FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of compound of formula I and its pharmaceutical acceptable salts or solvates thereof, which is useful as an antiviral agent.

BACKGROUND OF THE INVENTION

Ledipasvir is chemically known as Methyl [(2S)-l- {(6S)-6-[5-(9,9-difluoro-7{2-

[(lR,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbu tanoyl}-

2azabicyclo [2.2.1] hept-3 -yl] - 1 H-benzimidazol-6-yl } -9H-fluoren-2-yl)- 1 H-imidazol-2- yl]-5azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carbam ate. Ledipasvir is a hepatitis C virus (HCV) NS5A inhibitor. Ledipasvir is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults (1) and it is marketed as under the brand name HARVONI®.

The present disclosure relates generally to the field of an improved process for the preparation of formula (I). Hepatitis C is recognized as a chronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness.

Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.

Ledipasvir and its pharmaceutical acceptable salts are first disclosed in US 8,088,368 B2, and its process for the preparation discloses as 2,7-dibromo-fluoren-9-one (II) is reacted with deoxofluor to produce 2,7-dibromo-9,9-difluoro-9H-fluorene (III). The compound of formula (III) is condensed with N-Cbz-4-cyclopropyl (L) proline in presence of Pd catalyst and ethoxyvinyltributyl tin and DIEA to produce the compound of formula (IV). The compound of formula (IV) is cyclized in presence of m-xylene / ammonium acetate to produce the compound of formula (V), Further it is condensed with 2-(L)- methoxycarbonylamino-3-butyric acid (VI) in presence of DIEA in HATU and solvent to produce the compound of formula (VII). The compound of formula (VII) is condensed with compound of formula (VIII) in presence of Pd catalyst and base to produce the compound of formula (IX). Finally the compound of formula (ΓΧ) is coupled with methoxy carbonyl L-valine of formula (VI) in presence of DIEA in HATU and solvent to produce the compound of formula (I).

The above process is schematically as shown in below:

US 9,056,860 B2 also discloses the process for the preparation of compound of formula (I) comprises as the compound of formula (V) is condensed with compound of formula (Vin) in presence of PdCb [P (t-Bu) ₂ Ph]2 or palladium acetate and base to produce the compound of formula (III), followed by deprotection to produce the compound of formula (IV). Finally the compound of formula (IV) is coupled with carbonyl L-valine of formula (VI) to produce compound of formula (I).

The above process is schematically as shown in below

WO 2013/184698 Al discloses amorphous form and various crystalline forms of compound of formula (I) and its salts or solvates thereof, This disclosure also provides process for the preparation of making the amorphous form and crystalline forms and methods for using them in the treatment of HCV.

The major disadvantage with the above prior art process was used catalysts and solvents are very high expensive cost and effects the yield with the amount of by-products and impurities, the said prior art process for preparing Ledipasvir is not optimal for industrial scale production.

Hence, there is consequently a need for an improved method for the preparation of Ledipasvir and its intermediates which does not involves the problems described above. The present invention for the preparation of Ledipasvir particularly should be in fewer impurities, industrially applicable, allowing the desired compounds to be obtained with high yields.

The inventors of the present invention have developed an improved process for preparing Ledipasvir towards as eco-friendly, cost-effective, good yield and high purity. SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of compound of formula I and it's also provides industrial applicable, commercially and eco-friendly viable process for the preparation of Ledipasvir.

One aspect of the present invention is to provide an improved process for the preparation of Ledipasvir of compound of formula (I) and its salts comprising the steps of;

a. (lR,3S,4S)-3-(6-bromo-lH-benzimidazol-2-yl)-2-azabicyclo[2.2 .1]heptane-2- carboxylic acid 1,1 -dimethyl ethyl ester of formula (X) is reacted with bis(pinacolato)diboron in presence of base / Pd or Ni catalyst and solvent to produce (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )-lH- benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane -2-carboxylic acid 1,1- dimeth lethyl ester (VIII).

Wherein Pd or Ni catalyst selected from dichloro bis (di-tert- butylphenylphosphine) palladium (II) or dichloro bis (di-tert- butylphenylphosphine) nickel (II),

b. condensing (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- benz imidazol-2-yl]-2-azabicyclo [2.2.1] heptane-2-carboxylic acid 1,1- dimethylethyl ester of formula (VIII) with (6S)-6-[5-(7-bromo-9,9-difluoro-9H- fluoren-2-yl)-lH-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-car boxylic acid 1,1- dimethylethyl ester of formula (V) in presence of palladium or nickel catalyst / solvent; optionally using triphenyl phosphine (TPP) at argon atmosphere to produce (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5- azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9-difluoro-9H- fluoren-2-yl)-lH- benzo [d]imidazol-2-yl)-2-azabicyclo[2.2.1] heptane -2-carboxylate of formula (III).

