Related applications:
This patent application claims the benefit of priority of our Indian patent application number IN 201641008937 filed on 15th March 2016. which is incorporated herein by reference. Field of the invention:
The present invention provides a novel process for the preparation of methyl [(25)-1-{(65)-6-[5-(939-difluoro-7-{-2-[(l/?,35;45)-2-{(25)-2-[(methoxycarbonyl)amino]-3-methyl butanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-l^-benzimidazol-6-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carbamate of formula (I). The compound of formula-I is represented by the following structural formula.
Background of the invention:
Ledipasvir known by a chemical name of methyl [(25)-l-{(6S)-6-[5-(9,9-difluoro-7-{2-[(lJR,35J4S)-2-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-l//-benzimidazol-6-yl}-9//-fluoren-2-yl)-l^-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carbamate herein after referred as "formula-(I)".
Ledipasvir is a component of a two-drug, fixed-dose combination for hepatitis C virus (HCV) NS5A treatment Ledipasvir/Sofosbuvir (known as Harvoni®). The Harvoni® was approved by the FDA on October 14, 2014 for use in the United States. Ledipasvir is a hepatitis C virus (HCV) NS5A inhibitor and is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
US Patent No. 8088368 B2 discloses Ledipasvir product and its methods for the preparation thereof.

The manufacturing methods for Ledipasvir reported in US 8088368 suffer from low yield and serious disadvantages on the use of toxic vinyl reagents such as tributyl(ethoxyvinyl)stannane and thus raises serious safety demands so as to prevent poisonous contamination during the reaction and in the final product.
Hence, there is a need in the art to develop a safe, robust, ecofriendly process which should provide Ledipasvir with high yields by avoiding all possible impurities. It should have lesser_number of steps~and-should utilize-simple andcommercially available raw materials. The process should be economically viable and be reproducible at large scale industrial process.
Brief description of the invention:
The first aspect of the present invention is to provide a process for the preparation of methyl[(2^)-l-{(65)-6-[5-(9)9-difluoro-7-{2-[(l/?J35,45)-2-{(25)-2-[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-l//-benzimidazol-6-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carba--mate of formula (I) or salts or solvates.
The second aspect of the present invention is to provide a process for the preparation of compound of general formula (VIII)
Wherein, X is bromo, chloro or iodo.
The third aspect of the present invention is to provide the crystalline trifluoro acetate salt of (5)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl 5-azaspiro[2.4]heptane-6-carboxylate compound of formula (Va) and its process for the preparation thereof.

Brief description of the drawings
FIG 1: Illustrates characteristic powdered X-Ray Diffraction (PXRD) pattern of crystalline
trifluoro acetate salt of (S>2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl 5-
azaspiro[2:4]heptane-6-carboxylate of formula (Va).
FIG. 2: Illustrates characteristic PXRD pattern of pure Ledipasvir obtained according to
example-8.
Detailed description of the invention:
The present invention provides a novel process for the preparation of methyl [(25)-1-{(6S)-6-[5-(9)9-difluoro-7-{2-[(l^135)45)-2-{(25)-2-[(methoxycarbonyl)amino]-3-methyl butanoyl}-2-azabicyclo[2.2.1 ]hept-3-yl]-1 //-benzimidazol-6-yl}-9//-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-1 -oxobutan-2-yl]carbamate of formula
(I)-
Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvent selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" such as to toluene, hexane, heptane and cyclohexane; "nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate and isopropyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.
As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal alkoxides like sodium tertiary butoxide, potassium

tertiary butoxide; organic bases like methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia or their aqueous solution.
As used herein the term "suitable acid" refers to the acid selected from inorganic acids like hydrochloric acid (HC1), ethyl acetate-hydrochloric acid, acetonitrile-hydrochloric acid, hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H2SO4); organic acids like acetic acid (AcOH), methanesulfonic acid (MsOH), p-toluenesulfonic acid (p-TsOH), trifluoro acetic acid (TFA).
As used herein the term "amino protection group" refers to a protection group which protects the amino functional group from involving in any reaction. For example, the amino protecting groups are carbobenzyloxy (Cbz) group, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl (BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, benzyl (Em) group, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group and tosyl group.
The first aspect of the present invention provides a novel process for the preparation of methyl [(25)-l-{(65)-6-[5-(9,9-difluoro-7-{2-[(l^J35,45)-2-{(25')-2-[(methoxycarbonyl) amino]-3-methyl butanoyl}-2-azabicyclo[2.2.1] hept-3-yl]-l//-benzimidazol-6-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl] carbamate of formula-(I) (Also known as "Ledipasvir"), or its pharmaceutically acceptable salts or solvates thereof, which comprises the steps of:
a) Treating the compound of general formula (IV) with a suitable deprotecting agent in a suitable solvent to provide the compound of general formula (V) or its acid addition salts,
b) optionally, isolating the compound of general formula (V) or its acid addition salt using suitable organic solvent,
c) reacting the product obtained in step-a) or step-b) with (5)-2-((methoxycarbonyl) amino)-3-methylbutanoic acid formula (VI) in presence of a suitable coupling agent, suitable base in suitable solvent to provide the compound of general formula (VII),
d) reacting the compound of general formula (VII) with suitable ammonium source in a suitable solvent to provide the compound of general formula (VIII),

