WO2010036904A2

WO2010036904A2 - Preparation of valganciclovir and its salts

Info

Publication number: WO2010036904A2
Application number: PCT/US2009/058397
Authority: WO
Inventors: Pratap Reddy Padi; Vijaya Anand Ramasamy; Babu Ireni; Srihari Babu Karrothu; Madhusudhan Reddy Ganta; Krishna Jonnada; Srinivas Polavarapu; Venkata Madhavi Yaddanapudi; Pranab Haldar; Krishna Vinigari; Narasimha Rao Pagadala; Ravindra Vedantham; Satyanarayana Kisara; Venkata Naga Kali Varaprasada Raju Vetukuri; Sateesh Kamath Suchitra; Sakthivel Shanmugam; Rama Krishna Venkata Medisetti; Kushal Surajmal Manudhane
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2008-09-26
Filing date: 2009-09-25
Publication date: 2010-04-01
Also published as: WO2010036904A3

Abstract

Processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, as well as intermediates for the processes.

Description

PREPARATION OF VALGANCICLOVIR AND ITS SALTS

INTRODUCTION

Aspects of the present application relate to processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, as well as intermediates for the processes.

The drug compound having the adopted name "valganciclovir" has a chemical name L-valine, 2-[(2-amino-1 ,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3- hydroxypropyl ester, and is represented by structural Formula I. Valganciclovir is a mono-L-valyl ester (prodrug) of the antiviral compound ganciclovir, represented by Formula III.

FORMULA I FORMULA Il

FORMULA III

Valganciclovir hydrochloride, represented by Formula II, is a cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor, prescribed for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) in adults and prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk in adults, and prevention of CMV disease in kidney and heart transplant patients at high risk in pediatric patients.

European Patent Application O 375 329 discloses processes for preparing antiviral esters of pyhmidine and purine nucleosides containing an acyclic side chain. The nucleosides have Formula IV,

FORMULA IV wherein R and R¹ are independently a hydrogen atom or a valine residue, provided at least one of R and R¹ representing a valine residue and B represents a group of the Formula V or Vl,

FORMULA V FORMULA VI in which R² represents a C₁-6 straight chain, C3-6 branched chain, or C3-6 cyclic alkoxy group, or a hydroxy or amino group, or a hydrogen atom, and the physiologically acceptable salts thereof.

U.S. Patent No. 5,856,481 provides compounds of Formula VII that are useful intermediates for preparing mono-L-valine ganciclovir (i.e., valganciclovir),

FORMULA VII wherein P₁ is a hydroxyl-protecting group, P₂ is an amino-protecting group, and P₃ is hydrogen or P₂. The patent also provides processes for preparing valganciclovir. The processes involve the sequential esterification of ganciclovir and its derivatives, the removal of protecting groups from ganciclovir esterified with L-valine, the partial hydrolysis of ganciclovir bis-L-valine ester to valganciclovir, the optical resolution of valganciclovir and the formation of salts of the valganciclovir. U. S. Patent No. 5,756,736 describes processes for preparing valganciclovir comprising: reacting ganciclovir with a trityl compound of the Formula (Ph)₃CX, wherein Ph is phenyl, optionally substituted with methoxy, and X is bromo or chloro, to produce a compound of Formula VIII,

FORMULA VIII wherein Tr is the trityl group, esterifying the compound of Formula VIII with an activated protected derivative of L- valine of Formula IX or Formula IXa,

FORMULA IX FORMULA IXa wherein P³ is an amino protecting group and A is a carboxy-activating group, and deprotecting the resulting compound to valganciclovir, optionally followed by converting valganciclovir into a pharmaceutically acceptable salt or separating into its diastereomers.

European Patent Application 0 694 547 discloses a process for partial hydrolysis of the bis ester 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-1 ,3- propanediyl bis (L-valinate) or a salt thereof, to afford the monoester 2-(2-amino-

1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1 -propanyl-L-valinate or a pharmaceutically acceptable salt thereof. The process disclosed in Example 6 involves use of preparative reverse phase HPLC column, which makes the process unsuitable for commercial scale manufacturing. There remains a need to provide processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, which are simple, cost-effective, commercially viable, environment friendly and avoid multiple protection- deprotection steps. SUMMARY

In an aspect, the present invention includes processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, embodiments comprising one or more of the following steps, individually or in the sequence recited: a) reacting a compound of Formula III or a salt thereof, or a protected derivative of Formula X or a salt thereof, with 2-(S)-azido-3-methylbutanoic acid of Formula Xl or a salt thereof or an activated derivative thereof, to obtain a compound of Formula XII or a salt thereof,

FORMULA X FORMULA FORMULA Xl

FORMULA XII FORMULA XIII wherein P₁, P₂, and P₄ are individually hydrogen or a protecting group; optionally, followed by one or more of the following steps: b) converting a compound of Formula XII to a compound of Formula XIII or a salt thereof; c) converting a compound of Formula XIII to valganciclovir, or optionally converting a compound of Formula XII to valganciclovir in a single step.

In an aspect, the present invention provides a compound of Formula XII or a salt thereof,

FORMULA XII wherein P₁, P₂, and P₄ are individually hydrogen or a protecting group.

In an aspect, the present invention provides a compound 2-((2-amino-1 ,6- dihydro-6-oxo-9H-puπn-9-yl)methoxy)-3-hydroxypropyl (2S)-azido-3- methylbutanoate of Formula XIII or a salt thereof.

FORMULA XIII In an aspect, the present invention provides a compound of Formula XIV or a salt thereof.

FORMULA XIV

In an aspect, the present invention provides processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, embodiments comprising one or more of the following steps, individually or in the sequence recited: a) converting a compound of Formula X or a salt thereof,

P₁

FORMULA X wherein P₁, P₂, and P₄ are as defined above, into a compound of Formula XV or a salt thereof,

FORMULA XV wherein P₁, P₂, and P₄ are as defined above and A is an activating group; b) converting a compound of Formula XV or a salt thereof into a compound of Formula XVI or a salt thereof,

FORMULA XVI wherein A is same as defined above; and c) converting a compound of Formula XVI or a salt thereof into valganciclovir.

Processes according to the present invention may further comprise one or more of the following optional steps: i) converting valganciclovir to a salt thereof; ii) converting a salt of valganciclovir to valganciclovir; or iii) converting a first salt of valganciclovir into a second salt of valganciclovir. In an aspect, the present invention provides processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, embodiments comprising one or more of the following steps, individually or in the sequence recited: a) reacting a compound of Formula III with 2-(S)-azido-3- methylbutanoic acid of Formula Xl to obtain a compound of Formula XIV; b) partially hydrolyzing a compound of Formula XIV to obtain a compound of Formula XIII; and c) converting a compound Formula XIII to valganciclovir or a salt thereof. BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous valganciclovir hydrochloride prepared according to Example 26.

DETAILED DESCRIPTION

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25^CC and about atmospheric 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. 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) preserves 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.

This document may refer to a material, such as in this instance, salts of valganciclovir, and its crystalline forms, solvates, or optical isomers by reference to patterns, spectra, or other graphical data, "substantially" as shown in a drawing, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra, and other graphical data can be shifted somewhat in their positions, relative intensities, and/or values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation: the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, and the like. However, those of ordinary skill in the art will be able to compare the drawing herein with a pattern generated of an unknown form of, in this case, salts of valganciclovir, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques which may be reported herein.

In addition, where a reference is made to a drawing, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the drawing that uniquely define the crystalline form, salt, or optical isomer.

In an aspect, the present invention includes processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, embodiments comprising the steps of: a) reacting a compound of Formula III or a salt thereof or a protected derivative of Formula X or a salt thereof with 2-(S)-azido-3-methylbutanoic acid of Formula Xl or a salt thereof or an activated derivative thereof to obtain a compound of Formula XII or a salt thereof;

FORMULA X FORMULA III

P₁

FORMULA XII FORMULA XIII wherein P₁, P₂, and P₄ are individually hydrogen or a protecting group; optionally followed by one or more of the following steps: b) converting a compound of Formula XII to a compound of Formula XIII or a salt thereof; and c) converting a compound of Formula XIII to valganciclovir, or optionally converting a compound of Formula XII to valganciclovir in a single step;

Step a) involves reacting a compound of Formula III or a salt thereof or a protected derivative of Formula X or a salt thereof with 2-(S)-azido-3- methylbutanoic acid of Formula Xl or a salt thereof or an activated derivative thereof to obtain a compound of Formula XII or a salt thereof.

The compound of Formula X may be prepared by any process known in the art. For example, the compound of Formula X may be prepared by a process described in U.S. Patent No. 5,756,736, which is incorporated herein by reference in its entirety. The compound of Formula III may be prepared by any process known in the art.

2-(S)-azido-3-methylbutanoic acid of Formula Xl 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, pages 3797-3800 (2007) which is incorporated herein by reference in its entirety. For example, the process is described in Examples 2 and 3 hereof.

Step a) may be optionally carried out in the presence of a suitable base, including organic bases, inorganic bases, and resins, such as, for example: aliphatic amines (e.g., triethylamine, thbutylamine, N-methylmorpholine, N₁N- diisopropylethylamine, N-methyl pyrrolidine, and the like); aromatic amines (e.g., pyridine, N,N-dimethylaminopyridine, and the like); alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and the like); alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, and the like); alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, and the like), ammonia; resins bound to ions (such as sodium, potassium, lithium, calcium, and magnesium and the like); and any mixtures thereof or any other suitable bases, either alone or as their aqueous solutions. Step a) may be optionally carried out in the presence of a suitable catalyst, including but 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, and 2,3,5,6-tetramethylpyhdine (TEMP), and the like.

