorphous form of Ledipasvir which is stable and has no detectable quantities of other polymorphic forms.
The term “suitable solvents” and “suitable anti-solvents” as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, DMSO, DMF, pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.
Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1, 2-propane diol and S (+)-1, 2-propane diol.
Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1, 2-dichloro ethane.
Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermograms, thermal gravimetric analyzers thermograms, melting point information, polarized light microscopy, hotstage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.

EXAMPLES
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.
Example: 1 Preparation of compound-III
Compound I (10 g), compound II (7.3 g), PdCl2[P(tBu)2Ph]2 (0.271 g), sodium bicarbonate (4.2 g), were dissolved in DME (130 mL)/water (60 mL) under nitrogen atmosphere. The mixture was heated for 4 hours at 80-90?C. cooled the reaction to room temperature. Ethyl acetate (50 mL) and process water (50 mL) were charged and the reaction mixture was filtered through hyflo bed. Organic layer was separated out and aqueous layer was back extracted using ethyl acetate (50mL). Both organic layers were combined and treated with N-acetyl cysteine (3 g) at 35-45°C for 2 hours. Aqueous sodium hydroxide solution (50 mL) was charged and the reaction mass was filtered through hyflo bed. Organic layer was separated out and washed with water (10 mL). Solvent was removed by vacuum to yield compound III (20 g) which is used for preparation of compound III-a without any purification.

Example: 2 Preparation of compound III-a
Compound III (20 g) as obtained in example-1 and oxalic acid dehydrate (2.5 g) were dissolved in dioxane (150mL) at 90-100°C and stirred for 1 hr. The reaction mass was cooled to 40-50°C and stirred for 1 hour. The solid was filtered and washed with 1,4-dioxane. Wet product was again dissolved in dioxane (150 mL) at 90-100°C and stirred for 1 hr. The reaction mass was cooled to 40-50°C and stirred for 1 hour. The solid was filtered and washed with 1,4-dioxane. Wet product was dried under vacuum at 50-60°C to obtain compound-III-a (10 g).

Example: 3 Preparation of compound-IV
To a stirred solution of oxalic acid salt of compound-III (10 g) in MeOH (140 mL) was added conc. hydrochloric acid (10 mL) at 25-30°C. The reaction mixture was stirred for 10-14 hours at 25-35°C. The product was filtered and washed with MeOH (30 mL). The wet product was dried for 8 hours at 25-35°C under vacuum to get compound-IV (8.5 g).

Example: 4 Preparation of compound-IV-a
Conc. HCl (25 mL) was added into clear solution of oxalic acid salt of compound-III (compound-III-a) (10 g) in methanol (100 mL) at 20-30°C followed by heating to 40-50°C for 3 hours. After completion of reaction, MDC (100 mL) was charged and pH of the reaction mass adjusted to 9-10 using aqueous sodium carbonate solution (100 mL) at 0-10°C. Organic layer was separated at 20-30°C and water (100 mL) was added. MDC layer was separated and distilled out under vacuum at temperature 40-50°C. Residue was dissolved in ethyl acetate (50 mL) and clear solution of ethyl acetate added into n-Heptane (100 mL) at 20-30°C. After stirring for 3 hours the material was filtered out and washed with n-heptane (20 mL) followed by drying to get 6.0 g of compound-IV-a hemi hydrate.

Example: 5 Preparation of compound-IV-a
Conc. HCl (25 mL) was added into clear solution of oxalic acid salt of compound-III (compound-III-a) (10 g) in methanol (100 mL) at 20-30°C followed by heating to 40-50°C for 3 hours. After completion of reaction, MDC (100 mL) was charged and pH of the reaction mass adjusted to 9-10 using aqueous sodium carbonate solution (100 mL) at 0-10°C. Organic layer was separated at 20-30°C and water (100 mL) was added. MDC layer was separated and distilled out under vacuum at temperature 40-50°C. Residue was dissolved in ethyl acetate (50 mL) and stirred for 8-9 hours at 20-30°C. Solid material was filtered out and washed with ethyl acetate (20 mL) followed by drying to get 6.0 g of compound-IV-a hemi ethyl acetate solvate.

Example: 6 Preparation of compound-IV-a
To a stirred solution of compound-IV obtained in example-3 (10 g) in dichloromehane (70 mL) was added aqueous solution of sodium carbonate (5 g) till basic pH was obtained. Ethyl acetate was added to above reaction mixture and organic layer was separated and washed with ethyl acetate. Organic layer was distilled to obtain compound-IV-a (8.0 g).

Example: 7 Preparation of Ledipasvir
Pivaloyl chloride (0.987 g) added into cold solution of N-(Methoxycarbonyl)-L-valine (1.2 g), tetrahydrofuran (25 mL) and N,N-diisopropylethylamine (1.5 g) followed by stirring for 6 hour at -10° to -5°C. Compound IV-a (4.2 g) in tetrahydrofuran (25 mL) was added slowly into reaction mass and stirred for 2 hours. After completion of reaction, water (25 mL) added to reaction mass and material extracted out in dichloromethane followed by aqueous sodium bicarbonate (25 mL) wash to the organic layer. Organic layer distilled out to get Ledipasvir (4 g).

