FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION (see section 10 and rule 13)
AN IMPROVED PROCESS FOR THE PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
PIRAMAL HEALTHCARE LIMITED, a company incorporated under the Companies Act 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, States of Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2-[(2-amino-1.6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester hydrochloride, hereinafter referred to as valacyctovir hydrochloride, represented by a compound of formula J. The present invention further relates to an improved process for the preparation of valacyclovir hydrochloride.
BACKGROUND OF THE INVENTION
Valacyclovir hydrochloride, 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-
yl)methoxy]ethyl L-valine ester hydrochloride, structurally represented herein below as formula I, is an oral antiviral drug, which is used in the treatment of genital herpes and herpes zoster.

Formula I
Valacyclovir is a prodrug, an esterified version of acyclovir that has greater oral bioavailability than acyclovir. Valacyclovir hydrochloride is not active itself, rather it gets converted in-vivo to acyclovir which is active against the virus.


The oral administration of valacyclovir hydrochloride is more advantageous rather than acyclovir, as acyclovir is poorly absorbed from the gastrointestinal tract. In contrast, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract after oral administration. Valacyclovir hydrochloride is available in the market under the trade names Valtrex® or Zelitrex®.
The process for the preparation of valacyclovir hydrochloride of formula I is discussed in several prior arts. Generally, the process involves deprotection of N-[(benzyJoxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yJ) methoxy] ethyl ester, of formula II using a reducing agent such as; palladium on carbon, palladium on aluminum oxide in the presence of a organic solvent and mineral acid to obtain valacyclovir hydrochloride of formula I.


The product valacyclovir and its pharmaceutically acceptable salts is disclosed in US Patent No. 4,957,924 (hereinafter referred to as US;924 Patent). The US'924 Patent describes a process for the preparation of valacyclovir hydrochloride which comprises deprotection of N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-1.6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl ester, of formula II using 5% palladium on carbon catalyst in the presence of 26.8 volumes of methanol, 26.8 volume of tetrahydrofuran and 4.8 volume of 0.5M hydrochloric acid solution at 50 psi hydrogen pressure for one day. The reaction mixture is then filtered to obtain a white solid. The solid obtained is then recrystallized from water/ethanol to yield 60% valacyclovir hydrochloride. The process described in the US:924 Patent requires use of a large volume of organic solvents such as 26.8 volumes of methanol and tetrahydrofuran, also the disposal of such large volume of organic solvents during commercial manufacturing is very difficult. Moreover, the reaction is required to be carried out over a longer duration that is one day at 50 psi hydrogen pressure. Thus the above discussed process for the preparation of valacyclovir is industrially not feasible.
US Patent No. 6,107,302 (hereinafter referred to as US!302 Patent) discloses a process for the deprotection of N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-y])methoxy] ethyl ester, of formula II using 5% palladium on carbon in the presence of 4.5 volumes of denatured alcohol and formic acid to obtain valacyclovir. The resulting valacyclovir on further treatment with hydrochloric acid and subsequent purification using acetone yields 87.6% valacyclovir hydrochloride. The process described in US'302 Patent requires use of an organic solvent and a mineral acid for the deprotection of said compound of formula JI to yield valacyclovir hydrochloride. Also the use of formic acid as a source of hydrogen generates impurities such as 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethy.l N-formyl L-valine ester (N-formyl impurity), 2-[(2-

amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl N-methyl L-valine ester (N-methyl impurity), 2-[(2-amino-l ,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyI N-ethyl L-valine ester (N-ethyl impurity), thereby making the process disadvantageous.
US Patent Application Publication No. 2007/0112193 (hereinafter referred to as US'193 patent appln.) discloses a process for the preparation of valacyclovir hydrochloride which comprises a reaction of N-[(benzyloxy)carbonyI]-L-valine-2-[(2-amino-],6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester, of formula II with 5% palladium on aluminum oxide in the presence of 10 volume of dimethylformamide (DMF) for 30 minutes at 4kg/cm hydrogen pressure and subsequent treatment of the resulting compound with hydrochloric acid yields valacyclovir hydrochloride having purity of 96.60%. The process for the preparation of pure valacyclovir hydrochloride further comprises three steps of purification to yield valacyclovir hydrochloride having purity of 99.70%. The process disclosed in the US'193 patent appln. discloses the use of deprotecting catalyst such as palladium on aluminum oxide, which is certainly costly as compared to palladium on carbon catalyst. Also, the process disclosed in this patent appln. involves use of 10 volumes of dimethylformamide and use of such large volumes of organic solvents renders the reaction process costly for the industrial manufacturing, thereby making the process industrially not viable. Moreover, the process requires three purifications to yield valacyclovir hydrochloride having purity of 99.70% which eventually renders the process tedious and lengthy.
The process for the preparation of valacyclovir hydrochloride, of formula I can be improved particularly in terms of cost, by providing simple, efficient and industrially applicable process for the preparation of valacyclovir hydrochloride that would result in good yield and purity of valacyclovir hydrochloride. The

processes for the preparation of valacyclovir hydrochloride described in the cited prior art references mostly involve use of large volume of organic solvents and mineral acids. Also the purification of valacyclovir hydrochloride as reported in the prior art references involve more than a single purification steps thereby rendering the process complicated. In view of this, there is a need to develop a process for the preparation of pure valacyclovir hydrochloride, which is simple, cost-effective. efficient and industrially applicable.
The inventors of the present invention have now found that valacyclovir hydrochloride of formula I can be obtained in good yield and high purity from N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester of formula II through an improved process, which although involves use of a catalyst such as palladium on carbon for the deprotection of the compound of formula II. further this process also avoids the use of large volume of organic solvents and use of mineral acids, which in-turn reduces the generation of impurities. Thus, the present invention provides a simple, cost-effective, efficient and industrially applicable process for the preparation of valacyclovir hydrochloride, which is used for the treatment of genital herpes and herpes zoster.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a process for the preparation of 2-
[(2-amino-l .6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester
hydrochloride (valacyclovir hydrochloride) of formula I from N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-I.6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester, of formula II.

Another object of the present invention is to provide a process for the preparation of valacyclovir hydrochloride with yield of >85% and purity of >98%.
Yet another object of the present invention is to provide a process for the preparation of vaJacycJovir hydrochloride using water as a reaction solvent.
Yet another object of the present invention is to provide a process for the preparation of valacyclovir hydrochloride which is simple and efficient.
Further object of the present invention is to provide a process for the preparation of valacyclovir hydrochloride which is cost-effective and industrially applicable.
STATEMENT OF THE INVENTION
In accordance with the objects of the present invention there is provided a process for the preparation of 2-[(2-amino-1.6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester hydrochloride (valacyclovir hydrochloride) of formula I from N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-1.6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester of formula II comprising deprotection of a compound of formula 11 using palladium on carbon in the presence of water as a solvent and acetic acid under the hydrogen pressure to yield valacyclovir. The resulting valacyclovir is subsequently treated with hydrochloric acid and organic solvent to yield valacyclovir hydrochloride.
The process of the present invention is depicted in the following scheme:


Formula I (Valacyclovir hydrochloride)
In accordance with another aspect of the present invention, the compound valacyclovir hydrochloride is prepared in a yield >85% having purity of >98%.
In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantages associated with the process disclosed in the cited prior arts, which concerns with the use of large volume of organic solvents and mineral acids, which leads to generation unwanted impurities.
in accordance with yet another aspect of the present invention, the process for the preparation of valacyclovir hydrochloride uses water as a reaction solvent and avoids use of an organic solvents and mineral acid, hence making the process simple, efficient, cost-effective and industrially applicable.

DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing 2-[(2-ammo-L6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester hydrochloride (valacyclovir hydrochloride) of formula I

Formula I
comprising the steps of: (a) deprotection of N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, of formula U using 5% palladium on carbon in the presence of water as a solvent and acetic acid under hydrogen pressure to obtain valacyclovir and (b) valacyclovir obtained in step (a) is then treated with hydrochloric acid and organic solvent to yield valacyclovir hydrochloride having purity of >98%.