e) reacting the compound of general formula (VIII) with the compound of general formula (IX) in presence of suitable catalyst, suitable base in a suitable solvent to provide the compound of formula (X),
f) treating the compound of general formula (X) with a suitable deprotecting agent in a suitable solvent to provide the compound of formula (XI) or its acid addition salt,
g) optionally, isolating the compound of formula (XI) or its acid addition salt using
, .„__suitahle nrganir.=snl.ve.nt;^__,—= _ = __„„„_
h) reacting the product obtained in step-f) or step-g) with (S)-2-((methoxycarbonyl) amino)-3-methylbutanoic acid of formula (VI) in presence of a suitable condensing agent to provide the methyl [(25)-l-{(6S)-6-[5-(9)9-difluoro-7-{2-[(lJ?,35,45)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl} -2-azabicyclo[2.2.1]hept-3-yl]-l//-benzimidazol-6-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carbamate compound of formula (I). wherein, in step-a), the suitable deprotecting agent is selected from trifluoroacetic acid, ethyl acetate hydrochloride, acetonitrile hydrochloride, aqueous phosphoric acid, hydrochloric acid-methanol, hydrochloric acid-l,3-dioxane, HC1, HBr, HCOOH, MsOH and the like.
In step-b), the suitable organic solvent used for isolation can be selected from ether solvents such as methyl tert-butyl ether (MTBE), diethyl ether, propyl ether; alkane solvents having C5-C7 straight or branched alkyl groups, preferably n-heptane; aromatic hydrocarbon solvents such as toluene, xylene and the like; halo hydrocarbons such as dichloromethane, chloroform and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and the like and the mixture of solvents thereof.
In step-c), the suitable coupling reagent is selected from hydroxybenzotriazole (HOBt), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), berizotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Bromo-tris-pyrrolidino phosphonium hexafluorophosphate (PyBrOP), 0-(benzo\riazo\-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoro borate (TBTU), 2-(l//-Benzotriazole-l-yl)-l)l)3,3-tetramethyluronium hexafluorophosphate (HBTU), l-[bis(dimethylamino)methylene]-lH-

l^-triazolof^S-bJpyridinium 3-oxid hexafluorophosphate (HATU), l-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate(COMU) and tetramethylfluoroformamidinium hexafluorophosphate (TFFH) the presence of a base di-isopropyl ethylamine (DIPEA), N-methyl-morpholine (NMM), pyridine and the like.
In step-d), the suitable ammonium source is selected from ammonium acetate,
ammonium carbonate, ammonium bicarbonate, ammonia and the like; preferably ammonium
—.acetate.. - -
In step-e), the suitable catalyst is selected from metal catalyst selected from Pt, PdCl2dppf2j Pd(PPh3)4, Pd(OAc)2, Pd, PdCl2; preferably PdCl2dppf2; the suitable base is selected from Na2C03, K2C03, DIPEA, NMM and the like, preferably K2C03; the suitable solvent is selected from 1,2-dimethoxyethane, 1,3-dioxane, dimethylformamide, ethyl acetate, isopropyl acetate and the like or mixtures thereof.
In step-f), the suitable deprotecting reagent is selected from ethyl acetate hydrochloride, aqueous phosphoric acid, hydrochloric acid-methanol, hydrochloric acid-1,3-dioxane, HC1, HBr, HCOOH, TFA, methanesulfonic acid and the like;
In step-g), the optionally, the isolation of compound of formula (XI) can be carried out by using a suitable organic solvent. The organic solvent is selected from ether solvents such as MTBE, diethyl ether, propyl ether; alkane solvents having C5-C7 straight or branched alkyl groups; aromatic hydrocarbon solvents such as toluene, xylene and the like; halo hydrocarbon solvents such as CH2C12, CHCI3 and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and the like or mixtures thereof. Preferably n-heptane or MTBE.
In step-h), the suitable coupling reagent is selected from HOBt, EDC.HC1, PyBOP, PyBrOP, TBTU, HBTU, HATU, COMU and TFFH the presence of a base selected from DIPEA, NMM, pyridine and the like. The coupling reaction is carried out in presence of a polar aprotic solvent selected from DMF, DMSO, acetonitrile, DMAc and the like; preferably DMF.
The preferred embodiment, the present invention provides a process for the preparation of methyl [(2S)-1 -{(6S)-6-[5-(9,9-difluoro-7-{2-[(l/?,35J4S)-2-{(25)-2-[(methoxy

carbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-l//-benzimidazol-6-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl} -3 -methyl-1-oxobutan-2-yljcarbamate of formula (I) or salts or solvates, comprising the steps of:
a) Treating (S>6-(2-(7-bromo-9,9-difiuoro-9//-fluoren-2-yl)-2-oxoethyl) 5-tert-butyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate of formula (IVa) with trifluoro acetic acid in methylene chloride to provide trifluoro acetate salt of (S)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl-5-azaspiro [2.4]heptane-6-carboxylate of formula (Va),
b) isolating the crystalline compound of formula (Va) using methyl tert-butyi ether,
c) reacting the compound of formula (Va) with (S)-2-((methoxycarbonyl) amino)-3-methylbutanoic acid of formula (VI) in presence of EDC.HC1, HOBt and DIPEA in DMF to provide (S)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl 5-((S>2-((methoxycarbonyl) amino)-3 -methylbutanoyl)-5 -azaspiro [2.4] heptane-6-carboxylate of formula (Vila),
d) reacting the compound of formula (Vila) with ammonium acetate to provide methyl ((5)-1 -((S)-6-(5-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-1 #-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl) -3-methyl-l-oxobutan-2-yl)carbamate of formula (Villa),
e) reacting the compound of formula (Villa) with (lR,3S,4S)-tert-b\\tyl 3-(6-(4,4,5,5-tetramethyl-l,3,2-dioxoborolan-2-yl)-l//-benzo[d] imidazol-2-yl)-2-azabicyclo [2.2.1]heptane-2-carboxylate of formula (IXa) to provide (\R,3S,4S)-tert-buty\ 3-(6-(9,9-difluoro-7-(2-((S>5-((S>2-((methoxycarbonyl) amino)-3-methylbutanoyl)-5-azaspiro[2.4] heptan-6-yl)-l//-imidazol-5-yl)-9//-fluoren-2-yl)-l//-benzo[d] imidazol-2-yl)-2-azabicyclo[2.2.1] heptane-2-carboxylate of formula (Xa),
f) treating the compound of formula (Xa) with ethyl acetate hydrochloride in ethyl acetate to provide tri hydrochloride salt of compound of formula (XIa),
g) isolating the compound of formula (XIa) using acetonitrile to provide pure compound of formula-(XIa),
h) reacting the product obtained in step-g) with (S)-2-((methoxycarbonyl)amino)-3-
methylbutanoic acid of formula (VI) to provide the compound of formula (I). In another aspect of the present invention provides a process for the preparation of Ledipasvir of formula (I), comprising the steps of:

a) Reacting the compound of general formula (XIII) with the compound of general formula (XIV) in presence of a suitable catalyst, suitable base in a suitable solvent to provide the compound of general formula (XV),
b) treating the compound of formula (XV) with suitable acid in presence of suitable solvent to provide the compound of formula (XVI),
c) reacting the compound of formula (XVI) with the compound of formula (VI) in
_^. ^-prf,sp:nr,e-nf_a_coupling_agent,-base^iii,.a^solvent^to_provide_the Ledipasvir of
formula (I). Wherein, in step-a) and step-c), the suitable coupling agent is selected from EDC.HC1, HOBt, PyBOP, PyBrOP, TBTU, HBTU, HATU, COMU and TFFH. Prefarebly EDC. HC1 and HOBt; the suitable base is selected from DIPEA, NMM, pyridine and the like; the suitable solvent is polar aprotic solvent such as DMF, DMSO, acetonitrile, DMAc and the like; preferably DMF.
In step-c), the suitable acid is selected from ethyl acetate hydrochloride,'aqueous phosphoric acid, hydrochloric acid-methanol, hydrochloric acid-l,3-dioxane, hydrochloric acid acetonitrile, hydrochloric acid, HBr, HCOOH, CF3COOH3 methanesulfonic acid and the like; the suitable solvent is ethyl acetate, methyl acetate, acetonitrile, propionitrile, butyronitrile and the like.
The preferred embodiment of the present invention provides a process for the preparation of Ledipasvir of formula (I), comprising the steps of:
a) Reacting the compound of formula (XUIa) with the compound of formula (XlVa) in
presence of Pd(PPh3)4 / potassium carbonate in isoprdpyl acetate to provide the compound of formula (XVa),
b) treating the compound of formula (XVa) with hydrochloric acid in presence of
acetonitrile to provide the compound of formula (XVIa);
c) reacting the compound of formula (XVIa) with the compound of formula (VI) in
presence of EDC. HC1, HOBt, DIPEA in dimethylformamide to produce the compound of formula (I). The another preferred embodiment of the present invention provides a process for the preparation of Ledipasvir of formula (I), comprising the steps of:

a) Reacting the compound of formula (Xlllb) with the compound of formula (XlVb) in
presence of PdfPPhsVpotassium carbonate in isopropyl acetate to provide the compound of formula (XVa),
b) treating the compound of formula (XVa) with hydrochloric acid in presence of
acetonitrile to provide the compound of formula (XVIa);
c) reacting the compound of formula (XVIa) with the compound of formula (VI) in
presence of EDC, HC1, HOBt, DIPEA in dimethylformamide to produce the compound of formula (I).
The second aspect of the present invention provides a process for the preparation of compound of general formula (VIII), comprising the steps of:
a) Treating the compound of general formula (IV) with the suitable deprotecting agent to provide the compound of general formula (V) or its acid addition salts,
b) optionally, isolating compound of general formula (V) or its acid addition salts from a suitable organic solvent,
c) reacting the product obtained in step-a) or step-b) with the (S)-2-((methoxy carbonyl)amino)-3-methylbutanoic acid formula (VI) in presence of a suitable condensing agent in a suitable solvent to provide the compound of general formula (VII),
d) reacting the compound of general formula (VII) with a suitable ammonium source in a suitable solvent to provide the compound of general formula (VIII). Wherein, in step-a), the suitable deprotecting agent is selected from trifluoroacetic
acid, ethyl acetate hydrochloride, acetonitrile hydrochloride, aqueous phosphoric acid, hydrochloric acid-methanol, hydrochloric acid-l,3-dioxane, HC1, HBr, HCOOH, MsOH and the like.
In step-b), the suitable organic solvent can be selected from ether solvents such as MTBE, diethyl ether, propyl ether; alkane solvents having C5-C7 straight or branched alkyl groups, preferably n-heptane; aromatic hydrocarbon solvents such as toluene, xylene and the like; halo hydrocarbons such as dichloromethane, chloroform and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ester solvents such as methyl acetate, ethyl

acetate, propyl acetate and the like and the mixture of solvents thereof. Preferably, n-heptane or methyl /er/-butyl ether.
In step-c), the suitable coupling reagent is selected from HOBt, EDC.HC1, PyBOP, PyBrOP, TBTU, HBTU, HATU, COMU and TFFH; base is DIPEA, NMM, pyridine & the like.
In step-d), the suitable ammonium source is selected from ammonium acetate, ammonium carbonate, ammonium bicarbonate, ammonia and the like; preferably ammonium acetate.
The preferred embodiment, the present invention provides a process for the preparation of methyl ((5)-1 -((S)-6-(5-(7-bromo-9>9-difluoro-9//-fluoren-2-yl)-1 //-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-l-oxobutan-2-yl)carbamate of formula (Villa), comprising the steps of:
a) Treating the compound of formula (IVa) with trifluoro acetic acid in methylene chloride to provide trifluoro acetate salt (S)-2-(7-bromo-939-difluoro-9//-fluoren-2-yl)-2-oxoethyl-5-azaspiro [2.4]heptane-6-carboxylate of formula (Va),
b) isolating crystalline salt of trifluoro acetate salt of (5)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl-5-azaspiro [2.4]heptane-6-carboxylate of formula (Va) using methyl tert-butyl ether,
c) reacting the compound of formula (Va) with (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid in presence of N-(3-dimethylaminopropyl)-N'-ethylcarbonate hydrochloride (EDC.HC1), 1-hydroxybenzotriazole (HOBt) in dimethylformamide to provide (5)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl5-((S)-2-((methoxy carbonyl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]heptane-6-carboxylate of formula (Vila),
d) reacting the compound of formula (Vila) with ammonium acetate to provide methyl ((5)-l-((5)-6-(5-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-l//-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methyl-l-oxobutan-2-yl)carbamate of formula (Villa).
The third aspect of the present invention provides crystalline trifluoro acetate salt of (iS)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl5-azaspiro[2.4]heptane-6-

carDoxyiate compound 01 tormula va, characterized by:
a) Its PXRD pattern having characteristic peaks at about 3.9, 6.6 and 23.7 ± 0.2° of 29;
b) its PXRD pattern as illustrated in figure-1.
Another aspect of the present invention provides a process for the preparation of crystalline trifluoro acetate salt of (S)-2-(7-bromo-9,9-difiuoro-9//-fluoren-2-yl)-2-oxoethyl 5-azaspiro[2.4]heptane-6-carboxylate of formula (Va), comprising the steps of:
a) Treating the (i')-6-(2-(7-bromo-9,9-ditluoro-9//-tluoren-2-yl)-2-oxoethyl) 5-(N-tert butoxy carbonyl)-5-azaspiro[2.4]heptane-5,6-dicarboxylate of formula (IVa) with trifluoro acetic acid in dichloromethane;
b) isolating the product obtained in step-a) to provide crystalline trifluoro acetate salt of (S)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl 5-azaspiro[2.4]heptane-6-carboxylate of formula (Va).
wherein, isolation is carried out as recrystallization from a suitable organic solvent selected from MTBE, diethyl ether, propyl ether; alkanes having C5-C7 straight or branched alkyl groups, preferably n-heptane or MTBE; aromatic hydrocarbons such as toluene, xylene and the like; halo hydrocarbons such as CH2C12, CHC13 and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and the like and the mixture of solvents.
Processes of the present invention are schematically represented as follows:
Schcmc-I:

