DESC:Field of the Invention:
The present invention relates to a process for the preparation of anti-HCV compound Ledipasvir, having the chemical name (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl ]-3H -imidazol-4-yl} -9H-fluoren-2-yl)-lH-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methylpropyl)-carbamic acid methyl ester by using novel intermediates.
The present complete specification is prepared by cognating the contents provisional patent specification of application numbered 201621016582 dated May 12, 2016 with the contents of the specification of patent application no. 201621016651 dated May 12, 2016. The combined contents of the present specification constitute a single invention within the meaning of the Act.

Background of the Invention:
Ledipasvir is a HCV NS5A inhibitor that has demonstrated potent anti-HCV activity against genotype (1a and 1b) HCV infection. Ledipasvir has the following chemical formula:

Formula 1
Ledipasvir is described in US 8,088,368B2 and US 9,056,860 B2 describes a process for the preparation of Ledipasvir.

Summary of the Invention:
In one aspect, the present invention relates to a process for the preparation of Ledipasvir of formula I and intermediates thereof.

The process for preparation of ledipasvir and intermediates thereof according to present invention is described by reaction schemes-1 & 2:

Scheme-1:
Step-1
Process for preparation of Ledipasvir

Step-2: Process for preparation of intermediate of Formula-4

Step-3: Process for preparation of intermediate of Formula-5

Scheme-2
Step-1

Step-2

Step-3

In another aspect, the present invention provides novel intermediates of formula 2, formula 3, formula 4, formula 4’, formula 5, formula 13, formula 15, formula 16, formula 17 or pharmaceutically acceptable salts thereof and process for the preparation thereof.
In another aspect, the invention provides use of novel intermediates of formula 2, formula 3, formula 4, formula 4’, formula 5, formula 13, formula 15, formula 16, formula 17 or pharmaceutically acceptable salts thereof in the preparation of Ledipasvir.
Detail Description of the Invention:
There is always a need for alternative preparative routes, which is cost effective, involve use of optimum amounts of ecofriendly reagents and solvents, commercially scalable and produces a product in higher purity and yield.
The substituents R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); provided that one of the R1 or R2 is -COOCH3.
Each PG independently is an amine protecting group.
The term “amine protecting group” is well understood by the person skilled in synthetic organic chemistry as a moiety that can be selectively installed onto and removed from a suitable amine functional group. The field of protecting group methodology is advanced, and many amine protecting groups, and methods for using them, are well known in the art. The amine protecting group can be selected from tert-butyloxycarbonyl (BOC), Fluorenylmethyloxycarbonyl (F-MOC), N-benzyl, Trityl, substituted Carboxybenzyl (CBZ) group, etc.
Substituents X and Y are leaving groups and can be independently selected from any halogen, pseudohalogen and —B(OR)(OR'). In one embodiment, when Y is —B(OR)(OR'), then X is halogen or pseudohalogen, and in another embodiment, when Y is halogen or pseudohalogen, then X is —B(OR)(OR').
The substituents R and R' are independently selected from the group consisting of hydrogen and straight or branched C1-8-alkyl, or R and R' together represent a straight or branched C1-8-alkylene, C3-8-cycloalkylene, or C6-12-arylene. Any alkyl, alkylene, cycloalkylene, or arylene as defined herein is optionally substituted with one or more substituents selected from the group consisting of C1-6-alkyl, —C(O)N(C1-6-alkyl)2, and —C(O)O(C1-6-alkyl).

The halogen can be selected from chlorine, bromine, iodine or fluorine.
The pseudo-halogens are polyatomic halogen analogues can be selected from p-toluene sulfonate, methyl sulfonate, trifluoromethyl sulfonate, p-nitro benzene sulfonate and the like.
The phrase "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, Mg2+, Ca2+, NHgR'''4-g+, in which R''' is a C1-3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
According to one aspect, the present invention provides a process for the preparation of Ledipasvir of formula I:

Formula I
comprising the steps of:
i) reacting a compound of formula 4 or pharmaceutically acceptable salt thereof with a compound of formula 5 or pharmaceutically acceptable salt thereof to obtain a compound of formula 3:

Wherein X and Y are leaving groups, PG is an amine protecting group;
ii) deprotecting the compound of formula 3 or the pharmaceutically acceptable salt thereof; to obtain a compound of formula 2 or pharmaceutically acceptable salt thereof; and

iii) converting the compound of formula 2 or the pharmaceutically acceptable salt thereof to Ledipasvir of formula 1.
The reaction of Step-(i) can be performed in presence of base like organic bases such as but not limited to tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic bases such as but not limited to sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride & tripotassium phosphate (K3PO4).
The reaction of Step-(i) can optionally be performed in presence of metal catalyst such as but not limited to palladium, platinum, nickel, iron with or without ligands and salts thereof.
The solvent for the reaction of step- (i) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

Reaction of step-(ii) can be performed by maintaining the pH of the reaction to acidic by using reagents such as hydrogen halide likes hydrochloric acid in the solvent selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1, 2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine; acids like acetic acid and acetonitrile or mixtures thereof. In particular, the solvent is acetic acid, methylene dichloride, tetrahydrofuran, 1,2-dimethoxy ether (DME) and acetonitrile or mixtures thereof.
The reaction of step-(iii) can be performed in the presence of methyl chloroformate; methyl pentafluoro phenyl carbonate;dimethyl carbonate; anhydrides such as acetic anhydride, acetic formic anhydride and the like.

The solvent for the reaction of step- (iii) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

In another aspect, the present invention provides a novel intermediate of formula 4 or a pharmaceutically acceptable salt thereof.

wherein PG is an amine protecting group, X is a leaving group.
In another aspect, the invention provides a process for preparation of a novel intermediate of formula 4 or pharmaceutically acceptable salts thereof, comprising reacting a compound of formula 7 or pharmaceutically acceptable salts thereof with compound of formula 6 pharmaceutically acceptable salts thereof.

wherein PG is an amine protecting group, X is a leaving group.
The above reaction is carried out in the presence of base like organic bases such as but not limited to tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic bases such as but not limited to sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
In another aspect, the present invention provides a novel intermediate of formula-5 or pharmaceutically acceptable salt thereof.

wherein Y is a leaving group.
In another aspect, the invention provides a process for preparation of a novel intermediate of formula 5 or pharmaceutically acceptable salt thereof; comprising reacting a compound of formula 13 or pharmaceutically acceptable salt thereof with compound of formula 10 or pharmaceutically acceptable salt thereof.

Wherein Y is a leaving group.
The above reaction is carried out in the presence of base like organic bases such as but not limited to tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic bases such as but not limited to sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
In another aspect, the present invention provides a novel intermediate of formula 3 or pharmaceutically acceptable salt thereof.

wherein PG is an amine protecting group.
In another aspect, the invention provides a process for preparation of a novel intermediate of formula 3 or pharmaceutically acceptable salt thereof comprising reacting a compound of formula 4 or pharmaceutically acceptable salt thereof with a compound of formula 5 or pharmaceutically acceptable salt thereof.

wherein X &Y are leaving groups; PG s an amine protecting group.
The above reaction is carried out in the presence of base like organic bases such as but not limited to tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic bases such as but not limited to sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
The process for preparation of compound of formula 3 or pharmaceutically acceptable salt thereof can optionally be performed in presence of metal catalyst such as but not limited to palladium, platinum, nickel, iron with or without ligands and salts thereof.
In another aspect, the present invention provides a novel intermediate of formula 2 or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a process for the preparation of a novel intermediate of formula 2 or pharmaceutically acceptable salt thereof, comprising deprotecting a compound of formula 3 or pharmaceutically acceptable salt thereof by maintaining the pH of the reaction medium as an acidic medium by using reagents such as hydrogen halide like hydrochloric acid in a solvent.

wherein PG is an amine protecting group.
In another aspect, the present invention provides a novel intermediate of formula 13 or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a process for the preparation of a novel intermediate of formula 13 or pharmaceutically acceptable salt thereof, comprising reacting a compound of formula 10 or pharmaceutically acceptable salt thereof with a compound of formula 9 or pharmaceutically acceptable salt thereof.

wherein X is a leaving group.

