IMPROVED PROCESS FOR PREPARATION OF VALACYCLOVIR HYDROCHLORIDE

INTRODUCTION

The present invention relates to improved processes for the preparation of valacyclovir hydrochloride and intermediates thereof.

Valacyclovir hydrochloride, the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir, has the chemical names (2-[2-amino-1,6-dihydro-6-oxo-9H (purin-9-yl)methoxy]ethyl-L-valinate hydrochloride, or L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride, and may be depicted by structural Formula I.

An aspect of the present invention relates to an improved process for the preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl)methoxy]ethyl-N-[(benzyl oxy)carbonyl]-L-valinate having the structure shown in Formula II, which is an intermediate in the synthesis of valacyclovir hydrochloride.

Formula II Valacyclovir hydrochloride is useful for the treatment of herpes simplex and
varicella-zoster viral infections in humans, and is commercially available in
pharmaceutical products sold by GlaxoSmithKline using the trademark VALTREX®,
as caplets containing the equivalent of 500 mg or 1 gram of valacyclovir. U.S. Patent No. 4,957,924 discloses valacyclovir hydrochloride, its pharmaceutical composition, and a method of treatment using this composition.

International Application Publication No. WO 2006/0029253 A1 discloses the isolation and process for the preparation of an N-formyl valacyclovir impurity and use of the N-formyl valacyclovir impurity as a reference standard in the quantitative analysis of valacyclovir or its pharmaceutically acceptable salts. U.S. Patent application publication No. 2008/0281099A1 discloses the purification process to reduce the D-isomer content in valacyclovir hydrochloride and its intermediates. The specification for valacyclovir D-isomer content in valacyclovir hydrochloride, in the pending monographs of United States Pharmacopoeia is not more than 1.0% by weight. Therefore, regulatory authorities require that the valacyclovir hydrochloride active pharmaceutical ingredient to be used for making formulations meet this valacyclovir D-isomer content specification.

There is a need to provide simple, economical, eco-friendly and robust processes for the preparation of valacyclovir hydrochloride, which meets the specification for valacyclovir D-isomer content is not more than 1.0%. The processes of the present invention are simple, cost effective, eco-friendly, and reproducible, afford high yields and purity, and are well suited for commercial production.

SUMMARY

The present invention relates to improved processes for the preparation of valacyclovir hydrochloride and intermediates thereof.

In one aspect, there is provided the compound 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl) methoxy]ethyl-N-[(benzyloxy) carbonyl]-L-valinate of Formula II, which contains not more than 1.0% w/w of its D-isomeric impurity of formula V as determined by high performance liquid chromatography ("HPLC").

In another aspect, there are provided processes for the preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl)methoxy]ethyl-N-[(benzyloxy)carbonyl]-L-valinate of Formula II, providing a product that contains not more than 1.0% w/w of its D-isomeric impurity as determined by high performance liquid chromatography ("HPLC"), an embodiment of a process comprising condensation of 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one of Formula III (acyclovir) and carbobenzyloxy-L-valine of Formula IV.

In yet another aspect, there is provided pure valacyclovir hydrochloride of
Formula I having chiral purity greater than or equal to about 99% w/w as determined
by high performance liquid chromatography (HPLC), prepared by a process
comprising:

(i) deprotecting 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl
2-[(benzyloxy)carbonyl] L-valinate of Formula II;

(ii) converting valacyclovir into valacyclovir hydrochloride of formula (I); and

(iii) isolating valacyclovir hydrochloride of formula (I).

In another aspect, there are provided pharmaceutical compositions comprising valacyclovir or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

In one aspect, there is provided the compound 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl) methoxy]ethyl-N-[(benzyloxy) carbonyl]-L-valinate of Formula II, which contains not more than 1.0% w/w of its D-isomeric impurity as determined by high performance liquid chromatography ("HPLC").

In another aspect, there are provided processes for the preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl)methoxy]ethyl-N-[(benzyloxy)carbonyl]-L-valinate of Formula II, providing a product that contains not more than 1.0% w/w of its D-isomeric impurity as determined by high performance liquid chromatography ("HPLC"), an embodiment of a process comprising condensation of 2-amino-1,9- dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one (acyclovir) of Formula III and carbobenzyloxy-L-valine of Formula IV.