Wherein the Pd or Ni catalyst selected from dichloro bis triphenyl phosphene palladium (II) or dichloro bis triphenyl phosphene nickel (II),

c. deprotecting (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5- azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9-difluoro-9H- fluoren-2-yl)-lH- benzo[d]imidazol-2-yl)-2-azabicyclo[2.2. l]heptane-2-carboxylate of formula (III) in presence of acid to produce 6-(7-(2-((S)-5-azaspiro[2.4]heptan-6-yl)-lH- imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((lR,3S,4S)-2 - azabicyclo[2.2. l]heptan-3-yl)-lH-benzo[d]imidazole, free base of formula (IV).

d. coupling of compound of formula (IV) with methoxy carbonyl L-valine of formula (VI) in presence of HOBT / EDC.HCl (or) HATU / EDC.HCl and base to produce Ledipasvir (I).

Another aspect of the present invention also provides an improved process for the preparation of compound of formula (III) by novel catalysts.

condensing (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- benz imidazol-2-yl]-2-azabicyclo [2.2.1] heptane-2-carboxylic acid 1,1- dimethylethyl ester of formula (VIII) with (6S)-6-[5-(7-bromo-9,9-difluoro-9H- fluoren-2-yl)-lH-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-car boxylic acid 1,1- dimethylethyl ester of formula (V) in presence of palladium or nickel catalyst / solvent; optionally using triphenyl phosphine (TPP) at argon atmosphere to produce (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5- azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9-difluoro-9H- fluoren-2-yl)-lH- benzo [d]imidazol-2-yl)-2-azabicyclo[2.2.1] heptane -2-carboxylate of formula (III).

Wherein the Pd or Ni catalyst selected from dichloro bis triphenyl phosphene palladium (II) or dichloro bis triphenyl phosphene nickel (II). In another aspect of the present invention also provides a process for the preparation of Ledipasvir acetone solvate and further converts into amorphous form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved, cost-effective and eco-friendly process for the preparation of Ledipasvir (I) in good yield with high purity.

In one embodiment of the present invention is to provide an improved process for the preparation of Ledipasvir of compound of formula (I) and its salts comprising the steps of; a. (lR,3S,4S)-3-(6-bromo-lH-benzimidazol-2-yl)-2-azabicyclo[2.2 .1]heptane-2- carboxylic acid 1,1 -dimethyl ethyl ester of formula (X) is reacted with bis(pinacolato)diboron in presence of base / Pd or Ni catalyst and solvent to produce (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )-lH- benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane -2-carboxylic acid 1,1- dimeth lethyl ester (VIII).

Wherein Pd or Ni catalyst selected from dichloro bis (di-tert- butylphenylphosphine) palladium (Π) or dichloro bis (di-tert- butylphenylphosphine) nickel (II), b. condensing (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- benz imidazol-2-yl]-2-azabicyclo [2.2.1] heptane-2-carboxylic acid 1,1- dimethylethyl ester of formula (VIII) with (6S)-6-[5-(7-bromo-9,9-difiuoro-9H- fluoren-2-yl)-lH-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-car boxylic acid 1,1- dimethylethyl ester of formula (V) in presence of palladium or nickel catalyst / solvent; optionally using triphenyl phosphine (TPP) at argon atmosphere to produce (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5- azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9-difluoro-9H- fluoren-2-yl)-lH- benzo [d]imidazol-2-yl)-2-azabicyclo[2.2.1] heptane -2-carboxylate of formula

(III).

Wherein the Pd or Ni catalyst selected from dichloro bis triphenyl phosphene palladium (II) or dichloro bis triphenyl phosphene nickel (II),

c. deprotecting (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5- azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9-difluoro-9H- fluoren-2-yl)-lH- benzo[d]imidazol-2-yl)-2-azabicyclo[2.2. l]heptane-2-carboxylate of formula (III) in presence of acid to produce 6-(7-(2-((S)-5-azaspiro[2.4]heptan-6-yl)-lH- imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((lR,3S,4S)-2 - azabicyclo[2.2. l]heptan-3-yl)-lH-benzo[d]imidazole, free base of formula (IV).

d. coupling of compound of formula (IV) with methoxy carbonyl L-valine of formula

(VI) in presence of HOBT / EDC.HC1 (or) HATU / EDC.HC1 and base to produce Ledipasvir (I).