Example: 8 Preparation of Ledipasvir
Compound IV-a was dissolved in DMF (2 mL) and DIEA (50 mg) was added. A solution of O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU) (50 mg) and DIEA (15 mg) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. The reaction mixture was filtered and solvents were removed under vacuum to get Ledipasvir (8 g).
Example: 9 Preparation of iso-butyl acetate solvate of Ledipasvir
Ledipasvir (2.0g) was dissolved in iso-butyl acetate (10mL). Acetone (1 mL) was charged at 20-30°C. The reaction mixture was stirred for 2 hours at 20-30°C. The solids were filtered and dried at 50-55°C to get 0.8 g of iso-butyl acetate solvate of Ledipasvir.

Example: 10 Preparation of iso-butyl acetate solvate of Ledipasvir
Ledipasvir (3.0g) was dissolved in iso-butyl acetate (15mL). The reaction mixture was stirred for 2 hours at 20-30°C. The solids were filtered and dried at 50-55°C to get 1.9 g of iso-butyl acetate solvate of Ledipasvir.

Example: 11 Preparation of amorphous form of Ledipasvir
Ledipasvir iso-butyl acetate solvate (3.0g) was dissolved in acetonitrile (15mL). Water (30 mL) was charged at 20-30°C. The reaction mixture was stirred for 2 hours at 20-30°C. The solids were filtered and dried under pressure at 50-55°C to get 1.8 g of amorphous form of Ledipasvir.

Example: 12 Preparation of amorphous form of Ledipasvir
Ledipasvir iso-butyl acetate solvate (3.0g) was dissolved in acetonitrile (20 mL). The reaction mixture was stirred for 2 hours at 20-30°C. The solids were filtered and dried under pressure at 50-55°C to get 1.9 g of amorphous form of Ledipasvir.

Example: 13 Preparation of oxalic acid salt of Ledipasvir
Oxalic acid dehydrate (0.34 g) in clear solution of Ledipasvir (2 g) in isopropyl alcohol (30 mL) and heated to 60-70°C for 1 hour. Reaction mass was gradually cooled to room temperature and filtered the material after 1 hour stirring at room temperature and filtered. Wet solid material was dried under vacuum to get oxalic acid salt of Ledipasvir (1.4 g).

Example: 14 Preparation of camphor sulfonic acid salt of Ledipasvir
Ledipasvir (2 g), toluene (30 mL) and camphor sulfonic acid (0.626 g) mixture heated to reflux temperature to get clear solution followed by gradually cooling to room temperature and filtered the material after 1 hour stirring at room temperature and filtered. Wet solid material was dried under vacuum to get camphor sulfonate salt of Ledipasvir (1.4 g).

Dated this 16th October 2017

,CLAIMS:WE CLAIM:
1. A process for the preparation of Ledipasvir (I)

(I)
comprising:
reacting a compound of formula (IV-a):

or acid addition salt thereof:

with N-(methoxycarbonyl)-L-valine (V)

in presence of coupling agent to obtain Ledipasvir (I).

2. The process according to claim-1, wherein coupling agent is selected from group comprising of O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium, acid halide, hexa-
fluorophosphate(HATU),1-hydroxybenzotriazole (HOBt), 1-Hydroxy-7-aza-1H-benzotriazole (HOAt), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 2-(6-Chloro-1H-
benzotriazol-1-yl)-N,N,N’,N’-tetramethylaminium hexafluoro-
phosphate (HCTU), 1-[1-(Cyano-2-ethoxy-2-oxoethylidene-
aminooxy)-dimethylamino-morpholino]- uronium hexafluoro-
phosphate (COMU).

3. A process for the preparation of compound of formula (III)

or an acid addition salt thereof:

comprising:
reacting a compound of formula (I):

with a compound of formula (II):

in presence of palladium catalyst to obtain compound of formula (III) and optionally treating compound of formula (III) with acid to obtain acid addition salt of compound of formula (III-a)

4. The process according to claim-3, wherein coupling agent is selected from group comprising of trans-dichlorobis(di-tert-butylphosphine)palladium(II) or PdCl2[P(tBu)2Ph]2, [1,1'-Bis-(diphenylphosphino)ferrocene]dichloro palladium(II) or Pd(dppf)Cl2, Bis[di-(tert-butyl)(4-trifluoromethylphenyl)phosphine]palladium(II) chloride,Tetrakis(triphenylphosphine)palladium(0) or Pd(PPh3)4, Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloro-palladium(II) or Pd(amphos)Cl2.

5. A process for the preparation of compound of formula (IV-a)

or an acid addition salt thereof:

comprising:
deprotecting compound of formula (III):

or acid addition salt thereof:

to obtain compound of formula (IV-a) and optionally treating compound of formula (IV-a) with acid to obtain acid addition salt of compound of formula (IV).

6. The process according to claim-3 or claim-5, further comprises converting compound of formula III or III-a or IV or IV-a to Ledipasvir (I).

7. A process for the preparation of process for the preparation of iso-butyl acetate solvate of Ledipasvir comprising steps of:
a) dissolving Ledipasvir in iso-butyl acetate;
b) optionally, adding one or more of solvent(s);
c) isolating iso-butyl acetate solvate of Ledipasvir.

8. The process according to claim-7, wherein solvent used in step-b) is selected from group comprising of acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone.

9. A process for the preparation of process for the preparation of iso-butyl acetate solvate of Ledipasvir comprising steps of:
a) dissolving iso-butyl acetate solvate of Ledipasvir in one or more of organic solvent(s);
b) optionally, adding anti-solvent;
c) isolating amorphous form of Ledipasvir.

10. The process according to claim-9, wherein solvent used in step-b) is selected from group comprising of acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone.

Dated this 16th October 2017