INTRODUCTION
The present invention relates to processes for preparing valacyclovir and pharmaceutically acceptable salts thereof, as well as chemical intermediates for the processes.
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 II.

Formula II
Valacyclovir hydrochloride, commercially available as VALTREX® in United States, is indicated for treatment of cold sores (herpes labialis), initial episode of genital herpes in immunocompetent adults, recurrent episodes of genital herpes in immunocompetent adults, chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults, reduction of transmission of genital herpes in immunocompetent adults, treatment of herpes zoster (shingles) in immunocompetent adults, treatment of cold sores (herpes labialis) in pediatric patients ≥12 years of age and for the treatment of chickenpox in immunocompetent pediatric patients 2 to <18 years of age.
U.S. Patent No. 4,957,924 discloses a process for reacting optionally protected acyclovir:

wherein X is an optionally protected hydroxyl group, and Y is an optionally protected amino group, with an optionally protected L-valine or a functional equivalent thereof, and deprotecting the resulting compound, to obtain valacyclovir or a pharmaceutically acceptable salt thereof.
There are several drawbacks in the above process as it requires costly reactants such as benzyloxycarbonyl chloride and involves multiple protection-deprotection steps.
There remains a need to provide processes for preparing valacyclovir and pharmaceutically acceptable salts thereof, which are simple, cost-effective, environment friendly and avoid multiple protection-deprotection steps.

SUMMARY
An aspect of the present invention includes processes for preparing valacyclovir and pharmaceutically acceptable salts thereof, an embodiment comprising:
a) reacting a compound of Formula III or a salt thereof, with 2-(S)-azido-3-methylbutanoic acid of Formula IV or a salt thereof, or a derivative thereof, to obtain a compound of Formula V or a salt thereof,

b) converting a compound of Formula V or a salt thereof to valacyclovir or a salt thereof; and
c) optionally converting valacyclovir to its pharmaceutically acceptable salt thereof.
An aspect of the present invention includes the compound 2-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-3-hydroxypropyl (2S)-azido-3-methylbutanoate of Formula VII or a salt thereof.

DETAILED DESCRIPTION
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” (open ended) means the elements recited, or their equivalent in structure or function, plus any other element or elements that are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about,” “generally,” “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
“Protecting group” means a chemical group that (a) prevents a reactive group from participating in an undesirable chemical reaction; and (b) can be removed after protection of the reactive group is no longer required. For example, a benzyl group is a protecting group for a primary hydroxyl function. “Amino-protecting group” means a protecting group that preserves a reactive amino group that otherwise would be modified by certain chemical reactions. “Hydroxy-protecting group” means a protecting group that preserves a hydroxy group that otherwise would be modified by certain chemical reactions.
An aspect of the present invention includes processes for preparing valacyclovir or a pharmaceutically acceptable salt thereof, an embodiment comprising:
a) reacting a compound of Formula III or a salt thereof, with 2-(S)-azido-3-methylbutanoic acid of Formula IV or a salt thereof, or a derivative thereof, to obtain a compound of Formula V or a salt thereof,