According to the embodiment of present invention, wherein step a) the compound of formula (X) is reacted with bis (pinacolato) diboron of formula (XI) in presence of base / Pd or Ni catalyst and solvent to produce compound of formula (VIII), further it is condensing with compound of formula (V) in presence of dichloro bis triphenyl phosphene palladium (II) or dichloro bis triphenyl phosphene nickel (II) / solvent; optionally using triphenyl phosphine (TPP) at argon atmosphere to produce the compound of formula (III); followed by deprotecting in presence of acid to produce the free base compound of formula (IV). Finally, coupling of compound of formula (IV) with methoxy carbonyl L-valine of formula (VI) in presence of HOBT / EDC.HC1 (or) HATU / EDC.HC1 and base to produce Ledipasvir (I).

Another embodiment of the present invention is providing an improved process for the preparation of compound of formula (III) by novel catalysts. condensing (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benz imidazol-2-yl]-2-azabicyclo [2.2.1] heptane-2-carboxylic acid 1 , 1 -dimethylethyl ester of formula (VIII) with (6S)-6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol -2- yl]-5-azaspiro[2.4]heptane-5-carboxylic acid 1,1-dimethylethyl ester of formula (V) in presence of palladium or nickel catalyst / solvent; optionally using triphenyl phosphine (TPP) at argon atmosphere to produce (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert- butoxy carbonyl)-5-azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9- difluoro-9H- fluoren-2-yl)-lH-benzo [d]imidazol-2-yl)-2-azabicyclo[2.2.1] heptane -2-carboxylate of formula (III).

Wherein the Pd or Ni catalyst selected from dichloro bis triphenyl phosphene palladium (II) or dichloro bis triphenyl phosphene nickel (II),

According to the embodiments of the present invention, the solvent is selected from dimethyl formamide, 1,4-dioxane, ethanol, methanol, dichloromethane (DCM), tetrahydrofuran (THF), ethylacetate, acetone and water; the alkali carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate; the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium propionate, potassium propionate, sodium acetate, potassium acetate, lithium propionate, methyl amine, ethyl amine, Ν,Ν-diisopropyl ethyl amine, aniline; the catalyst is selected from palladium acetate, tetrakis triphenyl phosphene palladium (II), dichloro bis(di-tert- butylphenylphosphine)palladium (II), dichloro bis triphenyl phosphene palladium (II), dichloro [ 1 , 1 ' -bis(diphenylphosphino)f errocene] palladium(II), bis [di-tert-butyl(4- dimethylaminophenyl)phosphino] palladium(II) chloride, bis [di-(tert-butyl(4- dimethylaminophenyl)phosphino] palladium (II) chloride, and bis[di-(tert-butyl)(4- fluoromethylphenyl)phosphine]palladium(II) chloride; the nickel catalyst is selected from tetrakis triphenyl phosphene nickel (II), dichloro bis(di-tert-butylphenylphosphine)nickel (II), dichloro bis triphenyl phosphene nickel (II), dichloro[l,l '- bis(diphenylphosphino)ferrocene]nickel(II), bis[di-tert-butyl(4- dimethylaminophenyl)phosphino] nickel (II) chloride, bis[di-(tert-butyl(4- dimethylaminophenyl)phosphino] nickel (Π) chloride, and bis[di-(tert-butyl)(4- fluoromethylphenyl)phosphine]nickel(II) chloride; the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydro sulfuric acid, acetic acid, trifluoroacetic acid, coupling agents HOBT / EDC.HCl (or) HATU / EDC.HCl; the phosphine is selected from triphenylphosphine, tri(2-methoxyphenyl)phosphine, tricyclohexylphosphine, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino- 2'-methylbiphenyl, 2-(dicyclohexylphosphino)-2'-(N,N-dimethylamino)biphenyl, 2-(di- tert-butylphosphino)-2'-(N,N-dimethylamino)biphenyl, dicyclohexyl(2,2-diphenyl-l- methylvinyl)phosphine like that.

