FORM 2THE PATENT ACT 1970 (39 of 1970) &The Patents Rules, 2003 COMPLETE SPECIFICATION(Sec section 10 and rule l3)

1. TITLE OF THE INVENTION:
IMPROVED PROCESS FOR THE PREPARATION OF OR SALT THEREOF VALACYCLOVIR
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.(b) NATIONALITY: INDIAN(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex,Mumbai-400 051. Bandra (East),
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an improved process for the preparation valacyclovir or salt thereof. of
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to an improved process for the preparation of valacyclovir or salt thereof.
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.

U.S. Patent No 4,957,924 provides process for preparation of valacyclovir or salt thereof wherein the process involves condensation of acyclovir with N-benzyloxycarbonyl-L-valine. The so obtained protected valacyclovir is hydrogenated to remove the protecting group in presence of methanol, tetrahydrofuran and 0.5N hydrochloric acid. The reaction takes about 24 hours and the volume of solvents is very high.
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 patent 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 have developed an improved process for preparation of valacyclovir or salt thereof. Present inventors while working on process for preparation of valacyclovir or salt thereof have surprisingly found that when the protected valacyclovir was deprotected and pH of reaction mixture was adjusted between 3 to 4, the valacyclovir or salt thereof can be isolated in high purity after simply cooling the mass at 0 to -5°C. Valacyclovir hydrochloride obtained by this method has purity of 99% or above when measured by HPLC.
One of the aspects of the present invention provides a process for preparation of valacyclovir or salt thereof wherein the said process includes steps of:
a) deprotecting the compound of Formula II

wherein P1 is hydrogen and P2 is benzyloxy-carbonyl protecting group in presence of alcohol and 1N hydrochloric acid,
b) filtering and adjusting the pH to 3-4.
c) isolating valacyclovir or salt thereof from the reaction mass thereof.
The protected valacyclovir of Formula II is deprotected with a mixture of alcohol selected from the group of methanol or ethanol and 1N hydrochloric acid in presence of hydrogen pressure of 30 to 70 psi over noble metal catalysts such as


palladium on carbon, platinum oxide, palladium acetate, platinum chloride and the like. The reaction can be conveniently carried out at temperatures 25-35°C. After completion of reaction, the reaction mass is filtered to remove the catalyst. The pH of filtrate is adjusted between 3-4 and cooled to 0-5°C and filtered to get valacyclovir hydrochloride. The valacyclovir hydrochloride obtained thereof is further washed with ethanol to get pure valacyclovir hydrochloride. Valacyclovir hydrochloride obtained by this method has a purity of 99% or above when measured by HPLC.
The present invention is further illustrated by the following example which are 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 present invention.
EXAMPLE 1
PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
In a pressure vessel was charged a mixture of ethanol (500 ml) and hydrochloric acid (88 ml, 1N solution) at room temperature. To this was added N-benzyloxycarbonyl-valacyclovir (50 gm) under stirring and palladium on carbon (50% wet, 5%, 5 gm). Applied 50 psi hydrogen gas pressure and maintained at 25-35°C. On completion of the reaction, the reaction mixture was filtered. The catalyst was washed with ethanol. The washings and filtrate were mixed. The mixture obtained thereof cooled to 0° to -5°C for 4 hours and filtered to collect the solid product. The solid was washed with ethanol and dried under vacuum at 50-70°C to get title compound.
Yield = 26.0 g
Purity by HPLC = 98.76 %
EXAMPLE 2
PREPARATION OF VALACYCLOVIR HYDROCHLORIDE


In a pressure vessel was charged a mixture of ethanol (500 ml) and hydrochloric acid (100 ml, 1N solution) at room temperature. To this was added N-benzyloxycarbonyl-valacyclovir (50 gm) under stirring and palladium on carbon (50% wet, 5%, 5 gm). Applied 50 psi hydrogen gas pressure and maintained at 25-35°C. On completion of the reaction, the reaction mixture was filtered. The catalyst was washed with ethanol. The washings and filtrate were mixed and pH was adjusted to 3-4 at 22-25°C. The mixture obtained thereof cooled to 0° to -5°C for 3 hours and filtered to collect the solid product. The solid was washed with ethanol and dried under vacuum at 50-70°C to get title compound. Yield = 21.5 g Purity by HPLC = 99.19%
EXAMPLE 3
PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
In a pressure vessel was charged a mixture of methanol (2000 ml) and hydrochloric acid (200 ml, 2.5 N solution) at room temperature. To this was added N-benzyloxycarbonyl-valacyclovir (200 gm) under stirring and palladium on carbon (50% wet, 5%, 20 gm). Applied 50 psi hydrogen gas pressure and maintained at 25-35°C. On completion of the reaction, the reaction mixture was filtered. The catalyst is washed with methanol. The washings and filtrate were mixed. The mixture obtained thereof cooled to 0° to -5°C for 1 hour and filtered to collect the solid product. The solid was washed with ethanol and dried under vacuum at 50-70°C to get title compound. Yield = 82.5 g Purity by HPLC = 99.36%
EXAMPLE 4
PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
In a pressure vessel was charged a mixture of methanol (1000 ml) and hydrochloric acid (100 ml, 2.5 N solution) at room temperature. To this was added N-benzyloxycarbonyl-valacyclovir (100 gm) under stirring and palladium on carbon (50% wet, 5%, 10 gm). Applied 50 psi hydrogen gas pressure and maintained at


25-35°C. On completion of the reaction, the reaction mixture was filtered. The
catalyst was washed with ethanol. The washings and filtrate were mixed and pH
was adjusted to 3-4 at 22-25°C. The mixture obtained thereof cooled to 0° to -5°C
for 3 hours and filtered to collect the solid product. The solid was washed with
methanol and dried under vacuum at 50-70cC to get title compound.
Yield = 42.0 g
Purity by HPLC = 99.5 %


We Claim
1. A process for preparation of valacyclovir or salt thereof wherein the said
process comprises steps of:
a) deprotecting the compound of Formula II

wherein P1 is hydrogen and P2 is benzyloxy-carbonyl protecting group in presence of alcohol and 1N hydrochloric acid,
b) filtering and adjusting the pH to 3-4.
a) isolating valacyclovir or salt thereof from the reaction mass thereof.
2. A process as claimed in claim 1 wherein deprotection is carried out in presence of noble metal catalyst.
3. A process as claimed in claim 2 wherein the noble metal catalyst is palladium on carbon.
4. A process as claimed in claim 1 wherein the alcohol is selected from the group
of methanol and ethanol.
5. A process as claimed in claim 1 wherein after completion of deprotection
reaction, the reaction mixture was filtered and pH of filtrate was adjusted between
3 to 4.
6. A process as claimed in claim 1 wherein isolation of valacyclovir or salt thereof
is carried out by cooling the reaction mass at 0-5°C.


7. A process as claimed in claim 1 wherein valacyclovir or salt thereof is having the HPLC purity 99 % or more.






ABSTRACT
The present invention relates to an improved process for the preparation of valacyclovir or salt thereof.