The process described in the present invention was demonstrated in examples illustrated
below. These examples are provided as illustration only and therefore should not be
construed as limitation of the scope of the invention:
Examples:
Example-1: Preparation of (S)-6-(2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl)
5-tert-buty\ 5-azaspiro[2.4]heptanc-5,6-dicarboxylate
l-(7-Bromo-9,9-difluoro-9//-fIuoren-2-yl)-2-chloroethanone (6.399 gms) was added to a solution of potassium (S>5-(rer/-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylate (5 gms) in acetone (75 ml) at 25-30°C. Heated the reaction mixture to 55°C and stirred for 20-30 mins at same temperature. Cooled the reaction mixture to 50°C and add water (13.75 ml) and stirred for 1 hour at same temperature. Slowly cooled the reaction mixture to 20°C.

Filtered and washed the obtained compound with the mixture of acetone & water to get the solid compound and it is dried at 55°C (Yield: 8.5 gms).
Example-2: Preparation of crystalline trifluoro acetate salt of (5)-2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl-5-azaspiro [2.4]heptane-6-carboxylate
Dissolve (S>6-(2-(7-Bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl) 5-tert-butyl 5-azaspiro [2.4]heptane-5,6-dicarboxylate (5 gms) in methylene chloride (50 ml) at 25-30°C. To this reaction mixture,, trifluoroacetic acid (15 ml) was added at 25-30°C and stirred for 2 hours at same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. n-Heptane (50 ml) was added to the above obtained compound at 25-30°C and stirred for 30 min at the same temperature. Filtered the obtained compound and then dried to get solid crystalline compound (Yield: 4.5 gms MR: 98-100°C).
PXRD pattern of the solid compound obtained according to Ex-2 is illustrated in figure-1.
ExampIe-3: Preparation of crystalline trifluoro acetate salt of (S)-2-(7-bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl-5-azaspiro [2.4]heptane-6-carboxylate
Dissolve (S)-6-(2-(7-Bromo-9,9-difluoro-9//-fluoren-2-yI)-2-oxoethyl) 5-/er/-butyl 5-
azaspiro [2.4]heptane-5,6-dicarboxylate (5 gms) in methylene chloride (50 ml) at 25-30°C.
To this reaction mixture, trifluoroacetic acid (15 ml) was added at 25-30°C and stirred for 1-2
hours at the same temperature. Distilled off the solvent completely from the reaction mixture
under reduced pressure. Methyl tert-butyl ether (50 ml) was added to the obtained compound
at 25-30°C and stirred for 30 min. at the same temperature. Filtered the obtained compound
and then dried to get solid compound (Yield: 4.5 gms, MR: 98-100°C).
Example-4: Preparation of (S)-2-(7-bromo-9,9-difluoro-9iy-fluoren-2-yl)-2-oxoethyl 5-
((5)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]heptane-6-carboxy-late
(S>2-((Methoxycarbonyl)amino)-3-methylbutanoic acid (1.7 gms) and DMF (40 ml)
were charged into a clean and dried round bottom flask under nitrogen atmosphere. To this
reaction mixture, HOBt (1.2 gms) and EDC.HC1 (2.2 gms) were added and stirred for 10 to
15 min. at 25-30°C. Cooled the reaction mixture to 0-5°C and added trifluoro acetate salt of
(5)-2-(7-bromo-9!9-difluoro-9//-fluoren-2-yl)-2-oxoethyl-5-azaspiro[2.4]heptane-6-