Step a) may be optionally carried out in presence of a suitable coupling agent, such as, N-hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiirnide 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-CI), acid chlorides, ethyl chloroformate, and the like.

Step a) may be optionally carried out in a suitable solvent, including but 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 temperature for step a) may be less than about 100⁰C, or less than about 80⁰C, or less than about 60⁰C, or less than about 40°C, or less than about 20⁰C, or less than about 0°C, or any other suitable temperature. Suitable times for completing the reaction in step a) depends on the temperature and other conditions and may be generally less than about 30 hours, or less than about 20 hours, or less than about 10 hours, or less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or any other suitable times. Longer times may also be used.

The product formed in step a) may be optionally recovered as a solid by conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or 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 100⁰C, or less than about 60⁰C, or 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 period to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer. Optionally, the product of 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 (a) may lead to the formation of a compound of Formula XIV as a by- product.

FORMULA XIV

The compound of Formula XIV may be separated from the compound of Formula XIII by processes known in the art. For example, the separation of compound of Formula XIV from the compound of Formula XIII may be carried out by selective crystallization, chromatography, or any other suitable techniques.

Optionally, the compound of Formula XIV may be partially or completely hydrolyzed to obtain the compound of Formula XIII or Formula III, respectively, by treating the compound of Formula XIV with, for example, a suitable base. Optionally, the compound of Formula XIV may be converted directly to valganciclovir by any suitable technique, including, for example, by reduction in a suitable solvent.

If the partial hydrolysis of the compound of Formula XIV results in the formation of compound of Formula III, then it may be recovered using conventional methods and may be reused as the starting material in step a) of the present invention. If the compound formed by the hydrolysis of the compound of Formula XIV is a compound of Formula XIII, then it may be used in step c) of the process of the present invention. Step b) involves converting a compound of Formula XII to a compound of

Formula XIII or a salt thereof.

Step b) involves removal of protecting groups Pi, P₂, and/or P₄ of Formula XII to obtain a compound of Formula XIII or a salt thereof.

Step b) may be carried out by any suitable method, including reduction or by using a reagent, such as but not limited to 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 in step b) include but are not limited to catalytic hydrogenation or reduction by a reducing agent, such as lithium aluminum hydride, sodium borohydhde 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.

Catalytic hydrogenation or any other suitable method may be used to convert the azido group of Formula XIII to an amino group. Optionally, removal of the protecting groups P₁, P₂, and/or P₄ and conversion of the azido group may be accomplished in a single step (e.g., by catalytic hydrogenation), as mentioned in step c).

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.

Suitable temperatures for step b) may be less than about 100⁰C, or less than about 80°C, or less than about 60⁰C, or less than about 40⁰C, or less than about 20⁰C, or less than about 0⁰C, or any other suitable temperatures. Suitable times for completing step b) depend on temperature and other conditions and may be generally less than about 15 hours, or less than about 10 hours, or less than about 5 hours, less than about 2 hours, or less than about 30 minutes, or any other suitable times. Longer times also are useful.

The product formed in step b) may optionally be recovered as a solid by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or 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 150⁰C, or less than about 120°C, or less than about 100°C, or less than about 60°C, or less than about 40⁰C, 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 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 into a solvent.

Step c) involves converting a compound of Formula XIII to valganciclovir, or optionally converting a compound of Formula XII to valganciclovir in a single step. Step c) may be carried out by any suitable techniques, including, for example, reduction. Suitable reduction techniques, which may be used in step c) include but are not limited to: catalytic hydrogenation using hydrogen gas in the presence of metals, including Raney nickel, palladium on carbon, and the like; 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; or a combination thereof; or any other suitable reducing techniques known in the art.

If a compound of Formula XII or a salt thereof is used as the starting material in step c), optionally, the reduction may be preceded by a reaction of compound Formula XII 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, and the like; inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like. Suitable bases that may 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.

Suitable solvents that may be used 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 dichlohde, 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, propionithle, and the like); water; and any mixtures thereof.

Step c) may be carried out at suitable temperatures of less than about 150⁰C, or less than about 100⁰C, or less than about 60°C, or less than about 40°C, or any other suitable temperatures.

Optionally, step c) may be carried out at atmorpheric pressure or under pressure conditions. Suitable pressures that may be employed are less than about 10 kg/cm², or less than about 5 kg/cm², or less than about 3 kg/cm², or less than about 1 kg/cm², or any other suitable pressures.

Suitable times for completing the reaction in step c) depend on temperature and other conditions and may be generally less than about 15 hours, or less than about 10 hours, or less than about 5 hours, less than about 2 hours, or less than about 30 minutes, or any other suitable times. Longer times also are useful. Optionally, step c) may lead to the direct formation of a salt of valganciclovir, when an acid is present in the reaction mixture in step c).