According to another aspect, the present invention provides a process for the preparation of Ledipasvir of formula I:

Formula I
comprising the steps of:
i) reacting a compound of formula 4’ or pharmaceutically acceptable salt thereof with a compound of formula 15 or pharmaceutically acceptable salt thereof; to obtain a compound of formula 16 or pharmaceutically acceptable salt thereof;

wherein, R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); provided that one of the R1 or R2 is -COOCH3;X and Y are leaving groups;
ii) deprotecting the compound of formula 16 or the pharmaceutically acceptable salt thereof; when R1 or R2 is a amine protecting group (PG); to obtain a compound of formula 17 or pharmaceutically acceptable salt thereof; and

iii) converting the compound of formula 17 or the pharmaceutically acceptable salt thereof to Ledipasvir of formula 1.
The reaction of Step-(i) can be performed in presence of base like organic bases such as tertiary and secondary amines; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH; potassium fluoride, tripotassium phosphate (K3PO4) and the like.
The reaction of Step-(i) can optionally be performed in presence of metal catalyst such as palladium, platinum, nickel, iron with or without ligands and salts thereof.
The solvent for the reaction of step- (i) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

Reaction of step-(ii) can be performed by maintaining the pH of the reaction to acidic by using reagents such as hydrogen halide like hydrochloric acid in the solvent selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1, 2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine; acids like acetic acid and acetonitrile or mixtures thereof. In particular, the solvent is acetic acid, methylene dichloride, tetrahydrofuran, 1,2-dimethoxy ether (DME) and acetonitrile or mixtures thereof.
The reaction of step-(iii) can be performed in the presence of methyl chloroformate; methyl pentafluoro phenyl carbonate; dimethyl carbonate; anhydrides such as acetic anhydride, acetic formic anhydride and the like.

The solvent for the reaction of step- (iii) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

In another aspect, the present invention provides a novel intermediate of formula 4’ or a pharmaceutically acceptable salt thereof.

wherein, R1 is independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); X is a leaving group.
In another aspect, the invention provides a process for preparation of a novel intermediate of formula 4’, comprising:
(i) deprotecting compound of formula 8 or pharmaceutically acceptable salts thereof to obtain compound of formula 7 or pharmaceutically acceptable salts thereof;

Wherein, X is a leaving group and PG is an amine protecting group;
(ii) reacting a compound of formula 7 or pharmaceutically acceptable salts thereof with compound of formula 6’ or pharmaceutically acceptable salts thereof to obtain compound of formula 4’ or pharmaceutically acceptable salts thereof

Wherein, R1 is independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); X is a leaving group.
The reaction of step-(ii) can be performed in presence of base like organic bases such as tertiary and secondary amines; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4) and the like.
In another aspect, the present invention provides a novel intermediate of formula 15 or pharmaceutically acceptable salts thereof.

wherein ,R2 is independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); Y is a leaving group.
In another aspect, the invention provides a process for preparation of a novel intermediate of formula 15 or pharmaceutically acceptable salts thereof, comprising:
(i) deprotecting a compound of formula 11 to get compound of formula 12;

wherein Y is a leaving group and PG is an amine protecting group;
(ii) reacting a compound of formula 12 or pharmaceutically acceptable salts thereof, with compound of formula 14 or pharmaceutically acceptable salts thereof to obtain compound of formula 15:

wherein ,R2 is independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); Y is a leaving group.
The reaction of step-(ii) can be performed in presence of base like organic bases such as tertiary and secondary amines; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4) and the like.
In another aspect, the present invention provides a novel intermediate of formula 16 or pharmaceutically acceptable salt thereof.

wherein R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); provided that one of the R1 or R2 is -COOCH3.
In another aspect, the invention provides a process for preparation of a novel intermediate of formula 16 or pharmaceutically acceptable salt thereof, comprising:
i) reacting a compound of formula 4 or pharmaceutically acceptable salts thereof with a compound of formula 15 or pharmaceutically acceptable salt thereof to obtain compound of formula 16 or pharmaceutically acceptable salt thereof.

wherein, R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or ester such as (-COOCH3); provided that one of the R1 or R2 is -COOCH3;X and Y are leaving groups;
The reaction of step- i) can be performed in presence of base like organic bases such as tertiary and secondary amines; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4) and the like.
The process for preparation of compound of formula 16 can optionally be performed in the presence of metal catalyst such as palladium, platinum, nickel, iron with or without ligands and salts thereof.
In another aspect, the present invention provides a novel intermediate of formula 17 or pharmaceutically acceptable salt thereof.