b) converting a compound of Formula V or a salt thereof to valacyclovir or a salt thereof; and
c) optionally converting valacyclovir to its pharmaceutically acceptable salt thereof.
Step (a) involves reacting a compound of Formula III or a salt thereof, with 2-(S)-azido-3-methylbutanoic acid of Formula IV or a salt thereof, or a derivative thereof, to obtain a compound of Formula V or a salt thereof.
The compound of Formula III may be prepared by any process known in the art.
2-(S)-azido-3-methylbutanoic acid of Formula IV may be prepared by any process known in the art. For example, it may be prepared by a process according to Goddard-Borger et al., Organic Letters, Vol. 9, No. 19, 3797-3800 (2007), which is incorporated herein by reference in its entirety. A preparative process is described hereinbelow, in Examples 1 and 2.
Step (a) may be optionally carried out in presence of a suitable catalyst. Suitable catalysts that may be used in step (a) include, but are not limited to, triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1-methylmorpholine, 1-methylpiperidine, 1,5-diazabicyclo[4.3.0]non-5-ene, N,N-dimethylpiparazine, N,N-dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5,6-tetramethylpyridine (TEMP), and the like.
Step (a) may be optionally carried out in presence of a suitable coupling agent. Suitable coupling agents that may be used in step (a) include, but are not limited to, N-hydroxybenzotriazole, 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1,1’-carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-1,3-dioxolyl)]- methyl]carbodiimide, N,N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), acid chlorides, ethyl chloroformate, and the like.
Step (a) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (a) include, but are not limited to: alcohols, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like; ketones, e.g., acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons, e.g., toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons, e.g., dichloromethane, ethylene dichloride, chloroform, and the like; esters, e.g., ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers, e.g., diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles, e.g., acetonitrile, propionitrile, and the like; water; and any mixtures thereof.
Suitable temperatures for conducting step (a) may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, or any other suitable temperatures.
Suitable times for completing the reaction in step (a) depend on the temperature and other conditions, and may be generally less than about 30 hours, less than about 20 hours, less than about 10 hours, less than about 5 hours, less than about 2 hours, less than about 1 hour, or any other suitable times.
The product formed in step (a) may be optionally recovered as a solid by any methods, including decantation, centrifugation, gravity filtration, suction filtration, and other techniques known in the art for the recovery of solids. The resulting solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
Optionally, in place of compound of Formula III or a salt thereof, a protected derivative of Formula VI or a salt thereof, wherein P1, P2, and P3 are individually hydrogen or a protecting group may be reacted with 2-(S)-azido-3-methylbutanoic acid of Formula V or a salt thereof, or an activated derivative thereof, to obtain a compound of Formula VII or a salt thereof;