In an embodiment of the present invention, the step (a) of the process is carried out in a solvent, such as water in 5 to 10 volumes with respect to the compound of formula M, preferably the process is carried out using 7 volumes of water with respect to the compound of formula II.
In another embodiment of the present invention, the step (a) of the process is carried out in of 1 mole to 20 moles of acetic acid with respect to the compound of formula II. preferably the proce the presence of acetic acid. The process of the present invention involves usess is carried out using 12 moles to 16 moles of acetic acid with respect to the compound of formula II.
In accordance with another embodiment of the present invention, the step (a) of the process is carried out using a deprotection catalyst such as 5% palladium on carbon
which is 50% wet.
In accordance with another embodiment of the present invention, the step (a) of the process is carried out using a deprotection catalyst such as 5% palladium on carbon. The catalyst is used in an amount of 5% w/w based on the compound of formula II.
In accordance with another object of the present invention, the deprotection reaction of step (a) of the process is carried out under the hydrogen pressure of 5 kg/m to 15 kg/m . preferably the reaction is carried out using 8 kg/m to 12 kg/m" o f hyd ro ge n pre ss u re.
In accordance with another embodiment of the present invention, the valacyclovir obtained in step (a) of the process is further converted to its hydrochloride salt by which valacyclovir obtained is treated with hydrochloric acid. The process of the

present invention is carried out using 1 equivalent of hydrochloric acid with respect to the compound of formula II.
In accordance with another aspect of the present invention, the valacyclovir obtained in step (a) is treated with hydrochloric acid to obtain a white sticky residue. The obtained residue is then reacted with organic solvents to precipitate out solid valacyclovir hydrochloride. The organic solvent used to precipitate out valacyclovir hydrochloride is selected from isopropyl alconol or acetone.
In accordance with the present invention, the starting material, N-i;(benzyloxy)carbonyl]-L-valine-2-[(2-amino-ls6-dihydro-6-oxo-9H-purin-9-yl) methoxyjethyl ester, of formula 11 is charged to a reactor containing 5% palladium on carbon as the catalyst, water and acetic acid. The reaction mixture is stirred well. To the reaction mixture is then applied hydrogen p.ressure of 5 kg/m to 15 kg/m and the resulting reaction mixture is maintained for 12'15 hours at 25-35°C. At this stage the reaction completion is monitored using high performance liquid chromatography (HPLC). The starting material in the reaction mixture is not more than (NMT) 1%. Further the reaction mixture is filtered through hyflo bed and then washed with water. The filtrate obtained contains valacyclovir. To the filtrate is then added hydrochloric acid at room temperature. At this stage the pH of the reaction mixture is 3.5 to 4. The reaction mixture is then distilled under vacuum to obtain a white sticky residue. To the residue obtained organic solvent such as isopropyl alcohol or acetone is charged and stirred at room temperature for 1 hour. The resulting solid is then filtered and washed with isopropyl or acetone. The solid obtained is air dried and then dried at a temperature of 50°C to obtain valacyclovir hydrochloride having yield of >85% and purity of >98°A

The starting material of the process, N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-y])methoxy]ethyJ ester, of formula U is a known compound and can be prepared by a person skilled in the art by following the processes disclosed in the literature. For example, the compound of formula II may be prepared by following the process disclosed in the US Patent No. 4957924, which is incorporated herein by reference. The process involves reaction of acyclovir with N-(benzyloxy)carbonyl-L-valine (CBZ-L-valine) in the presence of dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodimide (DCC) at warm temperature to obtain a faint yellow solution. The faint yellow solution obtained was allowed to cool to room temperature and stirred overnight. A white precipitate was observed after 30 minutes. The reaction mixture was again recharged with the same amounts of CBZ-L-valine, DMAP and DCC, the cloudy suspension obtained is stirred at room temperature for 2 days. The suspension is filtered to remove the solid and the filtrate is concentrated to obtain a light yellow oil. The oil is purified by flash chromatography on silica gel to yield the compound of formula II.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention.
EXAMPLES
Example 1:
To an autoclave the compound of formula II (30g). 5% palladium on carbon (3g), water (210ml) and acetic acid (60ml) are charged and the reaction mixture is stirred

at room temperature. To the reaction mixture hydrogen is passed at a pressure of lOkg/nr and maintained the reaction mixture at a temperature of 25-35°C for 12-15 hours. At this stage the reaction mixture monitored using HPLC. the compound of formula II is NMT 1%. The reaction mixture is then filtered through hyflo bed and then washed with water. To the filtrate hydrochloric acid (8.5ml) is charged at room temperature. The reaction mixture is distilled under vacuum to obtain a white sticky residue. To the residue acetone (360ml) is added at room temperature and stirred for another 1 hour. The solid obtained is then filtered and then washed with acetone. The solid is dried under vacuum to yield valacyclovir hydrochloride having yield of 87% and purity of 98% (HPLC).
Example 2:
To an autoclave the compound of formula 1] (l00g), 5% palladium on carbon (5g). water (700ml) and acetic acid (200ml) are charged and the reaction mixture is stirred at room temperature. To the reaction mixture hydrogen is passed at a pressure of 1 0kg/m and maintained the reaction mixture at a temperature of 25-35°C for 12-15 hours. At this stage the reaction mixture monitored using HPLC, the compound of formula II is NMT 1%. The reaction mixture is then filtered through hyflo bed and then washed with water. To the filtrate hydrochloric acid (28ml) is charged at room temperature. The reaction mixture is distilled under vacuum to obtain a white sticky residue. To the residue isopropyl alcohol (800ml) is added at room temperature and stirred for another 1 hour. The solid obtained is then filtered and then washed with isopropyl alcohol. The solid is dried under vacuum to yield valacyclovir hydrochloride having yield of 90% and purity of 98% (HPLC).

Analytical method of analysis
HPLC column : USP LI, 4.6 x 150 mm, 3.5 μrn
(Zorbax SB-C18, Part # 863953-914)
Detector : UV 250nm
Mobile phase A : In a 1000ml volumetric flask add 2.8ml of tri ethyl amine,
800ml of purified water and adjust the pH to 5.00 ± 0.05
with glacial acetic acid. Complete the volume with purified
water.
iVIobile Phase B : Acetonitrile
Injection volume : 50μL
Column temperature : 30°C
Flow rate : 1 .OmL/minutes
Gradient :

Time (min) Mobile Phase A (%) Mobile Phase B (%)
0-12 97 3 j
12-24 97 3
24-35 70 30
35-36 97 3
36-45 97 3


WE CLAIM
1. A process for the preparation of 2-[(2-amino-1.6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester hydrochloride (valacyclovir hydrochloride) of formula I.

comprising the steps of

Formula II
(a) deprotection of N-[(benzyloxy)carbonylJ-L-va]me-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, of formula II using 5% palladium on carbon in the presence of water as a solvent and acetic acid under hydrogen pressure to obtain valacyclovir.

(b) valacyclovir obtained in step (a) is treated with hydrochloric acid and organic solvent to yield valacyclovir hydrochloride having purity of >98%.
2. The process as claimed in claim 1, wherein in the step (a) water is used in 5 to 10 volume with respect to the compound of formula II.
3. The process as claimed in claim 2. wherein water is used in 7 volume with respect to the compound of formula II.
4. The process as claimed in claim 1, wherein in the step (a) said acetic acid is used in 1 mole to 20 moles with respect to the compound of formula II.
5. The process as claimed in claim 4, wherein said acetic acid is used in 12 moles to 16 moles with respect to the compound of formula II.
6. The process as claimed in claim 1. wherein in the step (a) the catalyst, 5% palladium on carbon is used in an amount of 5% w/w based on the compound of formula II.
7. The process as claimed in claim 1. wherein the step (a) of the process is carried out at a hydrogen pressure of 5 kg/m*" tol 5 kg/irf.
8. The process as claimed in claim 7, wherein said process is carried out at a hydrogen pressure of 8 kg/m2 to 12 kg/m2.

9. The process as claimed in claim 1. wherein in the step (b) the process is carried out using 1 equivalent of hydrochloric acid with respect to the compound of formula II.
10. The process as claimed in claim 1. wherein in the step (b) valacyclovir hydrochloride is precipitate out using organic solvent selected from isopropyl alcohol or acetone.
11. A process for the preparation of 2-[(2-amino-1.6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester hydrochloride (valacyclovir hydrochloride) of formula I substantially as described herein with reference to examples 1 and 2.