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Publication Date: 2017-Apr-18
Document File: 6 page(s) / 41K

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The present disclosure relates to process for the preparation of Ledipasvir.

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Ledipasvir (known as GS-5885) is an inhibitor of the hepatitis C virus NS5A protein.  A combination drug containing ledipasvir and sofosbuvir is currently marketed as HARVONI® in the United States by Gilead Sciences.  HARVONI® is indicated for the treatment of hepatitis C virus (HCV) genotype 1, 4, 5, or 6 infections.

Ledipasvir is chemically known as methyl[(2S)-1-{(6S)-6-[5-(9,9-difluoro-7­{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2­azabicyclo [2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5­azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate and is represented by the following chemical structure:

The present disclosure relates to a process for the preparation of crystalline ledipasvir Form-M1 through oxalate salt of ledipasvir.

The present disclosure also relates to a process for the preparation of amorphous ledipasvir with particle size less than 300microns.


Example 1:  Preparation of (S)-1-((S)-6-(5-(7-(2-((1R,3S,4S)-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-ylcarbamate hydrochloride.

t-Butyl (1R,3S,4S)-3-(6-Bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (10 g), Bis(neopentylglycolato)diboron(6.3 g), potassium propionate (8.6 g) and dichloro bis(di-tert-butyl phenylphosphine) palladium (II) (0.8 g) was charged into isopropylacetate (100 mL) under argon atmosphere, and the reaction temperature was raised to 70°C and stirred the reaction mass for 210 minutes at 70-75°C under argon atmosphere. The reaction mass was cooled to 20-25°C, charged the (1-{6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (15.3 g) followed by potassium phosphate tribasic solution (18.9 g in 90 mL water) under argon atmosphere, and raised the reaction temperature to 70-75°C, maintain 90 minutes at the same temperature under argon atmosphere. The reaction mass was cooled to 25°C, separated the organic layer, organic layer wash with 2X100 mL of brine solution, To the organic layer charge N-Acetyl-L-Cystiene (2.5 g), stir the mass for 600 minutes add 5% Sodium hydroxide solution (50 mL) to the reaction mass. Separate the top organic layer, Organic layer washed with 3X50 mL of brine solution. Isopropyl acetate was distilled off completely from organic layer under vacuum to get the thick residue, acetonitrile (100 mL) was added to the residue, cooled to 35°C, charge CP HCl solution (7 mL in 20 mL), and raise the reaction temperature to 60-65°C, stir the reaction mass for 240 minutes at the same temperature, cool the reaction mass to 50-55°C, add acetonitrile (100 mL) to the reaction mass at 50-55°C, cooled the reaction mass to 20-25°C, collect the solid by filtration. Dry the compound at 60 – 65°C under vacuum fo...