The compound of Formula VII or a salt thereof thus obtained may be further converted to a compound of Formula V or a salt thereof by removal of protecting groups P1, P2, and/or P3 of the compound of Formula VII or a salt thereof.
The step of removal of protecting groups may be carried out by any suitable method, including reduction or by using a reagent such as, for example, trifluoroacetic acid, acetic acid, formic acid, p-toluenesulfonic acid, phosphoric acid, and hydrochloric acid, in a suitable solvent. The reagent may be optionally used in a mixture with water.
Suitable reduction techniques that may be used for the removal of protecting groups the compound of Formula VII or a salt thereof include, for example, catalytic hydrogenation or reduction by a reducing agent, such as lithium aluminum hydride, sodium borohydride in acidic conditions, sodium borohydride in pyridine, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, or a combination thereof, or any other suitable reducing agent known in the art.
The step of removal of protecting groups may be optionally carried out in presence of a suitable base. Suitable bases that may be used in step (b) include, but are not limited to: alkali metal alkoxides, such as sodium methoxide, potassium methoxide, potassium t-butoxide, and the like; alkaline earth metal alkoxides, such as, for example, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, and the like; triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, and the like; alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as, for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, and the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, and the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, and the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, and the like; ion exchange resins, including resins bound to ions such as sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium, and the like; and any other suitable bases.
Optionally, removal of the protecting groups P1, P2, and/or P3 and conversion of the azido group of the compound of Formula VII may be accomplished in a single step (e.g., by catalytic hydrogenation), as mentioned in step (b).
The above reaction may be optionally carried out in a suitable solvent. Solvents that may be used in said reaction include but are not limited to: alcohols, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like; ketones, e.g., acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons, e.g., toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons, e.g., dichloromethane, ethylene dichloride, chloroform, and the like; esters, e.g., ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers, e.g., diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles, e.g., acetonitrile, propionitrile, and the like; water; and any mixtures thereof.
Suitable temperatures for above reaction may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, or any other suitable temperatures.
Suitable times for completing the above reaction depend on temperature and other conditions, and may be generally less than about 15 hours, less than about 10 hours, less than about 5 hours, less than about 2 hours, less than about 30 minutes, or any other suitable times.
The product formed in above reaction may be optionally recovered as a solid by any methods including decantation, centrifugation, gravity filtration, suction filtration, and other techniques known in the art for the recovery of solids. The resulting solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than 120°C, less than 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
Optionally, the compound of V, or a salt thereof, obtained in step (a) may be directly used in step (b) without further isolation or after conventional work-up, such as, for example, quenching the reaction mixture with a quenching agent and extracting the product into a solvent.
Step (b) involves converting a compound of Formula V or a salt thereof to valacyclovir or a salt thereof, or
Step (b) may be carried out by any suitable technique, including, for example, reduction in a suitable solvent. Suitable reduction techniques, which may be used in step (b) include, but are not limited to: catalytic hydrogenation in the presence of metals, including Raney nickel, palladium on carbon, and the like; using metal mediated reduction, such as zinc and acetic acid, zinc and hydrochloric acid, iron and acetic acid, or any other suitable metal reducing agents; using a reducing agent, such as lithium aluminum hydride, sodium borohydride in acidic conditions, sodium borohydride in pyridine, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, and the like; a combination thereof; any any other suitable reducing agents.
Optionally, if the compound of Formula VII or a salt thereof is used as the starting material in step (b), the above reduction may be preceded by a reaction of a compound of Formula VII or a salt thereof with a suitable reagent. Suitable reagents that may be used include, but are not limited to, acids, bases, resins, and mixtures thereof, either alone or as their aqueous solutions or as their solutions in a suitable solvent or mixture of solvents. Suitable acids that may be used include, but are not limited to: organic acids, including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like; and inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, and the like. Suitable bases that can be used include, but are not limited to: inorganic bases, including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; and organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like. Suitable resins that may be used include, but are not limited to ion exchange resins, including: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulphonic, methanesulphonic, p-toluenesulphonic, and the like.
Step (b) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (b) include, but are not limited to: alcohols, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like; ketones, e.g., acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons, e.g., toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons, e.g., dichloromethane, ethylene dichloride, chloroform, and the like; esters, e.g., ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers, e.g., diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles, e.g., acetonitrile, propionitrile, and the like; water; and any mixtures thereof.
Step (b) may be carried out at suitable temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
Step (b) may be optionally carried out at suitable pressures less than about 10 kg/cm2, less than about 5 kg/cm2, less than about 3 kg/cm2, less than about 1 kg/cm2, or any other suitable pressures.
Suitable times for completing step (b) depend on temperature and other conditions, and may be generally less than about 15 hours, less than about 10 hours, less than about 5 hours, less than about 2 hours, less than about 30 minutes, or any other suitable times.
Optionally, step (b) may lead to the direct formation of a salt of valacyclovir.
The valacyclovir or salt thereof formed in step (b) may be optionally recovered as a solid by any methods, including decantation, centrifugation, gravity filtration, suction filtration, and other techniques known in the art for the recovery of solids. The valacyclovir or a salt thereof may be isolated in the form of a crystalline compound, a solvate, an amorphous compound or a combination thereof, depending on the requirements, by techniques known in the art. For example, valacyclovir or a salt thereof may be isolated by techniques that include, but are not limited to: concentrating, cooling, stirring, shaking, adding an anti-solvent, adding seed crystals, evaporation, flash evaporation, and the like. An anti-solvent as used herein refers to a solvent in which valacyclovir or a salt thereof is less soluble or poorly soluble. Evaporation as used herein includes distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent using a technique including but not limited to tray drying, spray drying, fludized bed drying, thin film drying, etc., under reduced pressure or at atmospheric pressure.
The valacyclovir or a salt thereof may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying may be carried out at temperatures less than about 120°C, less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired product purity, such as, for example, about 1 to about 15 hours, or longer.
The resulting valacyclovir or a salt thereof as described above may contain one or more of the impurity compounds of Formula VIII and Formula IX.