In yet another embodiment of the present invention provides a process for the preparation of Ledipasvir acetone solvate and further converts into amorphous form.

According to the present invention, the Ledipasvir is dissolved in organic solvent like THF / DCM / ethyl acetate / methanol / ethanol / Isopropanol / isopropyl acetate, stirred at room temperature; organic solvent was evaporated under reduced pressure to get a residue and followed by acetone to isolate Ledipasvir acetone solvate.

Further Ledipasvir acetone solvate is dissolved in an organic solvent to get a clear solution, added activated carbon, stirred at 0 to 5°C and filter through high flow bed. The obtain filtrate was stir and cooled to 0 to 5°C; optionally adding anti solvent like water, methyl tertiary butyl ether, hexane, heptane and the like to get solid. The resultant solid was filtered and dried at 70 to 90° to obtain Ledipasvir amorphous form. The process details of the invention are provided in the example given below, which are provide by way of illustration only and therefore should not be construed to limit the scope of the invention.

Examples;

Example-1: Preparation of (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-car boxylic acid 1,1- dimethylethyl ester

(lR,3S,4S)-3-(6-bromo-lH-benzimidazol-2-yl)-2-azabicyclo[2.2 .1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (25 g) was suspended in 1,4 dioxane (250 ml), followed by addition of bis(pinacolate) diboron (35.5 g), dichlorobis(di-tert- butylphenylphosphine)palladium(II) catalyst (1.5 g) and potassium acetate (18 g) at room temperature and allow to raise the temperature 80-85°C for 2-3 hours till it complies the reaction. The reaction completion is confirm by TLC, the solvent (1, 4 dioxane) was distilled out under reduced pressure and the reaction mass was cooled to room temperature by adding purified water and dichloromethane, to separate the layers. The organic layer was distilled out under reduced pressure to get a residue and further it is treated with cyclohexane to get a solid. Finally, the resultant solid was filtered and dried over at 40- 50°C to obtain a titled compound (26 g).

Example-2: Preparation of (lR,3S,4S)-3-[6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-car boxylic acid 1,1- dimethylethyl ester

(lR,3S,4S)-3-(6-bromo-lH-benzimidazol-2-yl)-2-azabicyclo[ 2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (25 g) was suspended in dimethyl formamide (250 ml), followed by addition of bis(pinacolate) diboron (35.5 g), dichlorobis(di-tert- butylphenylphosphine)nickel(II) catalyst (1.5 g) and sodium acetate (18 g) at room temperature and allow to raise the temperature 80-85°C for 2-3 hours till it complies the reaction. The reaction completion is confirm by TLC, the solvent (dimethyl formamide) was distilled out under reduced pressure and the reaction mass was cooled to room temperature by adding purified water and dichloromethane, to separate the layers. The organic layer was distilled out under reduced pressure to get a residue and further it is treated with hexane to get a solid. Finally, the resultant solid was filtered and dried over at 40-50°C to obtain a titled compound (29 g).

Example-3 : Preparation of (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9- difluoro-9H-fluoren-2- yl)- lH-benzo [d] imidazol-2-yl)-2-azabicyclo [2.2.1] heptane-2-carboxylate.

1,4 dioxane (370 ml) and purified water (250 ml) were added to (lR,3S,4S)-3-[6-(4,4,5,5- tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl] -2- azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (25 g) at room temperature, followed by addition of, dimethylformamide (35 ml ), sodium carbonate(15 g), (6S)-6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol -2-yl]-5- azaspiro[2.4]heptane-5-carboxylic acid 1,1-dimethylethyl ester (25 g), triphenyl phosphine (1.25 g) and dichloro bis triphenyl phosphine palladium (II) catalyst (0.6 gm) under argon atmosphere at room temperature. The reaction mixture temperature was raised to 80-85°C and maintained for 1-3 hours. After completion of reaction (checked by TLC), the solvent was filtered through high flow bed and the filtrate was distilled out under reduced pressure, cooled to room temperature, followed by addition of water to isolate free base solid of title compound (25 -30 g).