The valganciclovir or salt thereof formed in step c) may be optionally recovered as a solid by conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids. The valganciclovir or a salt thereof may be isolated in the form of a crystalline compound, a solvate, an amorphous compound or a mixture thereof, using techniques known in the art. For example, valganciclovir or a salt thereof may be isolated by a technique that includes but is not limited to: concentrating, cooling, stirring, shaking, adding an anti-solvent, adding seed crystals, evaporation, and the like. An anti-solvent is a liquid, in which valganciclovir or a salt thereof is less soluble or poorly soluble. Suitable anti- solvents include hydrocarbons (e.g., hexanes, n-heptane, cyclohexane, toluene, xylenes and the like); ethers (e.g., diethyl ether, diisopropyl ether, methyl t-butyl ether, and the like); or any other suitable anti-solvents. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Suitable evaporation techniques include but are not limited to tray drying, spray drying, fluidized bed drying, and thin film drying. The resulting valganciclovir or salt thereof may be recovered by any methods known in the art. For example, it may be isolated by a method that includes but is not limited to: filtration by gravity or suction, centrifugation, or slow evaporation, and the like.

Amorphous valganciclovir or a salt thereof may be isolated from a solution of valganciclovir or a salt thereof by methods that include but are not limited to: 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 valganciclovir 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 120⁰C, or less than about 100⁰C, or less than about 60⁰C, or less than about 40⁰C, 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 resulting valganciclovir or a salt thereof as described above may contain one or both of the compounds having Formulae XVII or XVIII, as process-related impurities.

FORMULA XVII FORMULA XVIII

Optionally, the product of step c) may be directly used in step d) 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.

The present invention includes a compound of Formula XII or a salt thereof,

FORMULA XII wherein Pi₁P₂, and P₄ are individually hydrogen or a protecting group.

Pi, P₂, and P₄, which may be same or different, refer to hydrogen or a suitable protecting group. A 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 group. Suitable protecting groups may be derived from halocarbonates, such as (C-6-Ci₂)aryl), lower alkyl carbonates (such N-benzyloxycarbonyl), biphenylalkyl halocarbonates, tertiary alkyl halocarbonates (such as tertiary-butylhalocarbonates), tertiary butylchlorocarbonate, di(lower)alkyldicarbonates (e.g., di(t-butyl)-dicarbonate), and phthalates.

The present invention includes 2-((2-amino-1 ,6-dihydro-6-oxo-9H-purin-9- yl)methoxy)-3-hydroxypropyl (2S)-azido-3-methylbutanoate of Formula XIII, or a salt thereof.

FORMULA XIII

The present invention includes a compound of Formula XIV, or a salt thereof.

FORMULA XIV

Valganciclovir or a salt thereof, such as valganciclovir hydrochloride, according to the present application may be substantially free of one or more of the process-related impurities as measured by high performance liquid chromatography (HPLC).

"Substantially free of one or more of the process-related impurities" as used herein, unless otherwise defined refers to the compound that contains less than about 2%, or less than about 1 %, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, by weight, of one or more of the impurities including, without limitation, guanine impurity of Formula (XIX), ganciclovir impurity of Formula (III), mono azido isobutyryl ester of ganciclovir of Formula (XIII), bis-azido isobutyryl ester of ganciclovir of Formula (XIV), bis-L-valinate ester of ganciclovir of Formula (XX), dimethyl acrylate mono ester of ganciclovir of Formula (XVII), mono isovalaryl ester of ganciclovir of Formula (XVIII), isovalganciclovir impurity of Formula (XXI), and an impurity at RRT (relative retention time) of 2.9 with respect to the RT (retention time) of valganciclovir according to the HPLC method below, or any other possible process- related impurity, and that contains a total amount of such impurities less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.3%, or less than about 0.1 %, or less than about 0.05%, by weight, as measured by HPLC.

FORMULA XIX FORMULA II I FORMULA XIII

FORMULA XIV FORMULA XX

FORMULA XVII FORMULA XVIII

FORMULA XXI

A high performance liquid chromatography (HPLC) method for measuring the chemical purity of valganciclovir or a salt thereof, such as valganciclovir hydrochloride, of the present application involves the use of a Zorbax SB-C18 150x4.6x3.5 μm or equivalent column. Other parameters of the method are as shown in Table 1 .

Table 1

In an aspect, the present invention provides processes for preparing valganciclovir or pharmaceutically acceptable salts thereof, embodiments comprising one or more of the following steps, individually or in the sequence recited: a) converting a compound of Formula X or a salt thereof,

FORMULA X wherein Pi, P₂, and P₄ are individually hydrogen or a protecting group, into a compound of Formula XV or a salt thereof,

FORMULA XV wherein Pi, P₂, and P₄ are as defined above and A is an activating group; b) converting a compound of Formula XV or a salt thereof into a compound of Formula XVI or a salt thereof,

FORMULA XVI wherein A is as defined above; and c) converting a compound of Formula XII or a salt thereof into valganciclovir; Step a) involves converting a compound of Formula X or a salt thereof into a compound of Formula XV or a salt thereof.