Optionally, the product of step (b) may be directly used in step (c) without further isolation or after conventional work-up, such as, for example, quenching the reaction mixture with a quenching agent and extracting the product in to a solvent.
Step (c) involves converting valacyclovir to a salt thereof.
Step (c) may be carried out by any process known in the art. The salt of valacyclovir may be prepared by a process described in examples 7-11 of U.S. Patent Application Publication No. 2007/0112193 A1, which is incorporated herein by reference in its entirety.
For example, step (c) may be carried out by reacting valacyclovir with a suitable acid, in a suitable solvent, to obtain the corresponding acid addition salt.
Suitable acids that may be used in step (c) include, but are not limited to: organic acids such as formic acid, acetic acid, oxalic acid, tartaric acid, n-propionic acid, isopropanoic acid, n-butyric acid, isobutyric acid, and the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, and the like.
Step (c) may be optionally carried out in a suitable solvent. Suitable solvents that may be used in step (c) include, but are not limited to: alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof, or any other suitable solvents.
The salt of valacyclovir resulting from step (c) may be isolated as a crystalline compound, a solvate, an amorphous compound, or any combination thereof, depending on the requirements.
The salt of valacyclovir may be isolated by any process. For example, it may be isolated by a method that includes filtration by gravity or suction, centrifugation, slow evaporation, or drying, which may be suitably carried out using a technique including tray drying, vacuum drying, air drying, fluidized bed drying, spin flash drying, flash drying, spray drying, thin film drying, freeze drying and the like, at atmospheric pressure or under reduced pressure.
The isolated solid salt of valacyclovir may carry a portion of occluded mother liquor containing higher levels of impurities. If desired the isolated solid may be washed with a solvent to wash out the mother liquor.
The isolated solid may be further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying may be carried out at temperatures less than about 140°C, less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired product purity, such as, for example, about 1 to about 15 hours, or longer.
Optionally, the conversion of salt of Valacyclovir to Valacyclovir free base is also contemplated. Such conversion may be carried out by any process known in the art.
The present invention includes a compound of Formula VII or a salt thereof,

wherein P1 and P2 are individually hydrogen or a protecting group.
P1 and P2, which may be same or different, refer to hydrogen or a suitable protecting group, which suitable protecting group may be, for example: a lower alkanoyl having 2 to 4 carbon atoms; trityl having phenyl groups that may be substituted with groups including, for example, monomethoxy, dimethoxy, 4,4’-dimethoxy, trifluoroacetyl, and 9H-fluoren-9-ylmethoxycarbonyl (FMOC); allyloxycarbonyl; and any other suitable protecting groups. Suitable protecting groups may be derived from halocarbonates, including: (C6 -C12)aryl); lower alkyl carbonates (such N-benzyloxycarbonyl); biphenylalkyl halo carbonates; tertiary alkyl halo carbonates (such as t-butylhalocarbonates, including t-butylchlorocarbonate; di(lower)alkyldicarbonates (e.g., di(t-butyl)-dicarbonate); imines; and phthalates.
The present invention includes the compound 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1’-ethyl-2’-(S)-azido-3’-methylbutanoate of Formula V, or a salt thereof.

Certain specific aspects and embodiments of the present invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES
EXAMPLE 1: PREPARATION OF IMIDAZOLE-1-SULFONYL AZIDE.
Sodium azide (100 g) and acetonitrile (1550 mL) are charged into a round bottom flask and cooled to 2.5±2.5°C. A solution of sulfonyl dichloride (124.8 mL) is added slowly over 20 minutes. The mixture is heated to 28±2°C and stirred for about 12½ hours. The mixture is cooled to 2.5±2.5°C, imidazole (199 g) is added over 30 minutes and the mixture is stirred for 40 minutes. The mixture is heated to 28±2°C and stirred for about 4 hours. The mixture is diluted with ethyl acetate (3100 mL) and water (3100 mL) and stirred for 30 minutes. The organic aqueous layers are separated. The organic layer is washed with a saturated solution of sodium bicarbonate (2×1550 mL). The organic layer is dried over sodium sulfate (25 g). Ethanol (577 mL) is placed into a round bottom flask and cooled to 2.5±2.5°C. Acetyl chloride (164 mL) is added slowly to the ethanol over 45 minutes and stirred for 60 minutes. This solution is added to the organic layer and the mixture is stirred for 3½ hours. The formed solid is filtered and dried at about 27°C for 3 hours to afford the title compound. Yield: ~167 g.