wherein R1 and R2 are independently selected from hydrogen or ester such as (-COOCH3); provided that one of the R1 or R2 is -COOCH3;
In another aspect, the invention provides a process for the preparation of a novel intermediate of formula 17 or pharmaceutically acceptable salt thereof, comprising:
i) deprotecting the compound of formula 16 or the pharmaceutically acceptable salt thereof; when R1 or R2 is a amine protecting group (PG) to obtain compound of formula 17 or pharmaceutically acceptable salt thereof:

The reaction of step-i) can be performed by maintaining the pH of the reaction medium as an acidic medium by using reagents such as hydrogen halide such hydrochloric acid in a solvent.
In another aspect, the present invention provides a process for preparation of ledipasvir comprising:
i) converting the compound of formula 17 or pharmaceutically acceptable salt thereof

Wherein R1 and R2 are independently selected from hydrogen or ester such as (-COOCH3); provided that one of the R1 or R2 is -COOCH3
The reaction of step-i) can be performed in presence of methyl chloroformate; dimethyl carbonate; anhydrides such as acetic anhydride, acetic formic anhydride and the like.
Compounds formula 8 and formula 11 can be synthesized by methods known in the literature via US8088368B2, US9056860B2.
To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
Examples:
Example 1: 6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro [2.4] heptane

Ethyl acetate (250ml) was charged to the flask, tert-butyl 6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazole-2-yl)-5-azaspiro[2.4] heptane-5-carboxylate (50g; 0.092Mol) was charged to the flask. 10% Solution of ethyl acetate and hydrochloric acid(250ml) was added to the reaction mass. Reaction mass was stirred for 2 hours at 50-55°C. Reaction mass was cooled at about 25°C. Titled compound was isolated by filtration.
Example 2: benzyl(1-(6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate

2-(((benzyloxy)carbonyl)amino)-3-methylbutanoic acid (1g; 43.9 mmol) was charged to the flask. Dimethylformaide(DMF; 85ml) was added to the reaction mixture. 6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro [2.4] heptane hydrochloride (21.0g; 43.9mMol) was added to the reaction mass. N,N-Diisopropylethylamine (DIPEA;42ml) was added to the reaction mixture. Reaction mixture was cooled to 0-5°C. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU;16.7g;43.9mMol) were added to the reaction mixture at 0-5°C. Reaction mixture was stirred for 70 minutes at 25-30°C. Water was added to the reaction mass. After addition of water a gummy mass was formed. Water was decanted from reaction mixture. Water (400ml) was added to reaction mass. Reaction mass was extracted with dichloromethane (3X80ml) to get benzyl(1-(6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate.Yield 35.0g
Example 3: 2-((1S,3R,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole hydrochloride

tert-butyl (1S,3R,4R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (150g;341mmol) was added to the flask. Ethyl acetate (750ml) was added to reaction mass.10% solution of hydrochloric acid in ethylacetate was added dropwise to the reaction mixture over the period of 30 minutes. Reaction mixture was stirred for 2 hours at 50-60°C. Reaction mixture was cooled to 20°C. 2-((1S,3R,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole hydrochloride was isolated by filtration and dried. Yield 137.2 g
Example 4: 2,2'-((((1,4-phenylenebis(methylene))bis(oxy))bis(carbonyl))bis(azanediyl))bis(3-methylbutanoic acid)

Sodium hydroxide (38g;), water (230ml) was added to the flask. Reaction mass was stirred at 25-30°C. L-valine(111.2g; 950mMol) was added to the reaction mixture. 50% solution of 1,4-phenylenebis(methylene)bis(carbonochloridate) (200ml) and 17.4% aqueous sodium hydroxide (230ml) were added simultaneously to the reaction mixture at 0-5°C. Reaction mass was stirred for 90 minutes at room temperature. Reaction mixture was extracted with equimolar solution of ethylacetate and Hexane (1.0L). Layers were separated and aqueous layer was acidified with Conc.HCl (190ml) at 20-25°C. Aqueous layer was extracted with ethyl acetate (3X300ml). Ethyl acetate layers were combined and stripped off to give titled compound as a white solid.
1H NMR (D2O, 400MHz): d 0.93 (s,12H);2.14(m,2H); 3.87(t,2H); 5.09(d,2H); 5.19(d,2H); 7.44(s,4H)
13C NMR (D2O, 100MHz): d 17.0, 18.96, 30.3, 62.1, 63.6, 66.6, 127.8, 135.9, 158.16, 179.6
MS(EI): C20H28N2O8 exact mass: 424.187 Observed mass442.2 (-ve mode)
Example 5: 4-((((3-methyl-1-((3-methyl-1-oxo-1-((3R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)amino)-1-oxobutan-2-yl)carbamoyl)oxy)methyl)benzyl (3-methyl-1-oxo-1-((1S,3R,4R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)carbamate