The compound of Formula X may be prepared by any process known in the art. For example, the compound of Formula X may be prepared by a process described in U.S. Patent No. 5,756,736, which is incorporated herein by reference in its entirety.

Suitable activating group A includes but is not limited to sulfonyl (-SO₂R), phosphonyl (-PO₂R), silyl (-SiR₃) and acyl (-COR), wherein R may be the same or different, including but not limited to alkyl, aryl and aralkyl.

Step (a) may be carried out in the presence of a suitable base including but not limited to: organic bases, inorganic bases, and resins, such as: aliphatic amines including triethylamine, tributylamine, Λ/-methylmorpholine, N, N- diisopropylethylamine, Λ/-methyl pyrrolidine, and the like; aromatic amines including pyridine, /V,Λ/-dimethylaminopyridine, and the like; alkali metal carbonates including sodium carbonate, potassium carbonate, and the like; alkali metal bicarbonates including sodium bicarbonate, potassium bicarbonate, and the like; resins bound to ions including sodium, potassium, lithium, calcium and magnesium; and the like or any other suitable bases.

Step a) may be carried out in presence of a suitable solvent, including, for example: alcohols including methanol, ethanol, isopropanol, n-propanol, n- butanol, 2-butanol, and the like; ketones including acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons including toluene, xylene, n- hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons including dichloromethane, ethylene dichloride, chloroform, and the like; esters including ethyl acetate, n-propyl acetate, n-butyl acetate, f-butyl acetate, and the like; ethers including diethyl ether, diisopropyl ether, methyl f-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents including N₁N- dimethylformamide, Λ/,Λ/-dimethylacetamide, dimethylsulphoxide (DMSO), sulpholane, Λ/-methyl pyrrol idone, and the like; nitriles including acetonitrile, propionithle, and the like; water; and any mixtures thereof.

Suitable temperatures for step a) may be less than about 100⁰C, or less than about 80⁰C, or less than about 60°C, or less than about 40°C, or less than about 20⁰C, or less than about 0⁰C, or any other suitable temperatures.

Suitable times for step (a) depend on the temperature and other conditions and may be generally be less than about 30 hours, or less than about 20 hours, or less than about 10 hours, or less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or any other suitable times. Longer times also are useful.

The product formed in step a) may be recovered as a solid by conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids. The resulting product 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, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, or less than about 60°C, or 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.

The product of step a) may be directly used in step b) after the reaction is complete 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 XV or a salt thereof into a compound of Formula XVI or a salt thereof.

Step b) may be carried out by any suitable method, including reduction or by using a reagent including but not limited to trifluoroacetic acid, acetic acid, formic acid, p-toluenesulfonic acid, phosphoric acid, and hydrochloric acid.. If used, the reagent may be used as a mixture with a solvent including but not limited to water.

Suitable reduction techniques that may be used in step b) include but are not limited to catalytic hydrogenation or reduction by a reducing agent, such as, for example, lithium aluminum hydride, sodium borohydhde 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 agents known in the art. 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, f-butyl acetate, and the like); ethers (e.g., diethyl ether, diisopropyl ether, methyl f-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 step b) may be less than about 100⁰C, or less than about 80⁰C, or less than about 60°C, or less than about 40°C, or less than about 20⁰C, or less than about 0°C, or any other suitable temperatures.

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, or less than about 5 hours, less than about 2 hours, or less than about 30 minutes, or any other suitable times.

The product formed in step b) may optionally be recovered as a solid by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or 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, or less than about 120⁰C, or less than about 100⁰C, or less than about 60°C, or less than about 40⁰C, 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 product of step b) may be directly used in step c) after the reaction is complete 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 c) involves converting a compound of Formula XVI or a salt thereof into valganciclovir.

The conversion in step c) may be effected by reaction of a compound of Formula XII or a salt thereof with L-valine or an activated derivative thereof.

Step c) may be carried out in the presence of a suitable phase transfer catalyst. Suitable phase transfer catalysts that may be used in step c) include but are not limited to tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, methyltrioctylammonium chloride, quaternary ammonium salts, ammonium salts, heterocyclic ammonium salts, phosphonium salts, and the like.

