FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION :
PROCESS FOR PREPARATION OF PURE VALACYCLOVIR HYDROCHLORIDE.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention provides process for preparation of pure valacyclovir
hydrochloride.
The following specification particularly describes the invention and the manner in
which it is to be performed.

4. DESCRIPTION
The invention provides process for preparation of pure valacyclovir hydrochloride. The invention further provides pure valacyclovir and salts thereof having 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one content of 1% or less. The invention also provides a pharmaceutical composition of valacyclovir or salts thereof having 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one content of 1% or less.
Valacyclovir is chemically, L-valyl ester of acyclovir designated as 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valyl ester. It is commercially available in form of its hydrochloride salt (Formula I) as Valtrex® Tablets. Valacyclovir hydrochloride is indicated for the treatment of Herpes Zoster, Genital Herpes and Herpes labialis.

o CH3 FORMULA I
U.S. Patent No 4,957,924 provides process for preparation of valacyclovir or salt thereof.
Several other processes are known in the art for preparation of valacyclovir such as U.S. Patent No 6,849,737; U.S. patent application No. 2005130993; U.S. patent application No 20050192296; U.S. patent application No 20050059684, U.S. patent application No 2005070711, U.S. patent application No 2007021444, PCT application Nos. WO 2006011874, WO 2006035452 and WO 2007013645.

There are several polymorphic forms of valacyclovir or its salt known in the art through U.S. Patent No 6,107,302 and U.S. Patent No 6,849,736; U.S. patent application No 2005043329, U.S. patent application No 20040197396, U.S. patent application No 20050085491 and U.S. patent application No 2005187229; and PCT Patent application WO 2004106338.
The present inventors while developing a process for the preparation of pure valacyclovir hydrochloride noted contamination of a compound of Formula II. The inventors found that, compound of Formula II is produced during the conversion of Cbz-protected valacyclovir (Formula-Ill) to valacyclovir hydrochloride (Formula-I) as depicted in scheme-l.

Scheme-I
In this disclosure, the term "pure valacyclovir hydrochloride" refers to valacyclovir hydrochloride having the 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one (Formula II) content of 1% or less. The compound of Formula II, chemically known as 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one.

V
-OMe
(II)
In one of the aspect of invention there is provided a process of preparation of pure valacyclovir hydrochloride, wherein the process includes steps of:
a) contacting Cbz-valacyclovir with alcohol and hydrochloric acid mixture,
b) treating the reaction mixture of step a with noble metal catalyst and
c) isolating the pure valacyclovir hydrochloride from the reaction mixture thereof.
The process of invention involves adding N-benzyloxycarbonyl-valacyclovir (Cbz-valacyclovir) in a mixture of methanol and hydrochloric acid and cooled below 20°C. To the reaction mixture, noble metal catalyst i.e. palladium on carbon (50% wet, 5%, 5 gm) was added followed by passing of hydrogen gas to get pressure of about 50 PSI and maintained at 20-25°C for 8-10 hours. Then the pure valacyclovir hydrochloride is isolated from the reaction mixture thereof.
In another aspect of invention there is provided pure valacyclovir hydrochloride having the 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one content of 1% or less.
In yet another aspect of invention there is provided a pharmaceutical composition of valacyclovir hydrochloride having 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one content of 1% or less.
The composition may comprise a formulations such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.

The examples of solid composition include compressed tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules. The examples of liquid composition include emulsions, solutions, suspensions, syrups and elixirs. The examples of injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example
Process for preparation of pure valacyclovir hydrochloride-
The mixture of methanol (875 ml) and hydrochloric acid (125 ml, 1N solution) was cooled to 18-20°C. To this reaction mixture added N-benzyloxycarbonyl-valacyclovir (Cbz-protected valacyclovir) (50 gm) under stirring followed by addition of palladium on carbon (50% wet, 5%, 5 gm). Hydrogen gas was passed through the mass to get a pressure of about 50 PS I, which was then maintained for about 6-7 hours at 20-25°C. The reaction mixture was filtered through celite bed. The clear filtrate was distilled under vacuum and to the residue obtained was added water (75 ml). The resultant mass was heated to 60°C and again filtered through celite bed. The filtrate was heated to 60-65°C and to it was added ethanol (350 ml). The resultant mixture was heated to reflux and then cooled to ambient temperature and maintained for 1 hour. The mass was further cooled and pure valacyclovir hydrochloride having the 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one (Formula II) content of 1% or less was isolated.
Yield of valacyclovir hydrochloride : 26 gm
HPLC purity: 99.84%
HPLC purity of 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one (compound II) :
0.07- 0.09%

We Claim:
1. A process of preparation of pure valacyclovir hydrochloride, wherein the
process comprises steps of:
a) contacting Cbz-valacyclovir with alcohol and hydrochloric acid mixture,
b) treating the reaction mixture of step a with noble metal catalyst and
c) isolating the pure valacyclovir hydrochloride from the reaction mixture thereof.

2. The process of claim 1, wherein alcohol is methanol.
3. The process of claim 1, wherein noble metal catalyst is palladium on carbon.
4. Pure valacyclovir hydrochloride having the 2-amino-9-(methoxymethyl)-1H-
purin-6(9H)-one content of 1% or less.
5. A pharmaceutical composition of valacyclovir hydrochloride having 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one or pharmaceutically acceptable salts thereof content of 1% or less.
6. The composition of claim 5, wherein composition comprise of formulations from the group of solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.

Abstract
The invention provides process for preparation of pure valacyclovir hydrochloride. The invention further provides pure valacyclovir and salts thereof having 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one content of 1% or less. The invention also provides a pharmaceutical composition of valacyclovir or salts thereof having 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one content of 1% or less.