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SOFOSBUVIR INTERMEDIATE POLYMORPHIC FORMS

IP.com Disclosure Number: IPCOM000248879D
Publication Date: 2017-Jan-19
Document File: 3 page(s) / 75K

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Abstract

SOFOSBUVIR INTERMEDIATE POLYMORPHIC FORMS

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SOFOSBUVIR INTERMEDIATE

Nucleoside phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Sofosbuvir is chemically named as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy)-(phenoxy)phosphorylamino) propanoate and is represented by the following chemical structure:

Formula-1

The present disclosure relates to crystalline forms of N-benzoyl sofosbuvir (formula-2), which is an intermediate in the preparation of sofosbuvir.

The schematic representation for the preparation of amorphous sofosbuvir is as shown below:

EXAMPLES:

Preparation of the crystalline N-benzoyl sofosbuvir form M1 & M2 (Isopropyl acetate solvate)

Under dry and inert atmosphere, diisopropylethylamine (1.78 g) was added over a period of 60 minutes at 25-35°C to a mixture of the compound of formula 4 (5 g), (S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (formula 3, 7.45 g) and anhydrous magnesium chloride (1.57 g) in tetrahydrofuran (36 mL) and acetonitrile (6.5 ml).  Stirring was continued at 37-41°C for 6 hours to complete the reaction which was then quenched with ~10% w/w aqueous ammonium chloride solution (35 mL).  Isopropyl acetate (50 mL) was added and the layers were separated.  The organic l...