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Preparation of (S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphorylamino]propionic acid isopropyl ester

IP.com Disclosure Number: IPCOM000248370D
Publication Date: 2016-Nov-22
Document File: 3 page(s) / 61K

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The IP.com Prior Art Database

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Sofosbuvir: IP.COM

Abstract

Phosphoramidate intermediate is the key starting material in the preparation of sofosbuvir. the present disclosure relates to improved process for the preparation of Phosphoramidate intermedieate.

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Preparation of (S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphorylamino]propionic acid isopropyl ester

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.

(S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphorylamino]propionic acid isopropyl ester is the key starting material in the preparation of HCV molecules, particularly in the preparation of sofosbuvir.

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:

The present disclosure relates to the process for the preparation of (S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxy phosphorylamino]propionic acid isopropyl ester (Phosphoramidate intermediate) with high enantiomeric purity. The schematic representation of this disclosure as shown below.

Examples:

Preparation of L- alanine isopropyl ester:

L- Alanine on reaction with thionyl chloride and isopropyl alcohol yields L- alanine isopropyl ester hydrochloride. The obtained compound was treated with sodium hydroxide and water followed by dichloromethane extractions. Concentrated the dichloromethane layer to get L- Alanine isopropyl ester obtained as thick residue.

Prepar...