Formula III Formula IV

Condensation reaction may be carried out in a suitable base. Suitable bases that may be used include, but are not limited to, organic bases such as, for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-
methylpyrrolidine, pyridine, 4-(N,N-dimethylamino) pyridine, morpholine, imidazole,
2-methylimidazole, 4-methylimidazole, or the like; inorganic bases, such as, for
example, alkaline metal hydroxides, such as, for example, aluminum hydroxide,
magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such
as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium
carbonate, or the like; alkaline earth metal carbonates, such as, for example,
magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates,
such as, for example, sodium bicarbonate, potassium bicarbonate, or the like;
mixtures thereof; or any other suitable bases.

The quantities of base that may be used may be less than about 3 molar equivalents, or less than about 2 molar equivalents, or less than about 1 molar equivalents, or less than about 0.75 molar equivalents, or less than about 0.60 molar equivalents, or less than about 0.50 molar equivalents, or less than about 0.30 molar equivalents, or less than about 0.20 molar equivalents, or any other suitable quantities, with respect to the moles of 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy) methyl]-6H-purin-6-one of Formula III.

Condensation may be carried out in a suitable solvent. Suitable organic solvents that may be used include but are not limited to: ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone or the like; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate or the like; nitrile solvents such as acetonitrile, propionitrile or the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) or the like; or mixtures thereof.

Optionally condensation reaction may be carried out by using water as catalyst. The quantities of water that may be used may be less than about 5 molar equivalents, or less than about 3 molar equivalents, or less than about 1 molar equivalents, or less than about 0.75 molar equivalents, or less than about 0.60 molar equivalents, or less than about 0.50 molar equivalents, or less than about 0.30 molar equivalents, or less than about 0.20 molar equivalents, or any other suitable quantities, with respect to the moles of 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy) methyl]-6H-purin-6-one of Formula III.

Suitable temperatures for the reaction may be less than about 100°C, or less than about 70°C, or less than about 50°C, or less than about 30°C, or less than about 20°C, or less than about 10°C, or less than about 0°C, or less than about -10°C or less than about -20°C or any other suitable temperatures.

The product may be isolated directly from the reaction mixture itself after the reaction is completed, or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

Isolation of compound of formula (II) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as, for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Suitable solvents that may be used for isolation compound of formula (II) include, but are not limited to: water; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichioromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; nitromethane; or any mixtures thereof.

The obtained compound of formula (II) may be optionally further purified by recrystallization or by slurrying in a suitable solvent. Suitable solvents that may be used for purification of the compound of formula (III) include, but are not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, or the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl iso-butyl ketone, or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetratiydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane, nitromethane, or the like; halogenated hydrocarbons such as dichioromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethane, or the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetralin, or the like; nitriles such as acetonitrile, propionitrile, or the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; water; or any mixtures thereof.

The resulting compound of formula (II) may be recovered as a solid using conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids.

The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 80°C, or less than about 60°C, or any other suitable temperatures as long as the compound of formula (II) is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 hour to about 10 hours, or longer.

In yet another aspect, there is provided pure valacyclovir hydrochloride of Formula I having chiral purity greater than or equal to about 99% w/w as determined by high performance liquid chromatography (HPLC), prepared by a process comprising:

(i) deprotecting 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl
2-[(benzyloxy)carbonyl] l-valinate of Formula II;

(ii) converting valacyclovir into valacyclovir hydrochloride of formula (I); and

(iii) isolating valacyclovir hydrochloride of formula (I).

Step (i) may be carried out in a suitable solvent. Suitable organic solvents that may be used include, but are not limited to, water; alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, tertiary-butyl alcohol, or the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone or the like; ester solvents such as ethyl acetate, nrpropyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate or the like; nitrile solvents such as acetonitrile, propionitrile or the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) or the like; or mixtures thereof.
The amount of palladium coated on the carbon used in step (i) can range from about 5% to about 10% w/w. Suitable temperatures for the reaction of step (i) may be less than about 100°C, less than about 70°C, less than about 50°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperatures.

Step (ii) may be carried out in a suitable solvent. Suitable organic solvents that may be used include but are not limited to: water; alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, tertiary-butyl alcohol, or the like; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone or the like; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tertiary-butyl acetate or the like; nitrile solvents such as acetonitrile, propionitrile or the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA) or the like; or mixtures thereof. Suitable temperatures for the conversion of step (ii) may be less than about less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 0°C, or any other suitable temperatures.