Step c) may be carried out in the presence of a suitable base including but not limited to organic bases, inorganic bases, and resins, such as: aliphatic amines including triethylamine, tributylamine, Λ/-methylmorpholine, N, N- diisopropylethylamine, Λ/-methyl pyrrolidine, and the like; aromatic amines including pyridine, Λ/,Λ/-dimethylaminopyhdine, and the like; alkali metal hydroxides including sodium hydroxide, potassium hydroxide, and the like; alkali metal carbonates including sodium carbonate, potassium carbonate, and the like; alkali metal bicarbonates including sodium bicarbonate, potassium bicarbonate, and the like; resins bound to ions including sodium, potassium, lithium, calcium and magnesium; and the like or any other suitable bases. Step c) may be carried out in the presence of a suitable solvent, such as, for example: alcohols including methanol, ethanol, isopropanol, n-propanol, n- butanol, 2-butanol, and the like; ketones including acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons including toluene, xylene, n- hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons including dichloromethane, ethylene dichloride, chloroform, and the like; esters including ethyl acetate, n-propyl acetate, n-butyl acetate, f-butyl acetate, and the like; ethers including diethyl ether, diisopropyl ether, methyl £-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents including N,N- dimethylformamide, Λ/,Λ/-dimethylacetamide, dimethylsulphoxide, sulpholane, N- methylpyrrolidone, and the like; nitriles including acetonitrile, propionitrile, and the like; water; and any mixtures thereof.

Suitable temperatures for step c) may be less than about 100⁰C, or less than about 80°C, or less than about 60⁰C, or less than about 40°C, or less than about 20⁰C, or less than about 0⁰C, or any other suitable temperatures.

Suitable times for step c) depend on the temperature and other conditions and may be generally less than about 30 hours, or less than about 20 hours, or less than about 10 hours, or less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or any other suitable times. The product formed in step c) may be recovered as a solid by conventional methods including decantation, centhfugation, gravity filtration, suction filtration, or 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 150⁰C, or less than about 120°C, or less than about 100°C, or less than about 60°C, or 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. The product formed in step c) may be further purified by purification techniques known in the art, for example by using column chromatography or various types of crystallization methods.

Optionally, the product of step c) may be directly used for further processing 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.

Processes according to the present invention may further comprise at least one of the following optional steps: i) converting valganciclovir to a salt thereof; ii) converting a salt of valganciclovir to vlaganciclovir; andr iii) converting a first salt of valganciclovir into a second salt of valganciclovir.

Optional step i) involves converting valganciclovir to a salt thereof. Step i) may be carried out by any process known in the art. For example,

Step i) may be carried out by reacting valganciclovir with a suitable acid in a suitable solvent to obtain the corresponding acid addition salt.

Suitable acids that may be used in step i) include but are not limited to: organic acids (e.g., formic acid, acetic acid, oxalic acid, tartaric acid, n-propionic acid, isopropanoic acid, n-butyric acid, isobutyric acid, and the like); and inorganic acids {e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, and the like). Optionally, valganciclovir may also be adsorbed onto an adsorbent ion exchange resin, silica gel, molecular sieve, and the like. Step i) may be carried out in a suitable solvent, such as, for example: 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, f-butyl acetate, and the like); ethers (e.g., diethyl ether, diisopropyl ether, methyl f-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, or any other suitable solvents.

The salt of valganciclovir resulting from step i) may be isolated as a crystalline compound, a solvate, an amorphous compound, or a mixture thereof, depending on the requirements.

The salt of valganciclovir may be isolated by any process known in the art. 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 valganciclovir 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 160⁰C, or less than about 100⁰C, or less than about 60°C, or less than about 40⁰C, 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. Optional step ii) involves converting a salt of valganciclovir to valganciclovir.

Step ii) may be carried out by any process known in the art. For example, step ii) may be carried out by treating a valganciclovir salt with a neutralizing agent. Suitable neutralizing agents include organic and inorganic bases, such as, for example: aliphatic amines (e.g., triethylamine, tributylamine, N- methylmorpholine, N,N-diisopropylethylamine, and N-methylpyrrolidine); aromatic amines [e.g., pyridine and N,N-dimethylaminopyridine); alkali metal carbonates (e.g., sodium carbonate and potassium carbonate); alkali metal bicarbonates {e.g., sodium bicarbonate and potassium bicarbonate); alkali metal hydroxides (e.g., sodium hydroxide and potassium hydroxide); resins bound to ions such as sodium, potassium, lithium, calcium, and magnesium; and the like, any mixtures thereof or any other suitable bases. Optional step iii) involves converting a first salt of valganciclovir to a second salt of valganciclovir.

Step iii) may be carried out by any process known in the art. For example, step iii) may be carried out by treating a first salt of valganciclovir obtained from step c) or step i) with a suitable acid in a suitable solvent to obtain the second salt of valganciclovir.

Suitable acids that may be used in step iii) include but are not limited to: organic acids, including formic acid, acetic acid, oxalic acid, tartaric acid, n- propionic acid, isopropanoic acid, n-butyric acid, isobutyric acid, and the like; inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphohc acid, and the like; ion exchange resins; any mixtures thereof; or any other suitable acids.