Example-4 Preparation of (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9- difluoro-9H-fluoren-2- yl)- lH-benzo [d] imidazol-2-yl)-2-azabicyclo [2.2.1] heptane-2-carboxylate

Tetrahydrofuran (370 ml) and purified water (250 ml) were added to (lR,3S,4S)-3-[6- (4,4, 5, 5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl] -2- azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (25 g) at room temperature, followed by addition of, sodium carbonate(15 g), (6S)-6-[5-(7-bromo-9,9- difluoro-9H-fluoren-2-yl)-lH-imidazol-2-yl]-5-azaspiro[2.4]h eptane-5-carboxylic acid 1,1-dimethylethyl ester (25 g), triphenyl phosphine (1.25 g) and palladium chloride catalyst (0.6 gm) under argon atmosphere at room temperature. The reaction mixture temperature was raised to 80-85°C and maintained for 1-3 hours. After completion of reaction (checked by TLC), the solvent was filtered through high flow bed and the filtrate was distilled out under reduced pressure, cooled to room temperature, followed by addition of water to isolate free base solid of title compound (25 -30 g).

Example-5 : Preparation of (lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptan-6-yl)-lH-imidazol-5-yl)-9,9- difluoro-9H-fluoren-2- yl)- lH-benzo [d] imidazol-2-yl)-2-azabicyclo [2.2.1] heptane-2-carboxylate

1,4 dioxane (370 ml) and purified water (250 ml) were added to (lR,3S,4S)-3-[6-(4,4,5,5- tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl] -2- azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl ester (25 g) at room temperature, followed by addition of, dimethyl formamide (35 ml), sodium carbonate(15 g), (6S)-6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-lH-imidazol -2-yl]-5- azaspiro[2.4]heptane-5-carboxylic acid 1,1-dimethylethyl ester (25 g), triphenyl phosphine (1.25 g) and dichloro bis triphenyl phosphine nickel (II) catalyst (0.6 gm) under argon atmosphere at room temperature. The reaction mixture temperature was raised to 80-85°C and maintained for 1-3 hours. After completion of reaction (checked by TLC), the solvent was filtered through high flow bed and the filtrate was distilled out under reduced pressure, cooled to room temperature, followed by addition of water to isolate free base solid of title compound (25 -30 g). Example-6 : Preparation of 6-(7-(2-((S)-5-azaspiro[2.4]heptan-6-yl)-lH-imidazol-5- yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((lR,3S,4S)-2-azabicyclo [2.2.1]heptan-3-yl)-lH- benzo[d] imidazole

(lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptan-6- yl)- 1 H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)- 1 H-benzo[d]imidazol-2-yl)-2- azabicyclo [2.2.1] heptane -2-carboxylate (30 g) was suspended in 1, 4 dioxane (180 ml) and treated with hydrochloric acid (30 ml) at room temperature, the reaction mixture temperature was raised to 70-75°C and maintained for 1-2 hours. After complies of reaction (checked by TLC), the reaction mass was cooled to 25-30°C. The resultant solid was filtered and washed with 1, 4-dioxane, obtain wet solid was suspended with purified water (100 ml) and its P ^H was adjusted to 8-9 with 5% sodium carbonate solution under stir condition and maintained for 30 minutes. The resulting slurry was filtered and dried under vacuum to obtain the titled compound 22-25 g.

Example-7: Preparation of 6-(7-(2-((S)-5-azaspiro [2.4] heptan-6-yl)-lH-imidazol-5- yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((lR,3S,4S)-2-azabicyclo [2.2.1]heptan-3-yl)-lH- benzo[d] imidazole

(lR,3S,4S)-tert-butyl 3-(6-(7-(2-((S)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptan-6- yl)- 1 H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)- 1 H-benzo[d]imidazol-2-yl)-2- azabicyclo [2.2.1] heptane -2-carboxylate (30 g) was suspended in ethyl acetate (180 ml) and treated with hydrochloric acid (30 ml) at room temperature, the reaction mixture temperature was raised to 70-75°C and maintained for 1-2 hours. After complies of reaction (checked by TLC), the reaction mass was cooled to 25-30°C. The resultant solid was filtered and washed with ethyl acetate, obtain wet solid was suspended with purified water (100 ml) and its P ^H was adjusted to 8-9 with 5% sodium carbonate solution under stir condition and maintained for 30 minutes. The resulting slurry was filtered and dried under vacuum to obtain the titled compound 22-25 g. Example-8 : Preparation of methyl[(2S)-l-{(6S)-6-[5-(9,9-difluoro-7-{2-[(lR,3S,4S)- 2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabi cyclo[2.2.1]hept-3- yl] - lH-benzimidazol-6-yl}-9H-fluoren-2-yl)- lH-imidazol-2-yl] -5-azaspiro [2.4] hept- 5-yl}-3-methyl-l-oxobutan-2-yl]carbamate propan-2-one [Ledipasvir Acetone solvate]