Compound obtained from Example 4 (20g;47.2mMol) was charged in the flask. Dimethyl formamide (130ml) was added to the reaction mass. DIPEA (25g) was added to the reaction mixture. 2-((1S,3R,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d] imidazole hydrochloride salt(36.4 g;103.8mMol) was added to reaction mixture. Reaction mixture was cooled to 0-5°C. HATU (39.4g, 103.8mMol) was added to the reaction mixture at 0-5°C. Reaction mass was stirred for 120 minutes at 25-30°C. Water was added to the reaction mass. Titled compound was isolated by filtration and purified by column chromatography.
FTIR(KBr):3320,2915,1723,1631,1445,1356,1144,857 cm-1
MS(EI):C63H85B2N9O11 exact mass: 1165.66 Observed mass:1067.60
Example 6: 4-((((1-((1-((3R)-3-(6-(7-(2-(5-(((benzyloxy)carbonyl)valyl)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)oxy)methyl)benzyl (1-((1S,3R,4R)-3-(6-(7-(2-(5-(((benzyloxy)carbonyl)valyl)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Potassium carbonate (8.8g; 63.9mMol) was added to the flask. Water(34ml) was added to the reaction mixture. (benzyl(1-(6-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate)(14.4g; 21.3mMol) was added to the reaction mixture. Benzyl(3-methyl-1-oxo-1-((1S,3R,4R)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)catbamate) (11.0g; 19.2mMol) was added to the reaction mixture. DME (420ml) was added to the reaction mixture. Reaction mixture was stirred for 30 minutes at 55-60°C. Pd(PPh3)4 (2.5g;2.1mMol) was added to reaction mixture at 55-60°C. Reaction mixture was stirred for 4 hours. (benzyl(3-methyl-1-oxo-1-((1S,3R,4R)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)catbamate) (4.8g;8.4mmol) was added to the reaction mixture. Reaction was monitored by using TLC. After completion of reaction, solvent was evaporated under reduced pressure to get titled compound. The obtained compound was purified by column chromatography (eluent ethyl acetate/hexanes). Yield 11.3 g
FTIR: 3285; 2966; 1714; 1630; 1441; 1240; 1045; 840 cm-1
MS (EI): C116H118F4N16O12 exact mass:2003.91 Observed mass:2004.486
Example 7: 2-amino-1-(6-(5-(7-(2-((3S)-2-(2-amino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methylbutan-1-one

The compound obtained in example 6(12.5g; 12.1mmol) was added to the flask. Acetic acid (12.5ml) was added to the reaction mixture.30% solution of hydrogen bromide in acetic acid (26ml;96.6mMol) was added dropwise to the reaction mixture at 20-25°C. Reaction mass was stirred for 3.5 hours at 20-25°C. DME(200ml) was added to the reaction mixture under vigorous stirring. The reaction mixture was stirred for 1 hour, titled compound was isolated by filtration as bis hydro-bromide salt, washed with 100ml DME and dried.
FTIR(KBr): 3411, 2966, 1642, 1454, 1054, 817 cm-1
MS(EI): C45H52Br2F2N8O2 exact mass 934.25; observed mass 773.6 (+1;without bromide counter ion).

Example 8: Preparation of Ledipasvir

2-amino-1-(6-(5-(7-(2-((3S)-2-(2-amino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4] heptan-5-yl)-3-methylbutan-1-one (10.0g; 10.7mMol) was charged to the flask. Dichloromethane (100ml) was added to the reaction mixture. Triethyl amine (9ml) was added to the reaction mixture. Methyl chloroformate (2.2g; 23.4mMol) was added dropwise to the reaction mixture at 0-5°C. Reaction mass was stirred for 3.5 hours at 5-30°C. Methyl amine(2ml) was added to reaction mixture. Reaction mixture was quenched by using 50% brine solution. Reaction mixture was stirred for 15 min. Layer were separated. Ledipasvir was isolated by distillation of solvent and purified.Yield 11.7g
MS(EI): C49H54F2N8O6 exact mass:889; observed mass 889.4(M+)
Example 9: methyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate

6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptane (13.60g, 28.4mMol) was charged to the flask. Dimethoxyethane (DME; 100ml) was charged to the reaction mass. Triethyl amine (8.6g) was added to reaction mass, (methoxycarbonyl)valine (5.47gm,31.2mMol) was added to reaction mass. Dimethoxyethane (DME; 36ml) was charged to the reaction mass. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU; 11.8g;31.2mMol) was added to the reaction mass at 0-5°C. Reaction mass was stirred for 70 minutes at 25-30°C. Solvent was distilled out under reduced pressure. Water (400ml) was added to the reaction mass, reaction mass was stirred for 80 minutes and titled compound was isolated by filtration, washed and dried overnight. Yield:11.7g.
MS (EI):C29H29BrF2N4O3 Exact mass: 598.14; observed mass: 599.4 & 601.3 (Bromo pattern)
FIR (KBr): 3410; 2966; 1716; 1637; 1522; 1457; 1247; 1058; 844; 771 cm-1
Example 10 methyl (3-methyl-1-oxo-1-((1S,3R,4R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)carbamate

2-((1S,3R,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (10g; 29.5mMol) was added to the flask. Dimethyl formamide (DMF;60ml) was added to the reaction mass, (methoxycarbonyl)valine (5.6g,5.6mMol) was added to the reaction mass. Triethyl amine (TEA; 3.3g) was added to the reaction mass. HATU (12.3g;32.4mMol) was added to the reaction mass at 0-5°C. Reaction mass was stirred at 70 minutes at 25-30°C. Water was added to the reaction mixture followed by decantation of water. Water (400ml) was added to the reaction mixture. Reaction mixture was extracted with dichloromethane (DCM, 3x80ml). DCM layer was washed with brine solution (200ml), titled compound was isolated by evaporation of the solvent. Yield 6.5g
MS(EI): C26H37BN4O5;Exact Mass:496.29; Observed mass:497.3
FTIR (KBr):3410; 1716; 1637;1522; 1457; 1247; 1058; 844; 771 cm-1
Example 11: methyl (1-(6-(4-(7-(2-((3S)-2-(((benzyloxy)carbonyl)valyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Water (36ml) was charged to the flask. Potassium carbonate (K2CO3 ; 8.28g; 60mMol) was added to the reaction mixture. Compound obtained from example 9 (11.98g; 20mMol) was added to the reaction mixture. Compound obtained from example 10( 11.44g; 20mMol) was added to the reaction mixture. Dimethoxyethane (DME, 360ml) was added to the reaction mixture. Reaction mass was stirred at 80°C for 30 min. Pd(PPH3)4 (0.5 g) was added to the reaction mixture at 80°C. Reaction mass was stirred for 20 hours at 80°C. Reaction was monitored using TLC. After completion of reaction, solvent was evaporated under reduced pressure. Water (100ml) was added to reaction mixture and product was precipitated. Titled compound was filtered and dried overnight. Yield 18.6g
MS(EI): C55H58F2N8O6 ; Exact mass:964.44; Observed mass: 966.3
FTIR (KBr):3289; 2963; 1719; 1632; 1439; 1232; 1041; 695 cm-1
Example 12: benzyl (1-(6-(4-(9,9-difluoro-7-(2-((3S)-2-((methoxycarbonyl)valyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Water (15 ml) was charged to the flask. Potassium carbonate (K2CO3 ; 4.148g; 30mMol) was added to the reaction mixture,benzyl (1-(6-(4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate (6g; 9mMol) was added to the reaction mixture. Methyl (3-methyl-1-oxo-1-((1S,3R,4R)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-yl)carbamate (5g; 10mMol) was added to the reaction mixture. Dimethoxyethane (DME, 150ml) was added to the reaction mixture. Reaction mass was stirred at 80°C for 30 min. Pd(PPH3)4 (0.5 g) was added to the reaction mixture at 80°C. Reaction mass was stirred for 20 hours at 80°C. Reaction was monitored using TLC. After completion of reaction, solvent was evaporated under reduced pressure. Water (200ml) was added to reaction mixture and product was precipitated. Titled compound was filtered and dried overnight. Yield 9.1g
MS(EI): C55H58F2N8O6 ; Exact mass:964.44; Observed mass: 966.9
FTIR (KBr):3285; 2964; 1715; 1630; 1516;1439; 1239; 1046; 840; 696 cm-1
Example 13 methyl (1-(6-(4-(9,9-difluoro-7-(2-((3S)-2-valyl-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Acetic acid (100ml) was added to the flask. Compound obtained from example 11 (10g; 10.3mmol) was added to reaction mixture. Hydro-bromide solution (30%; 25ml) in acetic acid was added to the reaction mass at 20-25°C, reaction mass was stirred for 2 hours at 25-30°C. Dimethoxyethane (DME, 125ml) was added to the reaction mixture. Reaction mixture was stirred was half hour. Hydrobromide salt of titled compound was isolated by filtration and dried overnight. Yield 9.4g
19F NMR (MeOD, 376MHz): d-111.8
FTIR (KBr): 3401; 2965; 1711; 1638; 1454; 1053; 814 cm-1
MS(EL): C47H52F2N8O4; Exact mass: 830.41; Observed Mass: 831.6 (+1; without bromide counter ion)
Example 14: methyl (1-((3S)-3-(6-(9,9-difluoro-7-(2-(5-valyl-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-4-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-yl)carbamate