carboxylate (4 gms) and diisopropylethylamine (6 ml) at 0-5°C. Raised the temperature of reaction mixture to 25-30°C and stirred for 1 hr. at the same temperature. Add water and ethyl acetate to the reaction mixture and separated the aqueous and organic layers. The organic layer was washed with aqueous sodium chloride followed by with sodium bicarbonate solutions. Separate the aqueous and organic layers. Distilled off the solvent completely from the organic layer under reduced pressure. Stirred the obtained compound in n-heptane (40 ml) for 10-15 mins. at-25-30°G, Filtered, washed and then dried the resulting material to provide the titled compound. (Yield: 2.9 gms).
Example-5: Preparation of methyl ((5)-l-((5)-6-(5-(7-bromo-9,9-difluoro-9i/-fluoren-2-yI)-l//-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyI-l-oxobutan-2-yl)carbamate
(S)-2-(7-Bromo-9,9-difluoro-9//-fluoren-2-yl)-2-oxoethyl 5-((S>2-((methoxycarbon-yl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]heptane-6-carboxylate (2.5 gms) and toluene (22.5 ml) were charged into a clean and dry round bottom flask. To this reaction mixture, ammonium acetate (1.56 gms) and 2-methoxy ethanol (1.25 ml) were added and heated the reaction mixture to 95-100°C and stirred for 5 hours. Cooled the reaction mixture to 25-30°C and added water to the reaction mixture. Separate the aqueous and organic layers. Distilled off the solvent completely from the organic layer to get the solid compound. Add n-heptane (25 ml) to the reaction mixture for 30 min at 25-30oC. The obtained compound was filtered, washed with n-heptane (5 ml) and dried to produce the title compound. (Yield: 1.89 gms.) Example-6: Preparation of (l/^S^-tert-butyl 3-(6-(9,9-difluoro-7-(2-((5)-5-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-azaspiro[2.4]heptan-6-yI)-l/r-imidazoI -5-yl)-9^-fluoren-2-yl)-l/^-benzo[d]imidazol-2-yl)-2-azabicycIo[2.2.1]heptane-2-carboxy late
(1 ^,35,4S)-7,e/-/-butyl3-(6-(4,4J5)5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1 tf-benzo [d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (3 gms) dissolved in 1,2-dimethoxyethane (30 ml) at 25-30°C. To this reaction mixture, methyl ((iS)-l-((5)-6-(5-(7-bromo-9,9-difluor6-9//-fluoren-2-yl)-l//-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-l-oxobutan-2-yl)carbamate (2.44 gms) and K2CO3 (2.91 gms) were added under nitrogen atmosphere and maintained for 10 to 15 min. at 25-30°C. Pd(PPh3)4 (0.785 gms) was charged into the above reaction mixture under nitrogen atmosphere and heated the

reaction mixture to reflux temperature and stirred for 45 mins. at same temperature. Cooled the reaction mixture to 25-30°C and dissolved in water (30 ml) and ethyl acetate (30 ml) mixture. Separated the aqueous and organic layers. Organic layer was washed with 10% NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure. Add n-heptane (30 ml) to the obtained compound and stirred for 1 hour at 25-30°C. The obtained compound was filtered, washed with n-heptane (6 ml) and dried to produce the title compound. (Yield; 3.75 gms.)
Example-7: Preparation of methyl [(21S)-l-{(65)-6-[5-(9,9-difluoro-7-{2-[(l/f,35,45)-2-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-a2abicyclo[2.2.1]hept-3-yI]-l/r-benzimidazol-6-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl] carbamate compound of formula (I)
(l*,3S,4S)-7erM>utyl 3-(6-(9,9-difluoro-7-(2-((S)-5-((S)-2-((methoxycarbonyl)
amino)-3-methylbutanoyl)-5-azaspiro[2.4]heptan-6-yl)-l//-imidazol-5-yl)-9//-fluoren-2-yl)-l//-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (3 gms) dissolved in ethyl acetate (9 ml) in a round bottom flask at 25-30°C. To this reaction mixture, ethyl acetate hydrochloride (30 ml) was added and stirred for 1-2 hours at 25-30°C. The obtained compound was filtered and washed with ethyl acetate (3 ml) to produce the tri hydrochloride salt compound.
(S)-2-((MethoxycarbonyI)amino)-3-methylbutanoic acid (1.74 gms) and dimethyl formamide (50 ml) were charged into a clean and dried round bottom flask under nitrogen atmosphere. To this reaction mixture, HOBt (1.2 gms) and EDC.HC1 (2.2 gms) were added and stirred for 10 to 15 min. at 25-30°C. Cooled the reaction mixture to 0-5°C and added the above obtained trihydrochloride salt compound. To this reaction mixture, N-methyl morpholine (3.41 ml) was slowly added at 0-5°C and raised the temperature to 25-30°C and stirred for 1-2 hours at 25-30°C temperature. Add water (2.5 ml) to the reaction mixture and stirred for 50-55 mins. at 25-30°C. Add water and ethyl acetate to the reaction mixture and separated the aqueous and organic layers. The organic layer was washed with aqueous sodium chloride solution and aqueous sodium bicarbonate solution. Separated the aqueous

