A process for the preparation of ledipasvir

A process for preparation of Ledipasvir compound of Formula I, its pharmaceutically acceptable salt or solvate thereof,

• comprising the steps of:
• i) coupling a compound of formula (II) or its reactive derivative with a compound of formula (III) in the presence of a solvent and optionally using a catalyst to give a compound of formula (IV);
• wherein
• PG is a protecting group selected from the group consisting of Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (Boc), p-Methoxy carbonyl (Moz or MeOZ), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl carbamate, Tosyl (Ts), and Sulfonamides;
• L is a leaving group selected from the group consisting of halogens, in particular Cl, Br, F or I;
• alkyl boronate esters, cycloalkyl boronate esters, mesyloxy, acyloxy, tosyloxy, benzyloxy, trifluoromethylsulfonyloxy, nonafluoraobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutylphenyl)sulfonyloxy, and (4-methoxy-phenyl)sulfonyloxy, preferably Cl;
• X is halo or (RO)2B—;
• R is C1-6 alkyl, aryl or R groups combined together to form substituted cycloalkyl group;
• ii) cyclization of the compound of formula (IV) as obtained in step (i) using a cyclizing agent in a solvent to obtain a compound of formula (V);
• iii) protecting the compound of formula of (V) as obtained in step (ii) with a protecting group [PG] and in a solvent to give a compound of formula (VI);
• iv) cyclopropanation on the compound of Formula (VI) as obtained in step (iii) to give a compound of Formula (VII) followed by fluorination on the compound of Formula (VII) to give a compound of Formula (IX), or fluorination on the compound of Formula (VI) to give a compound of Formula (VIII) followed by cyclopropanation on the compound of Formula (VIII) using a reagent and in a first solvent to give a compound of Formula of (IX);
• v) reacting the compound of Formula (IX) as obtained in step (iv) or its salts with a compound of Formula (IXa) using a metal catalyst and a base in the presence of a solvent to give a compound of Formula (X)
• wherein
• when X is halo in Formula IX, Y is —B(OR)2 in Formula IXa;
• vi) converting compound of Formula (IX) as obtained in step (iv) or its salts with a boronate ester using a metal catalyst and a base in the presence of a solvent to give a compound of Formula (XI);
• wherein
• X is —B(OR)2 in Formula IX, R is C1-6 alkyl, aryl or R groups combined together to form substituted cycloalkyl group.
• vii) alternatively, reacting the compound of Formula (XI) as obtained in step (vi) or its salts with the compound of Formula (XIa) using a metal catalyst and a base in the presence of a solvent to give a compound of Formula (X);
• wherein Y is halo (Formula of IXa);
• viii) removing protecting groups of the compound of Formula (X) as obtained in step (v) or step (vii) using an acid in a solvent followed by reaction with compound of a Formula (Xa) or its reactive derivative in the presence of a condensing agent and a solvent to give Ledipasvir of Formula I.