Step iii) may be carried out in a suitable solvent include including but not limited to: alcohols, including methanol, ethanol, isopropanol, n-propanol, n- butanol, 2-butanol, and the like; ketones, including acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; hydrocarbons, including toluene, xylene, n- hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons, including dichloromethane, ethylene dichloride, chloroform, and the like; esters, including ethyl acetate, n-propyl acetate, n-butyl acetate, £-butyl acetate, and the like; ethers, including diethyl ether, diisopropyl ether, methyl f-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents, including N, N- dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N- methylpyrrolidone, and the like; nitriles, including acetonitrile, propionitrile, and the like; water; and any mixtures thereof. The second salt of valganciclovir resulting from step iii) may be isolated as a crystalline compound, a solvate, an amorphous compound, or a mixture thereof, depending on the requirement. The second salt of valganciclovir may be isolated by any process known in the art. 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 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 160⁰C, or less than about 100⁰C, or less than about 60⁰C, or less than about 40⁰C, 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. In an aspect, the present invention provides processes for preparing valganciclovir and pharmaceutically acceptable salts thereof, embodiments comprising one or more of the following steps, individually or in the sequence recited: a) reacting a compound of Formula III with 2-(S)-azido-3- methylbutanoic acid of Formula Xl to obtain a compound of Formula XIV; b) partially hydrolyzing a compound of Formula XIV to obtain a compound of Formula XIII; and c) converting a compound Formula XIII to valganciclovir or a salt thereof. Step a) involves reacting a compound of Formula III with 2-(S)-azido-3- methylbutanoic acid of Formula Xl to obtain a compound of Formula XIV.

The compound of Formula III may be prepared by any process known in the art. 2-(S)-azido-3-methylbutanoic acid of Formula Xl 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, pages 3797-3800 (2007), incorporated herein by reference in its entirety. For example, the process is described in Examples 2 and 3 hereof.

Step a) may be optionally carried out in presence of a suitable base, including organic bases, inorganic bases, or resins, such as, for example: aliphatic amines {e.g., triethylamine, tributylamine, N-methylmorpholine, N, N- diisopropylethylamine, N-methyl pyrrolidine, and the like); aromatic amines (e.g., pyridine, N,N-dimethylaminopyridine, and the like); alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and the like); alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, and the like); alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, and the like), ammonia; resins bound to ions such as sodium, potassium, lithium, calcium, and magnesium and the like; any mixtures thereof or any other suitable bases either alone or as their aqueous solutions.

Step a) may be optionally carried out in the presence of a suitable catalyst, such as, for example: 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, N₁N- 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, such as N-hydroxybenzotriazole (HOBT), 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-CI), acid chlorides, ethyl chloroformate, and the like.

Step a) may be optionally carried out in a suitable solvent, such as, for example: 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 that may be employed in step a) are less than about

100°C, or less than about 80⁰C, or less than about 60⁰C, or less than about 40°C, or less than about 20⁰C, or less than about 0⁰C, 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, or less than about 20 hours, or less than about 10 hours, or less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or any other suitable times.

The product formed in step a) may be optionally recovered as a solid by conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or 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 100⁰C, or less than about 60°C, or 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 product of 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 partially hydrolyzing a compound of Formula XIV to obtain a compound of Formula XIII. Step b) may be optionally carried out in the presence of a suitable reagent such as a base, resin or any other suitable reagent. Suitable bases that may be used in step b) include but are not limited to: inorganic bases, such as, for example, ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; organic bases, such as, for example, triethylamine, pyridine, N-methylmorpholine, diisopropylamine or diisopropylethylamine, and the like; resins including but not limited to ion exchange resins, such as resins bound to metal ions, including lithium, sodium, potassium, and the like; any mixtures thereof; or any other suitable reagents either alone or as their aqueous solutions.

Optionally step b) may be carried out in a suitable solvent. Suitable solvents include but are not limited to: hydrocarbons, including toluene, xylene, n- hexane, n-heptane, cyclohexane, and the like; halogenated hydrocarbons, including dichloromethane, ethylene dichloride, chloroform, and the like; alcohols, including methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like; ketones, including acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters, including ethyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate, and the like; ethers, including diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents, including N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles, including acetonitrile, propionithle, and the like; water; any mixtures thereof or any other suitable solvents.

Step b) may be carried out at suitable temperatures less than about 150⁰C, or less than about 120⁰C, or less than about 100°C, or less than about 80⁰C, or less than about 60⁰C, or less than about 40°C, or any other suitable temperatures.

Suitable times for completion of hydrolysis in step b) depend on the temperature and other conditions and may be generally less than about 30 hours, or less than about 24 hours, or less than about 20 hours, or less than about 10 hours, or less than about 5 hours, or less than about 1 hour, or less than about 30 minutes, or any other suitable times.