and organic layers. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound (Yield: 5 gms).
Example-8: Purification of Ledipasvir of formula (I)
Add methyl [(25)-l-{(65)-6-[5-(9)9-difluoro-7-{2-[(lJR,35)4^-2-{(25)-2-[(methoxy carbonyOaminoJ-S-methylbutanoylJ^-azabicyclo^^.lJhept-S-ylJ-l^-benzimidazol-e-yl}-9//-fluoren-2-yl)-l//-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl] carbamate (1.5 gms) in acetonitrile (10.5 ml) solution to the water (60 ml) in a round bottom flask at 20±25°C and stirred the reaction mixture for 1 hr. at the same temperature. Filtered, washed the obtained compound with water (3 ml) and dried to get the pure title compound. (Yield: 66.6%)
Example-9: Preparation of (SJ-tert-butyl 6-(5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)-9H-fluoren-2-yl)-li/-iinidazol-2-yl)-S-azaspiro[2,4]heptane-5-
carboxylate
Add bis(pinacolato)diboran (2.57 gms) and potassium acetate (2.7 gms) to (S)-tert-butyl-6-(5-(7-bromo-9)9-difluoro-9//-fluoren-2-yl)-l//-imidazol-2-yl)-5-azaspiro[2J4] heptane-5-carboxylate (5 gms) in isopropyl acetate (50 ml) solution at 25-30°C. Pd(dppf)Cl2 (0.15 gms) was added to the reaction mixture at 25-30°C and then heated the reaction mixture to 80-85°C and stirring for 2 hrs at same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed with isopropyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure to get the title compound. (Yield: 4.7 gms).
Example-10: Preparation of (5)-tert-butyl 6-(5-(9,9-dinuoro-7-(2-((lJR,35,45)-2-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyI)-2-a2abicyclo[2.2.1]heptan-3-yl)-l^-
benzo[d]imidazo]-6-yI)-9ff-fluoren-2-yI)-l^/-imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylate
Add methyl ((5)-l-((l^335345)-3-(6-bromo-l//-benzo[d]imidazol-2-yl)-2-a2abicyclo [2.2.1]heptan-2-yl)-3-methyl-l-oxobutan-2-yl)carbamate (2.07 gms) to a solution of (S)-tert-butyl 6-(5-(9,9-difluoro-7-(43435,5-tetramethyl-1,332-dioxaborolan-2-yl)-9tf-fluoren-2-yl)-

l//-imidazol-2-yl)-5-azaspiro[2,4] heptane-5-carboxylate (3 gms) in isopropyl acetate (30 ml) under nitrogen atmosphere at 25-30°C. Pd(PPh3)4 (0.416 gms), K2C03 (1.9 gms) and water (9 ml) were added to the above reaction mixture at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 9-10 hours at the same temperature. Filtered the reaction mixture on hyflow bed and washed with isopropyl acetate. Separated the aqueous and organic layers and then distilled off the solvent completely from the organic layer under reduced pressure to get the title compound (Yield: 3.17 gms).
Example-11: Preparation of 2-((l/^3£,4S)-2-azabicyclo[2 J.l]heptan-3-yl)-6-bromo-li7-benzo[J] imidazole dihydrochloride
Ethyl acetate hydrochloride (100.0 ml) was added to a mixture of (lR,3S,4S)-tert-butyl 3-(6-bromo-1 //-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1 ] heptane-2-carboxylate (10.0 gms) and ethyl acetate (30.0 ml) at 25-30°C and stirred for 50 min. at same temperature. Filtered the obtained material and washed with methyl /erf-butyl ether and then dried to get the title compound (Yield: 7.0 gms, %: 75.2 %, Mass: 292.2).
Example-12: Preparation of methyl ((S)-l-((l/f,35,45)-3-(6-bromo-li/-benzold] imidazoI-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyI-l-oxobutan-2-yl)carbamate
2-((1^35,45)-2-A2abicyclo[2.2.1]heptan-3-yl)-6-bromo-l//-benzo[£/]imida2ole dihydrochloride (5.0 gms) was added to a mixture of dimethoxy ethane (50 ml), (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid (3.8 gms), HOBt (2.1 gms) and EDC.HC1 (4.17 gms) at 0-5°C. N-Methylmorpholine (7.5 ml) was added to the above reaction mixture at 0-5cC. Heated the reaction mixture to 25-30° and stirred for 30 min at same temperature. Quenched the reaction mixture in water and ethyl acetate was added to the reaction mixture. Separated the both organic & aqueous layers and extracted the aqueous layer with ethyl acetate. Combined all the organic layers and then washed with water. Separated the both organic & aqueous layers and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound (Yield: 2.6 gms, % of yield: 42.2%, Mass: 449.2).