Step (iii) involves the isolating of valacyclovir hydrochloride of formula (I). Suitable solvents that may be used for isolation include, but are not limited to: alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, or the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl iso-butyl ketone, or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethane, or the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetralin, or the like; nitriles such as acetonitrile, propionitrile, or the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, nitromethane, or the like; water; or any mixtures thereof.

The obtained compound of formula (I) may be optionally further purified by recrystallization or by slurrying in a suitable solvent. Suitable solvents that may be used for purification of the compound of formula (I) include, but are not limited to: alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, neopentyl alcohol, amyl alcohol, 2- methoxyethanol, 2-ethoxyethanol, ethylene glycol, glycerol, or the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl iso-butyl ketone, or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane, nitromethane, or the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethane, or the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetralin, or the like; nitriles such as acetonitrile, propionitrile, or the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; water; or any mixtures thereof.

The isolation may be effected by methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, adding seed crystals, or the like, Suitable temperatures for isolation may be less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 5°C, less than about 0°C, or any other suitable temperatures. The exact temperatures and times required for complete isolation may be readily determined by a person skilled in the art and will also depend on parameters, such as, for example, concentrations and temperatures of the solution or slurry. Stirring or other alternate methods, such as, for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

The isolated compound of formula (I) may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids. Suitable techniques that may be used for a removal of solvent include, but are not limited to rotational distillation using a device, such as, for example, Buchi Rotavapor®, spray drying, agitated thin-film drying, freeze drying (lyophilization), or the like, optionally under reduced pressure.

The recovered solid may be optionally further dried. Drying may be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, rotary cone vacuum drier and the like. The drying may be carried out at temperatures less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 80°C, or less than about 60°C, or any other suitable temperatures as long as the Valacyclovir of Formula (I) is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 to about 15 hours, or longer. In embodiments, drying is conducted in a reduced oxygen atmosphere, such as under nitrogen or another inert gas.

The dried product may be optionally milled to get desired particle size parameters. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include; without limitation; sifting; granulation; milling using mills, such as, for example, ball, roller and hammer mills, and jet mills, such as, for example, air jet mill, or any other conventional techniques.
The pressures that may be used for milling or micronization are less than about 20 kg/cm2, less than about 10 kg/cm2, less than about 8 kg/cm2, less than about 6 kg/cm2, less than about 4 kg/cm2, or less than about 3 kg/cm2. The pressure that is applied in the mill plays an important role in reduction of particle size. The more the pressure applied, the more the reduction in particle size. By appropriately adjusting the pressure in the mill, any desired reduction in particle size may be achieved. Generally nitrogen, air or any other suitable gas may be used for applying pressure in the mill depending on the characteristics of the material going to be milled. In some cases, an inert gas such as nitrogen may have to be used in the mill to apply pressure in order to avoid formation of unwanted impurities. In most of the particle size reduction mills, the feed rate into the mill is also an important factor in achieving reduction in particle sizes. Since the reduction in particle sizes is largely dependent on residence time of the material in the milling device, the feeder is an important device in controlling the residence time of the material in the mill, and subsequently achieving the reduction in particle sizes. It is generally observed that the higher the feed rate of the material, the lesser the reduction in particle sizes, which results in slightly coarser particle sizes of the material. On the other hand, the lower the feed rate of the material, the more the particle size reduction, which results in finer particle sizes of the material. By adjusting the appropriate feed rate, desired particle sizes may be achieved.

The desired particle sizes may also be achieved directly from the reaction mixture by selecting equipment that is able to provide valacyclovir hydrochloride with the desired particle sizes.

In an embodiment, the present application provides valacyclovir hydrochloride having bulk densities less than about 1.2 g/mL, less than about 1.0 g/mL, less than about 0.8 g/mL, or less than about 0.5 g/mL, or less than about 0.3 g/mL Bulk density may be determined using Test 616 "Bulk Density and Tapped Density," as in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, in method 2.
The desired bulk density of valacyclovir hydrochloride may be achieved directly from the reaction mixture or optionally by methods including granulation, such as for example rapid mixture granulation or any other suitable technique.

In another aspect, there are provided pharmaceutical compositions comprising valacyclovir or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.
The pharmaceutical compositions comprising valacyclovir or its pharmaceutically acceptable salt of the invention together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that are useful in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch or the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants or the like.

