FORM 2
THE PATENT ACT 1970
(39 of 1970)
& The Patents Riiles, 2003
COMPLETE SPECIFICATION
(See section 10 (and rule13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR PURIFICATION OF VALACYCLOVIR
HYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an improved process for the purification of valacyclovir hydrochloride.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to an improved process for the purification of valacyclovir hydrochloride.

Valacyclovir is chemically, L-valyl ester of acyclovir designated as 2-[(2-amino-1,6-dihydro-6-oxo-9W-purin-9-yl)methoxy) L-valyl ester
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.


H,N
.HC1

FORMULA I
US 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 in presence of N,N-dimethylformamide as solvent. Under these conditions it is observed that N-benzyloxycarbonyl-valacyclovir obtained has about 2-5% of the unwanted isomer. The reaction also takes about 40 hours for completion. 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 US Patent No 6,849,737; US Application No 2005130993; US Application No 20050192296; US Application No 20090059684, US Application No 2005070711.
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There are several polymorphic forms of v/valacyclovir known in the art through US

Patent No 6,107,302 and US Paten

No 6,849,736; US Application No

2005043329, US Application No 20040197396, US Application No 20050085491 and US Application No 2005187229|; and PCT Patent Application WO 2004106338.

The present inventors have developed

an improved process for purification of

valacyclovir hydrochloride through use of alkanol solvent. The present inventors have found that valacyclovir hydrochloride obtained by this method has high purity.
In one of the aspect of the present invention there is provided a process for purification of valacyclovir hydrochloride wherein the said process comprises of,
a) dissolving valacyclovir hydrochloride in water
b) adding a mixture of two or more organic solvent wherein one organic solvent comprises of an alkanol and other is selected from group comprising of tetrahydrofuran, acetone and dioxane to solution of step a)
c) isolating the valacyclovir hydrochloride from the reaction mixture thereof.
Valacyclovir hydrochloride used as starting material can be prepared by methods known in the art. It was dissolved in waler by heating at 50-60°C. To this solution a mixture of two or more organic solvent wherein one organic solvent comprises of an alkanol and other is selected from group comprising of tetrahydrofuran,

acetone and dioxane was added and

stirred. The reaction mixture was then

cooled and the pure valacyclovir hydrochloride was isolated. Present inventors used a number of organic solvents or mixture of organic solvents as tabulated in Table 1.
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Table -1
S. No. Solvents (Ratio) Yield(%)
01 Water (D Acetone (4) — 88
02 Water (1) THF (4) — 89
03 Water (1) 1,4-Dioxane (4) — 97
04 Water (1) Methanol (D Acetone (4) 85
05 Water (1) Methi (1 anol) THF (4) 85
06 Water (1) Methi (4 inol) Acetone (1) 59
07 Water (1) Methi (4 mol> THF (D 50
08 Water (D Methi (2 anol ) Acetone (2) 70
09 Water d) Methi (2 molI THF (2) 68
10 Water (D Methi (2 anolI 1,4-Dioxane (2) 60
The alkanol can be selected from the group comprising of straight chain and branched chain C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol and the like.
The maximum yield was achieved when valacyclovir hydrochloride was purified using dioxane organic solvent.
While the present invention has been described in terms of its specific embodiments, 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.
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EXAMPLE
Purification of valacyclovir hydrochloride

placed in 3 necked flask equipped with
Valacyclovir Hydrochloride (10 gm) was
was added and further stirred for 15 to cool gradually to 0-5°C and at this
reflux condenser. Water (20ml) was added and the slurry heated to 60°C, till all valacyclovir hydrochloride was dissolved. 80ml of organic solvent or organic
solvent mixture as specified in table-1 minutes. Reaction mixture was allowed
temperature the slurry stirred for 1 hr and filtered. The wet cake was dried at 60°C under vacuum for 5 hours.
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WE CLAIM

1. A process for purification of valacyclovir hydrochloride wherein the said process comprises of,
a) dissolving valacyclovir hydrochloride in water
b) adding a mixture of two or more solvent comprises of an alkanol
organic solvent wherein one organic
and other is selected from group
comprising of tetrahydrofuran, acetone and 1,4-dioxane to solution of step
a)
c) isolating the valacyclovir hydrochloride from the reaction mixture thereof.
2. A process as claimed in claim 1, valacyclovir hydrochloride was dissolved in water by heating.
3. A process as claimed in claim 1, alkanol can be selected from the group comprising of straight chain and branched chain C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol and the like.

Dated this 30th day of October, 2006

For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory