FIELD OF THE INVENTION
■The present invention relates to an improved process for the preparation of Valacyclovir or pharmaceutical^ acceptable salts thereof.
BACKGROUND OF THE INVENTION
Valacyclovir, chemically known as 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valinate and has a structure of formula I:
Valacyclovir, which is marketed in the form of its hydrochloride salt is an antiviral drug approved in United States and several other countries under the trade name VALTREX Valacyclovir hydrochloride is used in the treatment of viral infections such as Herpes Zoster and Genital Herpes in humans.
Valacyclovir is a prodrug that is derived from acyclovir by esterification of 3'-hydroxyl group of Acyclovir with L-valine. Acyclovir is also an antiviral nucleoside that possesses activity against human herpes viruses. Valacyclovir has enhanced bioavailability, when compared to Acyclovir.
Valacyclovir and its pharmaceutically acceptable salts were disclosed in the US patent No. 4,957,924. The US '924 discloses processes for the preparation of Valacyclovir, which involves esterification of Acyclovir with Carboxybenzyl (Cbz) protected Valine in presence of N,N'-dicyclohexylcarbodiimide (DCC) and 4-(Dimethylamino)pyridine (DMAP) in dimethylformamide to obtain Cbz-protected Valacyclovir, which is subsequently deprotected to obtain Valacyclovir. The process is as summarized in scheme 1. Scheme-1:

This process requires the removal Cbz group by catalytic hydrogenation using hydrogen gas and specialized equipment such as an autoclave.
US 6,849,737 discloses alternate process for the preparation of Valacyclovir using less severe deprotecting procedures and different protection group viz. tert-butyloxycarbonyl (Boc-group). US '737 process involves condensation of Boc-protected Valine with Acyclovir to obtain Boc-protected Valacyclovir, which is subsequently deprotected using hydrochloric acid to obtain Valacyclovir hydrochloride. The process of US '737 is as depicted in scheme 2.
The present inventors have observed that the Valacyclovir product obtained by the process disclosed in US '737 contains higher amount of impurities especially degradation products such as Acyclovir and Guanine. The product obtained by this process requires several

purification steps, which results into loss of yield and that makes the process unfeasible for production at large scale.
. It has been observed that the problems associated with increased impurities, and the corresponding reduced yields, is due to the higher residence time in the batch mode process disclosed in US '737.
Due to the challenges involved in the processes of the prior art, there is clearly a need for a process for the preparation of valacyclovir that employs less severe deprotecting procedures while retaining the higher purity of the final product.
Hence, present inventors have developed a process for preparing pure Valacyclovir hydrochloride suitable for use in the pharmaceutical composition,
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Valacyclovir or pharmaceutically acceptable salts thereof.
Another objective of the present invention is to provide a process for the preparation of pure Valacyclovir hydrochloride suitable for use in the pharmaceutical composition.
SUMMARY OF THE IVENTION
In one embodiment, the present invention provides a process for the preparation of Valacyclovir or pharmaceutically acceptable salt thereof, which comprises reaction of amine-protected Valacyclovir or its salt with deprotecting agent in a continuous flow reactor.
In another embodiment, the present invention provides a process for the preparation Valacyclovir hydrochloride, which comprises:
a) providing a solution of amine-protected Valacyclovir in a suitable solvent to obtain solution A;
b) providing a solution of deprotecting agent in a suitable solvent to obtain solution B;
c) feeding separately prepared solution A and solution B to a continuous flow reactor;
d) continuously eluting the reaction mass from the reactor; and
. r >,.-!-. e) ^precipitating the solid(from-ithe reaction mass to obtain -Valacyclovir hydrochloride.

In another embodiment, the present invention provides a process for the preparation of Valacyclovir hydrochloride, which comprises:
a) providing a solution of Boc-protected Valacyclovir in a suitable solvent to obtain solution A;
b) providing aqueous solution of hydrochloric acid to obtain solution B;
c) feeding separately prepared solution A and solution B to a continuous flow reactor;
d) continuously eluting the reaction mass from the reactor;
e) precipitating the solid from the reaction mass; and
f) drying the product to obtain Valacyclovir hydrochloride.
DETAILED DESCRIPTION OF THE IVENTION
The present invention provides an economical and commercially viable process for producing Valacyclovir or pharmaceutically acceptable salt thereof. The process employs application of reactors such as microreactor, lug flow reactor, microfluidic flow reactor, coil-type flow reactor, tubular flow reactor, laminar flow reactor, packed bed reactor, fluidized bed reactor and fixed bed reactor, for the preparation of Valacyclovir or pharmaceutically acceptable salt thereof in purity greater than 99% with enhanced in-process control on impurities specifically Acyclovir and Guanine. ,
In one embodiment, the present invention provides a process for the preparation of Valacyclovir or pharmaceutically acceptable salt thereof, which comprises reaction of amine-protected Valacyclovir or its salt with deprotecting agent in a continuous flow reactor.
The reaction of amine-protected Valacyclovir or its salt with deprotecting agent may be performed between solid and solid or solid and solution or between solution of Valacyclovir and solution of deprotecting agent.
Amine-protected Valacyclovir or its salt may be prepared from amine protected valine selected from N-t-butoxycarbonyl valine, N-formyl valine and N-carboxybenzyl valine, and acyclovir. Salt of Amine-protected Valacyclovir may be selected from hydrochloride, hydrobromide, acetate, oxalate, succinate, sulfate, phosphate and the like.

Valacycovir or pharmaceutically acceptable salt thereof and deprotecting agent can be added into the reactor at a temperature of about 0 to 100°C.
When the reaction between solutions, the solution of Valacyclovir or deprotecting agent is provided by dissolution of solid in a solvent or the solution can be taken from the previous reaction step. The solvent is used for dissolution is selected from same or different solvent of water, alcohols, hydrocarbons and chlorinated solvents or mixture thereof. The solution can be prepared at a temperature of about 0 to 50°C or at reflux of solvent used.
The solution is flowed with same or different rate continuously into the reactor. The flow rate may be 1 ml/minute to 50 ml/minute at a temperature of about 0 to 100°C or above. In an embodiment, the flow rate of Valacyclovir may be more than the flow rate of the solution of deprotecting agent.
After the reaction, the obtained reaction elute may be subjected for solid isolation using suitable techniques such acid/base treatment, recrystallization, anti-solvent, crash cooling, spray drying and the like.
In another embodiment, the present invention provides a process for the preparation Valacyclovir hydrochloride, which comprises:
a) providing a solution of amine-protected Valacyclovir in a suitable solvent to obtain solution A;
b) providing a solution.of deprotecting agent in suitable solvent to obtain solution B;
c) feeding separately prepared solution A and solution B to a continuous flow reactor;
d) continuously eluting the reaction mass from the reactor; and
e) precipitating the solid from the reaction mass to obtain Valacyclovir hydrochloride
Amine-protected Valacyclovir is protected with a suitable protecting group, which can be deprotected by using less severe deprotection methods such by using suitable acid. One of the suitable protecting group according to present invention is tert-butoxycarbonyl group (Boc). The amine protected Valacyclovir may be prepared by condensation of Acyclovir with corresponding amine-protected Valine or salt thereof in presence of suitable coupling agents selected from the group comprising of dicyclohexylcarbodiimide (DCC) or N,N'-c ^i^isopTOPtorbodiimidefpiCX,., T „.„ ,.. _ . . „, rt... _, _ .. _

The solvent used for the preparation of solution of A and solution of B may be selected from same or different solvent. The solvent used for the preparation of solution A is selected from the group comprising of lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol and isoamyl alcohol; hydrocarbons such as toluene, heptane, hexane, cyclohexane; chlorinated solvent such as methylene chloride, chloroform and carbon tetrachloride; or mixtures thereof;
The Solution-B is prepared by adding suitable deprotecting agent is acid to a suitable solvent. The acid is selected from the group comprising of hydrochloric acid, trifluoroacetic acid, phosphoric acid, formic acid or mixture thereof. The solvent is selected from the group comprising of water, lower alcohols such as methanol, ethanol, isopropanol or mixtures
thereof.
The Solution A and Solution B are fed simultaneously into the continuous mode reactor in a continuous flow. The solution A is added to the reactor at a flow rate of 5-15 ml/minute and preferably at about 8-10 ml/min. The solution B is added to the reactor at a rate of 2-10 ml/min and preferably at about 4-8 ml/min. The reaction mass is passed through a continuous mode reactor at a residence time of l-15minute and preferably at 2-5 minute. The reaction mass is passed at temperature 10-120°C and preferably at 80-100°C. The reaction mass eluted from the reactor is continuously collected for the isolation of product.
The aqueous layer containing Valacyclovir product from the eluted reaction mass may be separated by conventional methods. The excess of deprotecting agent used for deprotection may be quenched by adding suitable base selected from the organic base selected from the group comprising of triethylamine, diisopropylamine, diisopropylethylamine, or inorganic base selected from sodium bicarbonate, ammonia, potassium bicarbonate and sodium carbonate. The resultant aqueous solution may be subjected for precipitation by using conventional methods. The solid is isolated using suitable techniques such as filtration, decantation, centrifugation and the like. The solid obtained from the present invention is further dried at a temperature of about 20 to about 100°C under vacuum.

When the resultant compound from the reaction is Valacyclovir or its salt of other than hydrochloride, the resultant compound is converted into Valacyclovir hydrochloride salt by treating with hydrochloric acid.
In yet another embodiment of the present invention, Valacyclovir hydrochloride prepared according to present invention is converted to its pharmaceutical composition.
The invention is illustrated with the following examples, which are provided by way of -illustration only and should not be construed to limit the scope, of the invention.
EXAMPLE 1
PROCESS FOR THE PREPARATION BOC-L-VALACYCLOVIR
BOC L-Valine (120 g) was dissolved in 300 ml dimethylformamide (DMF) at 25-30°C. The solution was cooled to -5°C and DCC solution (137.47 g DCC in 350 ml DMF) was added at -5 to -10°C in 90 min followed by stirring for 10 min at -5 to 10°C. Acyclovir (100 g) was added to the obtained solution of Boc-Valine, followed by 4-dimethylaminopyridine (DMAP) (7g) was added at -5 to -10°C. After completion of the reaction, residue was washed with DMF (100 ml) and DMF was distilled out under vacuum at 55-60°C. Preheated DM water (2 lit) was added to the above residue at 70-75°C and stirred for 60 min at 70-75°C and cooled to 30-35°C. The product was filtered and washed with 300 ml DM water at 35-45°C; and further washed with 150 ml ethanol and dried the product at 45-50°C. Yield: Dry- 205 g crude Purily: 97.5 to 98% (by HPLC)
EXAMPLE 2
PROCESS FOR THE PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
Preparation of Solution-A
Boc-L-Valacyclovir crude (50 g) was charged into mixture of methylene chloride (375 ml)
and methanol (125 ml) at 25-30°C and stirred the reaction mass at 25-30°C to get the clear
solution-A.
Preparation of Solution-B
Cone. Hydrochloric acid (56 ml) was added to DM water (224 ml) over a period of 15-20 min
at 20-25°C. Thereafter methanol (56 ml) was added slowly to the obtained solution at 20-
25fC

Above separately prepared solution-A (Flow rate-8 ml/min) and solution-B (Flow rate-5.5 ml/min) were fed to the continuous flow micro reactor at 80°C. The elute reaction mass from micro reactor was continuously collected at 0-5°C. As the feed solutions A & B are consumed micro reactor is flush with methylene chloride (50 ml: 50 ml) each feed.. Immediately after the collection of reaction mass, aqueous layer and lower organic layers were separated. The pH of the aqueous layer containing product was adjusted to about 2.5 to 2.8 with triethyl amine (~ 46.28 g) at 0-5 °C). .Ethanol (300 ml) at 0-5°C was added slowly to the solution. The obtained reaction mass was distilled under reduced pressure (400-40 mm Hg) to get white. The obtained solid mass was cooled at 25-30°C and ethanol (300 ml) was added and continued stirring the above slurry mass at 25-30°C for 60-80 min. The solid was filtered and washed with chill ethanol (100 ml. 0-5°C). The obtained solid is dried in vacuum dryer at 40-45°C till moisture content is 5-8%. . Yield: 31 g Purity: 99% (by HPLC)
COMPARATIVE EXAMPLE
PROCESS FOR THE PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
Boc-L-Valacyclovir (50 g) was charged into DM Water (50 ml) at 20-25°C to obtain a
suspension. Then concentrated hydrochloric acid (23.29 g) was added slowly to the obtained
solution over a period of 15-20 min at 20-25°C and stirred for about 2.5 hours. After
completion of the reaction, iso-propanol (1100 ml) was added over a period of 2 hours and
stirred the mixture to 0-5°C for 1 hour. The obtained solid was filtered under nitrogen
atmosphere and washed with isopropanol (150 ml). The obtained solid was dried under
vacuum at 40-45°C till moisture is in the range of 5% to 8%.
Yield: 11.8 g
Purity: 96.64% (by HPLC),
Impurities: Acyclovir 2.45 %, Guanine 0.24 %.