Certain specific aspects and embodiments of the present application are explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES

EXAMPLE 1: Preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) charged into a round bottom flask at 26°C and cooled to -9°C. Dicyclohexylcarbodiimide (32.06 g) is charged into reaction mass at -9°C and stirred for 10 minutes. Acyclovir (20 g) and dimethylaminopyridine (6.5 g) is charged into reaction mixture at -9°C and stirred for 10 minutes. To the resultant reaction mixture carbobenzyloxy-L-valine solution (carbobenzyloxy-L-valine (33.46 g) dissolved in N, N-dimethylformamide (60 mL)) is added at -9°C over a period of 30 minutes and stirred for 30 minutes. Reaction mass temperature is increased to 1°C and stirred at 1°C for 16 hours. Further reaction mass temperature increased to 26°C and stirred for 90 minutes. The resultant reaction mass is filtered and washed with N, N-dimethylformamide (100 mL).

D-isomer content by HPLC: 0.535%

EXAMPLE 2: Preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) charged into a round bottom flask at 26°C and cooled to -9°C. Dicyclohexylcarbodiimide (32.06 g) is charged into reaction mass at -9°C and stirred for 10 minutes. Acyclovir (20 g) is charged into reaction mixture at -9°C and stirred for 30 minutes. Dimethylaminopyridine (10.84 g) is charged into the reaction mixture at -9°C and stirred for 30 minutes. To the resultant reaction mixture carbobenzyloxy-L-valine solution (carbobenzyloxy-L-valine (33.46 g) dissolved in N, N-dimethylformamide (60 mL)) is added at -9°C over a period of 35 minutes and stirred for 1 hour. Reaction mass temperature is increased to 1°C and stirred at 1 °C for 26 hours. The resultant reaction mass is filtered and washed with N, N-dimethylformamide (100 mL). D-isomer content by HPLC: 0.669%

EXAMPLE 3: Preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) charged into a round bottom flask at 26°C and cooled to -9°C. Dicyclohexylcarbodiimide (32.06 g) is charged into reaction mass at -9°C and stirred for 10 minutes. Acyclovir (20 g) is charged into reaction mixture at -9°C and stirred for 30 minutes. Dimethylaminopyridine (6.50 g) is charged into the reaction mixture at -9°C and stirred for 30 minutes. To the resultant reaction mixture carbobenzyloxy-L-valine solution (carbobenzyloxy-L-valine (33.46 g) dissolved in N, N-dimethylformamide (60 mL)) is added at -9°C over a period of 35 minutes and stirred for 30 minutes. Reaction mass temperature is increased to 1°C and stirred at 1°C for 17 hours. The resultant reaction mass is filtered and washed with N, N-dimethylformamide (100 mL). D-isomer content by HPLC: 0.646%
EXAMPLE 4: Preparation of 2-[(2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) charged into a round bottom flask at 26°C and cooled to -9°C. Carbobenzyloxy-L-valine (33.46 g) is charged into reaction mixture at -8°C and stirred for 5 minutes. Acyclovir (20 g) is charged into reaction mixture at -8°C and stirred for 5 minutes. Dimethylaminopyridine (1.62 g) is charged into the reaction mixture at -8°C and stirred for 5 minutes. To the resultant reaction mixture dicyclohexylcarbodiimide solution (dicyclohexylcarbodiimide (32.06 g) dissolved in N, N-dimethylformamide (60 mL)) is added at -8°C over a period of 20 minutes and stirred for 1 hour. Reaction mass temperature is increased to 1°C and stirred at 1°C for 16 hours. Further reaction mass temperature increased to 26°C and stirred for 2 hours. The resultant reaction mass is filtered and washed with N, N-dimethylformamide (100 mL). D-isomer content by HPLC: 0.584%

EXAMPLE 5: Preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) is charged into a round bottom flask at 26°C and cooled to 3°C. Carbobenzyloxy-L-valine (33.46 g) is charged into reaction mass at 3°C and stirred for 10 minutes. Acyclovir (20 g) is charged into reaction mixture at 3°C and stirred for-5 minutes. Dimethylaminopyridine (1.62 g) and sodium carbonate (0.9 g) are charged into the reaction mixture at 3°C and stirred for 10 minutes. Dicyclohexylcarbodiimide (32.06 g) is charged into reaction mass at 3°C and the obtained reaction mixture is stirred for 32 hours. The resultant reaction mass is filtered and washed with N, N-dimethylformamide (100 mL). D-isomer content by HPLC: 0.58%