Example-13: Preparation of (5)-tert-butyl 6-(5-(9,9-difluoro-7-(2-((l/?,35,45)-2-((5)-2-
((methoxycarbonyl)amino)-3-methylbutanoyI)-2-azabiyclo[2.2.1]heptan-3-yI)-l/T-
benzo[d]imidazol-6-yl)-9/T-fluoren-2-yl)-l^-imidazol-2-yl)-5-azaspiro[2,4]heptan-5-carboxylate
Methyl ((53-l-((l^)31SJ4^)-3-(6-bromo-l//-benzo[^imidazole-2-yl)-2-azabicyclo [2.2.1]heptane-2-yl)-3-methyl-l-oxobutan-2-yl)carbamate (25 gms), dimethoxy ethane (250 ml), bis(pinacolato)diboran (16.9 gms) and potassium acetate (16.3 gms) were mixed in a round bottom flask under nitrogen atmosphere at 25-30°C. Pd(dppf)Cl2 (1.36 gms) was added to the above reaction mixture and heated to 85-90°C and stirred for 2 hours at same temperature. Cooled the reaction mixture to 25-30°C followed by filtered through hyflow-bed and then washed with dimethoxy ethane to get borylated compound.
Methyl ((5)-l-((l^,35)45)-3-(6-bromo-l//-benzo[rf]imidazole-2-yl)-2-a2abicyclo [2.2.1]heptane-2-yl)-3-methyl-l-oxobutan-2-yl)carbamate (24.1 gms) and Pd(PPh3)4 (1.27 gms) were added to the above obtained borylated compound under nitrogen atmosphere at 25-30°C. Basify the reaction mixture with aqueous K2C03 solution (20.7 gms dissolved in 75 ml of water) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 6 hours at same temperature. Filtered the reaction mixture through hyflow supercell and washed with dimethoxy ethane. Separated the organic & aqueous layers and distilled off the solvent completely from the organic layer under reduced pressure. Cyclohexane (125 ml) was added to the above distillate at 25-30°C and stirred for 10 min at same temperature. Filtered the obtained material and then dried to get title compound (Yield: 43 gms, 92.9%).
Example-14: Preparation of methyl ((5)-l-((l/?,35,45)-3-(6-(7-(2-((5)-5-azaspiro
[2,4]heptan-6-yl)-l^-imidazol-5-yI)-9,9-difluoro-2-yl)-l^-fluoren-2-yl)-l^-benzo[d]
imidazo]-2-yl)-2-azabicycIo[2,2,l]heptan-2-yl)-3-methyl-l-oxobutan-2-yl)carbamate trihydrochloride
A mixture of (5)-tert-butyl 6-(5-(9,9-difluoro-7-(2-((l^,35,4S)-2-((S)-2-((methoxy carbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[2,2,1 ]heptan-3-yl)-1 //-benzo[d]imidazol-6-yl)-9//-fluoren-2-yl)-l //-imidazol-2-yl)-5-azaspiro[2,4]heptane-5-carboxylate (12 gms), acetonitrile (12 ml) and hydrochloric acid (18 ml) were stirred for 2 hours at 25-30°C.
20

Acetonitrile (240 ml) was slowly added to the above reaction mixture at 25-30°C and stirred for 15 min at same temperature. Filtered the material and washed with acetonitrile and then dried under reduced pressure to get the title compound. (Yield: 8.79 gms)
Example-15: Preparation of Ledipasvir of formula (I)
(S>2-((Methoxycarbonyl)amino)-3-methylbutanoic acid (0.69 gms) and dimethyl formamide (9 ml) were charged into a clean and dried round bottom flask under nitrogen
atmosphirFTOhis reactlohlmTt^
and stirred for 10 to 15 min. at 25-30°C. Cooled the reaction mixture to 0-5°C and added the methyl ((^-l-((l*,35,4S)0-(6-(7-(2-((5)-5-azaspiro[2J4]heptan-6-yl)-l//-imidazol-5-yl)-9,9-difluoro-2-yl)-1 //-fluoren-2-yl)-1 //-benzo[d]imidazol-2-yl)-2-azabicyclo[2,2,1 ]heptan-2-yl)-3-methyl-l-oxobutan-2-yl)carbamate trihydrochloride (3 gms). To this reaction mixture, diisopropylethylamine (3.1 ml) was slowly added at 0-5°C and raised the temperature to 25-30°C and stirred for 1-2 hours at 25-30°C temperature. Add water (2.5 ml) to the reaction mixture and stirred for 50-55 mins. at 25-30°C. Add ethyl acetate (24 ml) to the reaction mixture and separated the aqueous and organic layers. The organic layer was washed with 5% aqueous sodium bicarbonate solution and 10% aqueous sodium chloride solution consecutively. Separated the aqueous and organic layers. Distilled off the solvent completely from the organic layer under reduced pressure to get the crude material. The above obtained crude material was dissolved in ethyl acetate (6 ml) and added to acetone (24 ml) at 25-30QC and stirred for 70 min. at same temperature. Filtered the material and washed with acetone and then dried to get the title compound (Yield: 1.5 gms, 47.3%, Purity: 95.27%).
Mass: 889.5, IR Values: 3376.53, 3149.27, 3077.86, 2962.41, 2875.95, 2082.44, 1801.02, 1709.53, 1674.15, 1622.05, 1520.11, 1450.81, 1384.11, 1362.29, 1333.24, 1314.28, 1302.70, 1277.91, 1257.95, 1136.01, 1096.51, 1067.97, 1038.68, 1050.65, 1023.10, 990.46, 959.78, 940.61, 902.62, 872.52, 833.43, 809.85, 781.85, 743.29, 726.08, 665.60, 634.80, 622.08, 614.23,587.81,549.09,529.80.