EXAMPLE 2: PREPARATION OF 2-(S)-AZIDO-3-METHYLBUTANOIC ACID.
L-Valine (50.0 g), potassium carbonate (129.5 g) and methanol (450 mL) are charged into a round bottom flask, cooled to 2.5±2.5°C and stirred for 40 minutes. Copper (II) sulfate pentahydrate (0.5 g) is added, followed by imidazole-1-sulfonyl azide (107.0 g) and the suspension is warmed to 27.5±2.5°C and stirred for about 12½ hours. The solvent is distilled under reduced pressure. Water (1000 mL) is added to the residue and the resulting solution is cooled to 2.5±2.5°C and stirred for 1 hour. The pH of the solution is adjusted to ~1.5 using aqueous HCl (33%, 160 mL) and further stirred for 15 minutes. Ethyl acetate (350 mL) is added at 28°C and stirred for 30 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with ethyl acetate (2×350 mL). The organic layers are combined and dried over sodium sulfate (20 g). The solvent is evaporated at 40°C to afford the title compound. Yield: ~60.5 g.

EXAMPLE 3: PREPARATION OF 2-(2-AMINO-1,6-DIHYDRO-6-OXO-PURIN-9-YL)METHOXY-1’-ETHYL-2’-(S)-AZIDO-3’-METHYLBUTANOATE (FORMULA V).
A solution of 2-(S)-azido-3-methylbutanoic acid (21.26 g) in N,N-dimethylformamide (400 mL) is cooled to 12.5±2.5°C and dicyclohexyl carbodiimide (36.68 g) is added. The mixture is stirred for 30 minutes. Acyclovir (20.0 g) and 4-dimethylaminopyridine (1.62 g) are added and stirred for 60 minutes. The solid is filtered and washed with N,N-dimethylformamide (50 mL). The filtrate is cooled to 2.5±2.5°C and water (1350 mL) is slowly added over about 2½ hours. The mass is stirred for 60 minutes. The solid is filtered, washed with water (100 mL) and suction dried. The wet solid is dried under reduced pressure at 60°C for about 3½ hours.
The obtained solid and acetone (284 mL) are charged into a round bottom flask at 28°C and stirred for 45 minutes. The solid is filtered and suction dried. The wet solid is dried under reduced pressure at 50°C for about 3 hours to afford the title compound. Yield: ~25.4 g.

EXAMPLE 4: PREPARATION OF VALACYCLOVIR HYDROCHLORIDE.
To a solution of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1’-ethyl-2’-(S)-azido-3’-methylbutanoate (20.0 g) in ethanol (300 mL) at 28°C is added Raney nickel (4.0 g) and the mixture is heated to 57.5±2.5°C and stirred for about 7 hours. The mass is cooled to 28°C and filtered through a Hyflow (flux-calcined diatomaceous earth) bed under reduced pressure. The filtrate is cooled to 4°C and pH is adjusted to ~2.75 using aqueous HCl (10%, 35 mL). The mass is stirred for 15 minutes and activated carbon (5 g) is added. The mass is heated to 58°C for 45 minutes. The hot mixture is filtered through a Hyflow bed and the filtrate is distilled at 55°C. Acetone (100 mL) is added to the obtained residue at 28°C and stirred for 15 minutes. The solid is filtered and suction dried. The wet solid is dried under reduced pressure at 50°C for about 2½ hours to afford the title compound. Yield: ~16.9 g; Purity by HPLC: 98.33%.