Acetic acid (6 ml) was added to the flask. Compound obtained form example 12 (6 g; 6.21mMol) was added to reaction mixture. Hydrogen bromide solution (30%; 15ml) in acetic acid was added to the reaction mass at 20-25°C. Reaction mass was stirred for 2 hours at 25-30°C. Dimethoxyethane (DME, 105ml) was added to the reaction mixture. Reaction mixture was stirred was half hour. Hydrobromide salt of titled compound was isolated by filtration and dried under vacuum. Yield 5.3g
19F NMR (MeOD, 376MHz): d -112.07 & -112.34
FTIR (KBr): 3403; 2965; 1711; 1638; 1455; 1299; 1054; 819 cm-1
MS(EL): C47H52F2N8O4; Exact mass: 830.41; Observed Mass: 831.6 (+1; without bromide counter ion)
Example 15 Preparation of Ledipasvir:

Dichloromethane (15ml), Compound obtained from example 14 (2g; 1.82mMol) was added to the flask. Triethylamine (TEA; 1ml) was added to the reaction mixture. Solution of methyl chloroformate(0.19g; 2 mMol) in dichloromethane (15ml) was added dropwise to the reaction mass. Reaction mass was stirred for 18.5 hours at 30°C. Reaction mass was quenched in 20% brine solution (30ml). Reaction mass was stirred for 15 minutes. Dilute hydrochloric(15%, 30ml) was added to reaction mass. Layers were separated. Solvent was distilled out and ledipasvir was isolated. Yield 1.40g.
MS (EI): C49H54F2N8O=; Exact Mass:889.0; Observed mass: 889.6 (M+)
Example 16 Preparation of Ledipasvir:

Dichloromethane (15ml), Compound obtained from example 13(2g; 1.82mMol) was added to the flask. Triethylamine (TEA; 1ml) was added to the reaction mixture. Solution of methyl chloroformate(0.19g; 2 mMol) in dichloromethane (15ml) was added dropwise to the reaction mass. Reaction mass was stirred for 18.5 hours at 30°C. Reaction mass was quenched in 20% brine solution (30ml). Reaction mass was stirred for 15 minutes. Dilute hydrochloric(15%, 30ml) was added to reaction mass. Layers were separated. Solvent was distilled out and ledipasvir was isolated. Yield 1.40g.
MS (EI): C49H54F2N8O=; Exact Mass:889.0; Observed mass: 889.6 (M+)
,CLAIMS:1. A process for preparation of ledipasvir, comprising:
i) reacting a compound of formula 4 or pharmaceutically acceptable salt thereof with a compound of formula 5 or pharmaceutically acceptable salt thereof to obtain a compound of formula 3:

wherein PG is amine protecting group provided that amino protecting group is not carbomethyloxy (-COOCH3) group; X and Y are leaving groups;
ii) deprotecting the compound of formula 3 or the pharmaceutically acceptable salt thereof; to obtain a compound of formula 2 or pharmaceutically acceptable salt thereof; and

iii) converting the compound of formula 2 or the pharmaceutically acceptable salt thereof to Ledipasvir of formula 1.