EXAMPLE 6: Preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) and water (1.59 mL) charged into a round bottom flask at 26°C and cooled to -9°C. Dicyclohexylcarbodiimide (32.06 g) is charged into reaction mass at -9°C and stirred for 10 minutes. Acyclovir (20 g) is charged into reaction mixture at -9°C and stirred for 10 minutes. Dimethylaminopyridine (6.5 g) is charged into the reaction mixture at -9°C and stirred for 15 minutes. To the resultant reaction mixture Carbobenzyloxy-L-valine solution (Carbobenzyloxy-L-valine (33.46 g) is dissolved in N, N-dimethylformamide (60 mL)) is added over 30 minutes at -9°C and stirred for 30 minutes. Reaction mixture temperature increased to 1°C and stirred for 20 hours. The obtained reaction mixture is filtered, washed with N, N-Dimethylformamide (100 mL). The resultant filtrate charged into flask and stirred for 2 hours, again filtered the reaction mixture and washed with N, N-dimethylformamide (10 mL). Filtrate is evaporated at 66°C under reduced pressure until the filtrate volume reaches to 3-4 volumes with respect to acyclovir quantity. Water (180 mL) is added to the reaction mixture at 48°C, the resultant reaction mixture is heated to 69°C and stirred for 45 minutes, further cooled to 27°C, and stirred for 3 hours. Separated solid is collected by filtration, washed with water (80 mL). Charged wet compound and methanol (320 mL) into flask, heated to 67° and stirred for 45 minutes. The resultant reaction mass is cooled to 27°C and stirred for 3 hours. Separated solid is collected by filtration and washed with methanol (80 mL). The wet solid was dried at 60°C under reduced pressure for 10 hours to afford 34.05 g of title compound. D-isomer content by HPLC: 0.45%

EXAMPLE 7: Preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy] ethyl-N-[(benzyloxy) carbonyl]-L-valinate.

N, N-Dimethylformamide (300 mL) into a round bottom flask at 26°C and cooled to -8°C. Dicyclohexylcarbodiimide (32.06 g) is charged into reaction mass at -8°C and stirred for 30 minutes. Water (1.55 mL) is charged into reaction mixture and stirred for 5 minutes. Acyclovir (20 g) is charged into reaction mixture at -8°C and stirred for 20 minutes.

Dimethylaminopyridine (1.62 g) is charged into the reaction mixture at -8°C and stirred for 30 minutes. To the resultant reaction mixture carbobenzyloxy-L-valine solution (carbobenzyloxy-L-valine (33.46 g) is dissolved in N, N-dimethylformamide (60 mL)) is added over 45 minutes at -8°C and stirred for 15 minutes. Reaction mixture temperature increased to 1°C and stirred for 15 hours. Reaction mass temperature increased to 28°C and stirred for 2 hours 15 minutes. The resultant reaction mixture is filtered and washed with N, N-dimethylformamide (100 mL). Filtrate is stirred at 27° for 3 hours, again filtered, and washed with N, N-dimethylformamide (10 mL). Filtrate is evaporated at 65°C under reduced pressure until the filtrate volume reaches to 3 volumes with respect to acyclovir quantity. Water (180 mL) is added to the reaction mixture at 55°C, the resultant reaction mixture is heated to 70°C and stirred for 45 minutes, further cooled to 28°C and stirred for 2 hours 15 minutes. Separated solid is collected by filtration and washed with water (80 mL). Charged wet compound and methanol (320 mL) into flask, heated to 66°, and stirred for 45 minutes. The resultant reaction mass is cooled to 27°C and stirred for 3 hours. Separated solid is collected by filtration and washed with methanol (80 ml_). The wet solid was dried at 60°C under reduced pressure for 7 hours to afford 35.0 g of title compound. D-isomer content by HPLC: 0.62%

EXAMPLE 8: Process for the preparation of valacyclovir hydrochloride.

30 g of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl)methoxy]ethyl-N-[(benzyloxy) carbonyl]-L-valinate and N, N-dimethylformamide (90 mL) charged into a round bottom flask. 10% Palladium carbon (3.0 g) is charged into reaction mass and hydrogen bubbling is applied. The resultant reaction mixture is stirred at 27°C for 4 hours. Mixture of concentrated HCI (7.83 g) and water (105 mL) is added to the above reaction mixture at 16°C and stirred at 27°C for 1 hour while applying the hydrogen bubbling. The obtained reaction mass is filtered and washed with water (7.5 mL). Filtrate again filtered through 0.45 micron filter and washed with water (7.5 mL). Filtrate charged into round bottom flask and seeding is added to the reaction mass at 18°C. Reaction mass is further cooled to 2°C and stirred at 2°C for 70 minutes. Acetone (900 mL) is added to the reaction mass and stirred for 4 hours. Separated solid is collected by filtration and washed with acetone (60 mL). The obtained wet compound is charged into mixture of water (36 mL) and acetone (264 mL) at 2°C and stirred for 4 hours. Separated solid is collected by filtration, washed with mixture of water (2x7.2 mL) and acetone (2x52.8 mL), and dried in Buchi Rotavapor® at 55°C for 3 hours to afford 21.86 g of title compound. D-isomer content by HPLC: 0.754%

