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PROCESS FOR THE PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE

IP.com Disclosure Number: IPCOM000229961D
Publication Date: 2013-Aug-09
Document File: 4 page(s) / 26K

Publishing Venue

The IP.com Prior Art Database

Abstract

Provided herein is a process for the preparation of pure valganciclovir hydrochloride.

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PROCESS FOR THE PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE

Abstract

Provided herein is a process for the preparation of pure valganciclovir hydrochloride.

Reported herein is an improved process for removing ganciclovir (Formula II)

Formula II

from a reaction mixture comprising ganciclovir and mono-protected L-valyl ester of ganciclovir, comprising adjusting the pH of the reaction mixture to less than 3 by adding a base at ambient temperature, stirring for about 30 minutes to about 2 hours, filtering, washing with water, and drying.

A process for preparing enantiomerically pure valganciclovir hydrochloride of Formula I is provided, comprising adjusting the pH of the reaction mixture during crystallization of valganciclovir hydrochloride to less than 3 by adding a base, followed by slow addition of a solvent at ambient temperature to a temperature of about 60°C, stirring for about 1 hour to about 6 hours, cooling to about -10°C to about +10°C, further stirring for about 30 minutes to about 3 hours, filtering, and drying at a temperature of about 40°C to about 70°C under reduced pressure.

Formula I

Method

Quantity of ganciclovir of Formula II, mono-protected L-valyl ester of ganciclovir of Formula IV, and bis-protected L-valyl ester of ganciclovir was determined using high performance liquid chromatography.

Example: Preparation of Crystalline Valganciclovir Hydrochloride

Stage 1: Reaction of N-benzyloxycarbonyl-L-valine with ganciclovir

To a solution of ganciclovir (100 g) in dimethylsulphoxide (600 mL) was added N-benzyloxycarbonyl-L-valine (88.58 g) and dicyclohexylcarbodiimide (100.98 g), followed by the addition of 4-dimethylaminopyridine (1.0 g) at about 25°C.  The reaction was stirred for about 30 minutes, transferred into a mixture of water and concentrated hydrochloric acid (2000 mL + 250 mL), stirred, filtered, and washed with water (2 x 500 mL).  The combined filtrates and washing were taken for next stage.

Mono-protected L-valyl ester of ganciclovir: about 30%

Un-reacted ganciclovir: about 63%

Bis-protected L-valyl ester of ganciclovir: about 6%

Stage 2: Removal of bis-protected L-valyl ester of ganciclovir

Dichloromethane (700 mL) was added to the filtrate obtained from stage 1.  The contents were stirred at about 30°C for about 15 minutes.  The layers were separated, and the aqueous layer was extracted with dichloromethane (500 mL). 

Analysis of Aqueous Layer:

Mono-protected L-valyl ester of ganciclovir: about 35%

Un-reacted ganciclovir: about 63%

Bis-protected L-valyl ester of ganciclovir: about 0.03%

Stage 3: Removal of ganciclovir

The pH of the aqueous layer obtained from stage 2 was adjusted to about 1.7-1.9 by adding 20% aqueous sodium hydroxi...