Methoxycarbonyl L-valine (11.25 g), hydroxybenzotriazole (9.25 g) & l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.25 g) and dichloromethane (250 ml) were charged to a flask. The reaction mixture was agitated for 20 minutes for 23°C, and then solution was cooled to 0-5°C. 6-(7-(2-((S)-5-azaspiro [2.4] heptan-6-yl)- lH-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-2-((lR,3S,4S )-2- azabicyclo[2.2.1]heptan-3-yl)-lH-benzo[d]imidazole (25 g) and add di isopropyl ethylamine (20 g) were added to reaction mixture and contents were stirred for at same temperature and maintained for 4 hours. After complies of reaction, water was added to the reaction mass and separate the two layers. The organic layer was washed with sodium bi carbonate and water. The organic layer was distilled to half of volume and cooled; further acetone was added to the organic layer. The reaction contents were seeded with Ledipasvir (acetone as a solvate) and stirred for 4 hours. The contents were filtered and washed with acetone and the cake was dried to Ledipasvir acetone as a solvate (20-25 g).

Example-9 : Preparation of methyl[(2S)-l-{(6S)-6-[5-(9,9-difluoro-7-{2-[(lR,3S,4S)- 2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabi cyclo[2.2.1]hept-3- yl] - ΙΗ-benz imidazol-6-yl}-9H-fluoren-2-yl)- lH-imidazol-2-yl] -5-azaspiro [2.4] hep t- 5-yl}-3-methyl-l-oxobutan-2-yl]carbamate propan-2-one [Ledipasvir Acetone solvate ]

Methoxycarbonyl L-valine (11.25 g) was suspended in toluene (250 ml) to get a clear solution and allow to cool at 0-5°C, added hydroxybenzotriazole (9.25 g), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.25 g), 6-(7-(2-((S)-5- azaspiro [2.4] heptan-6-yl)-lH-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl) -2- ((lR,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-lH-benzo[d]imida zole (25 g) and di isopropyl ethylamine (20 g) at same temperature and allow to stir at 0-5 ° C till it complies the reaction. After complies of reaction, water was added to the reaction mass and separate the two layers. The organic layer was washed with sodium bi carbonate and water. The organic layer was distilled under reduced pressure to get a residue and followed by acetone (15 ml) to isolate Ledipasvir acetone solvate.

Example-10 : Preparation of methyl[(2S)-l-{(6S)-6-[5-(9,9-difluoro-7-{2- [(lR,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutan oyl}-2- azabicyclo [2.2.1] hept-3-yl] - lH-benzimidazol-6-yl}-9H-fluoren-2-yl)- lH-imidazol-2- yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carba mate propan-2-one [Ledipasvir Amorphous]

Ledipasvir acetone solvate (100 gm.) was suspended in methanol (500 ml) at 0-5°C and stir for 10 minutes to get a clear solution, added norit activated carbon (5 g) to the clear solution and stirred at 0-5°C for 20-30 minutes. The reaction mass was filter through high flow bed and obtain filtrate was added to pre-chilled purified water (500 ml) and stir for 60-90 minutes at 0-5°C. The resultant solid was filtered, washed with water and dried at 70-80°C to obtain 80-88gm of Ledipasvir amorphous form.

Example-11 : Preparation of methyl[(2S)-l-{(6S)-6-[5-(9,9-difluoro-7-{2- [(lR,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutan oyl}-2- azabicyclo [2.2.1] hept-3-yl] - lH-benzimidazol-6-yl}-9H-fluoren-2-yl)- lH-imidazol-2- yl]-5-azaspiro[2.4]hept-5-yl}-3-methyl-l-oxobutan-2-yl]carba mate propan-2-one [Ledipasvir Amorphous]

Ledipasvir acetone solvate (100 gm) was suspended in Tetrahydrofuran (500 ml) at 0-5°C and stir for 10 minutes to get a clear solution, added norit activated carbon (5 g) to the clear solution and stirred at 0-5°C for 20-30 minutes. The reaction mass was filter through high flow bed and obtain filtrate was added to pre-chilled purified water (500 ml ) and stir for 60-90 minutes at 0-5°C .The resultant solid was filtered, washed with water and dried at 70-80°C to obtain 80-88gm of Ledipasvir amorphous form.