EXAMPLE 9: Process for the preparation of valacyclovir hydrochloride.

30 g of 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9yl)methoxy]ethyl-N-[(benzyloxy) carbonyl]-L-valinate and N, N-dimethylformamide (90 mL) charged into a round bottom flask. 10% Palladium carbon (3.0 g) is charged into reaction mass and hydrogen bubbling is applied. The resultant reaction mixture is stirred at 27°C for 4 hours. Mixture of concentrated HCI (7.83 g) and water (105 mL) is added to the above reaction mixture at 17°C and stirred at 27°C for 1 hour while applying the hydrogen bubbling. The obtained reaction mass is filtered and washed with water (7.5 mL). Filtrate again filtered through micron filter and washed with water (7.5 mL).

Filtrate charged into round bottom flask and seeding is added to the reaction mass at 18°C. Reaction mass is further cooled to 2°C and stirred at 2°C for 70 minutes. Acetone (900 mL) is added to the reaction mass and stirred for 4 hours. Separated solid is collected by filtration and washed with acetone (60 mL). The obtained wet compound is charged into mixture of water (36 mL) and acetone (264 mL) at 2°C and stirred for 4 hours. Separated solid is collected by filtration, washed with mixture of water (2x7.2 mL) and acetone (2x52.8 mL), and dried in Buchi Rotavapor® at 55°C for 3 hours to afford 21.81 g of title compound. D-isomer content by HPLC: 0.568%

EXAMPLE 10: Purification of valacyclovir hydrochloride.

34.3 Kg of Valacyclovir hydrochloride, water (155 L) and N, N-dimethylformamide (34.3 L) is charged in to reactor and stirred for 45 minutes for clear solution. The obtained solution is filtered and washed with water (34 L). Filtrate charged into the reactor and cooled to 18°C. Valacyclovir hydrochloride (0.171 kg) seed is added at 17°C and stirred for 2 hours. The resultant reaction mixture further cooled to 4°C and stirred for 1 hour. Acetone (1029 L) is added to the reaction mixture at 3°C and stirred for 6 hours. Separated solid is filtered, washed with mixture of pre chilled acetone (61 L) and water (9 L). Water (41 L) and acetone (302 L) is charged into reactor and cooled to 3°C. Wet compound is charged into reactor at 3°C and stirred for 4 hours. Solid is filtered, washed with mixture of pre chilled acetone (61 L) and water (9 L). The obtained wet compound is subjected to rapid mixture granulation (RMG). Wet compound is further dried in fluid bed drier at 32°C for 1 hour and at 44°C for 19 hours. The resultant dry material is delumped using multi mill sieve to afford 22.4 kg of valacyclovir hydrochloride.

Claims:

1. A process for preparation of 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9yl) methoxy]ethyl-N-[(benzyloxy) carbonyl]-L-valinate of Formula II containing not more than 1.0% w/w of its D-isomeric impurity of formula V as determined by HPLC

Formula II

Formula V

comprising reacting 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methy|]-6H-purin-6- one of Formula III (acyclovir) with carbobenzyloxy-L-valine of Formula IV.

Formula III Formula IV

at temperature of -20°C to 20°C.

2. The process of claims 1, wherein the reaction is carried out at temperature -10°Cto10°C.

3. A process for preparing valacyclovir hydrochloride of Formula I having chiral purity greater than or equal to about 99% w/w as determined by HPLC comprising:

(i) deprotecting2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl 2 [(benzyloxy)carbonyl] L-valinate of Formula II;

(ii) converting valacycloyir into valacyclovir hydrochloride of formula (I); and

(iii) isolating valacyclovir hydrochloride of formula (I).

4. The process of claim 3, wherein the compound of formula II contains not more than 1.0% w/w of its D-isomeric impurity of formula V as determined by HPLC.