2. The process according to claim 1 wherein the step (i) is carried out in the presence of base and optionally in the presence of metal catalyst.
3. The process according to claim 2 wherein the base is selected from organic or inorganic base.
4. The process according to claim 2 wherein the metal catalyst is selected form palladium, platinum, nickel, iron with or without ligands and salts thereof.
5. The process according to claim 1, wherein the step (ii) is carried out in acidic medium.
6. The process according to claim 1, wherein the step (iii) is carried out in the presence of methyl chloroformate; methyl pentafluoro phenyl carbonate; dimethyl carbonate; acetic anhydride or acetic formic anhydrides.
7. A compound of formula 3 or its pharmaceutically acceptable salts or solvates thereof

wherein PG is an amine protecting group providing that amino protecting group is not carbomethyloxy (-COOCH3) group.
8. A process for the preparation of compound of formula 3 comprising reacting a compound of formula 4 with a compound of formula 5:

wherein PG is amine protecting group providing that amino protecting group is not carbomethyloxy (-COOCH3) group; X and Y are leaving groups.
9. The process according to claim 8 is carried out in the presence of base.
10. The process according to claim 9 wherein the base is selected from organic or inorganic base.
11. A process for preparation of compound of formula 2 comprising deprotecting a compound of formula 3;

wherein PG is an amine protecting group providing that amino protecting group is not carbomethyloxy (-COOCH3) group.
12. The process according to claim 11, wherein the deprotection is carried out in acidic medium.
13. A compound of formula 5

Wherein Y is a leaving group.
14. A process for preparation of compound of formula 5 comprising reacting of compound of
formula 10 with compound of formula 13;
wherein Y is a leaving group.
15. The process of claim 14 is carried out in the presence of base.
16. A compound of formula 13:

17 A process for preparation of compound of formula 13 comprising reacting a compound formula 10 with compound of formula 9

Wherein X is a leaving group.
18. A process for the preparation of Ledipasvir comprising:
i) reacting a compound of formula 4’ or pharmaceutically acceptable salt thereof with a compound of formula 15 or pharmaceutically acceptable salt thereof; to obtain a compound of formula 16 or pharmaceutically acceptable salt thereof;

wherein R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or -COOCH3; provided that one of the R1 or R2 is -COOCH3; X and Y are leaving groups;
ii) deprotecting the compound of formula 16 or the pharmaceutically acceptable salt thereof; when R1 or R2 is a amine protecting group (PG); to obtain a compound of formula 17 or pharmaceutically acceptable salt thereof; and

iii) converting the compound of formula 17 or the pharmaceutically acceptable salt thereof to Ledipasvir of formula 1.

19. The process according to claim 18 wherein the step (i) is carried out in presence of base and optionally in presence of metal catalyst.
20. The process according to claim 19 wherein the base is selected from organic or inorganic base.
21. The process according to claim 19 wherein the metal catalyst is selected form palladium, platinum, nickel, iron with or without ligands and salts thereof.
22. The process according to claim 18, wherein the step (ii) is carried out in acidic medium.
23. The process according to claim 18, wherein the step (iii) is carried out in the presence of methyl chloroformate; methyl pentafluoro phenyl carbonate; dimethyl carbonate; acetic anhydride or acetic formic anhydrides.
24. A compound of formula 16

wherein R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or -COOCH3; provided that one of the R1 or R2 is -COOCH3.
25. A process for the preparation of compound of formula 16 comprising reacting a compound of formula 4’ with compound of formula 15

wherein R1 and R2 are independently selected from hydrogen, amine protecting group (PG) or ester -COOCH3; provided that one of the R1 or R2 is -COOCH3; X and Y are leaving groups.
26. The process according to claim 25 is carried out in the presence of base.
27. The process according to claim 26 wherein the base is selected from organic or inorganic base.
28. A compound of formula 17

wherein R1 and R2 are independently selected from hydrogen or ester -COOCH3; provided that one of the R1 or R2 is -COOCH3.
29. A process for the preparation of compound of formula 17 comprising deprotecting a compound of formula 3; when R1 or R2 is an amine protecting group (PG);

30. The process according to claim 29, wherein the deprotection is carried out in acidic medium.