The product obtained in step b) may be recovered by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a residue or a solid. When it is in the form of a solid, it 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, or less than about 120°C, or less than about 100°C, or less than about 60⁰C, or less than about 40⁰C, 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 product of step b) may be further purified one or more times by any suitable techniques known in the art. For example the product of step b) may be purified by precipitation, slurrying in a suitable solvent, or any other suitable techniques. The precipitation may be achieved by crystallization or by adding an anti-solvent or any other suitable methods known in the art. Anti- solvents are liquids in which valganciclovir or its salt is poorly soluble. Suitable anti-solvents include but are not limited to: hydrocarbons (e.g., hexanes, n- heptane, cyclohexane, toluene, xylenes and the like); ethers (e.g., diethyl ether, diisopropyl ether, methyl t-butyl ether, and the like); and any other suitable anti- solvent.

Suitable solvents include but are not limited to: halogenated hydrocarbons, including dichloromethane, ethylene dichloride, chloroform, and the like; alcohols, including methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, and the like; ketones, including acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters, including ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; ethers, including diethyl ether, diisopropyl ether, methyl t- butyl ether, tetrahydrofuran, dioxane, and the like; polar aprotic solvents, including N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like; nitriles, including acetonitrile, propionitrile, and the like; water; any mixtures thereof; or any other suitable solvents.

Purification may be carried out at suitable temperatures less than about 150⁰C, or less than about 120⁰C, or less than about 100°C, or less than about 80⁰C, or less than about 60⁰C, or less than about 40⁰C, or any other suitable temperatures.

Suitable times for purification depend on the temperature and other conditions and may be generally less than about 30 hours, or less than about 24 hours, or less than about 20 hours, or less than about 10 hours, or less than about 5 hours, or less than about 1 hour, or less than about 30 minutes, or any other suitable times.

The product thus obtained may be recovered by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a residue or a solid. When it is in the form of a solid, it 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, or less than about 120⁰C, or less than about 100°C, or less than about 60°C, or 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. Step c) involves converting a compound of Formula XIII to valganciclovir or a salt thereof.

Step c) may be carried out by any suitable technique, including, for example, reduction. Suitable reduction techniques, which may be used in step c) include but are not limited to: catalytic hydrogenation using hydrogen gas in the presence of metals, including Raney nickel, palladium on carbon, and the like; 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; or any other suitable reducing agents known in the art. Optionally, the reduction may be carried out in the presence of a suitable reagent. Suitable reagents that may be used include but are not limited to acids, bases, resins; or mixtures thereof, either alone or as their solutions in water, organic solvents or their mixtures. Suitable acids that may be used in step c) 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, and the like; inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like. Suitable bases that may be used in step c) 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 in step c) 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.

Optionally, the reduction may be carried out in the presence of a suitable solvent. Suitable solvents that may be used in step c) include, for example: 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 c) may be carried out at suitable temperatures less than about 150⁰C, or less than about 100⁰C, less than about 60⁰C, less than about 40°C, or any other suitable temperatures.

Optionally, step c) may be carried out at atmospheric pressure or under pressure. Suitable pressures that may be used are 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 c) depend on temperature and other conditions and may be generally less than about 15 hours, or less than about 10 hours, or less than about 5 hours, less than about 2 hours, or less than about 30 minutes, or any other suitable times.

Optionally, the product formed in step c) after reduction, which comprises valganciclovir or a salt thereof, may be further treated with suitable reagents before or after conventional work-up process or after isolation of the compound. Suitable reagents that may be used include and are not limited to phosphines, resins, or mixture thereof, or any other suitable reagents. Suitable phosphines that may be used include but are not limited to triphenylphosphine, tri-n- butylphosphine, 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.

Optionally a suitable solvent may be used for the said treatment. Suitable solvents that may be used include, for example: 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.

The treatment may be carried out at suitable temperatures less than about 150⁰C, or less than about 100⁰C, or less than about 60°C, or less than about 40⁰C, or any other suitable temperatures, at atmospheric pressure or elevated pressures. Suitable pressures are 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 the treatment 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 obtained after said treatment may be recovered by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a residue or a solid. When it is in the form of a solid, it 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 150⁰C, or less than about 120°C, or less than about 100⁰C, or less than about 60°C, or less than about 40⁰C, 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 product thus obtained after said treatment, which comprises valganciclovir or a salt thereof, may be further purified by purification techniques known in the art, for example by using column chromatography or various types of isolation methods including precipitation, adding an anti solvent to a solution, and the like, in order to achieve a diastereomeric ratio of valganciclovir or its salt in the range of (45:55) to (55:45). An anti-solvent as used herein refers to a liquid in which valganciclovir or a salt thereof is less soluble or poorly soluble. Suitable anti-solvents include hydrocarbons {e.g., hexanes, n-heptane, cyclohexane, toluene, xylenes, and the like); ethers (e.g., diethyl ether, diisopropyl ether, methyl t-butyl ether, and the like); and any other suitable anti-solvent.

Suitable solvents that may be used for purification 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); esters (e.g., ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like); polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, and the like); water; any mixtures thereof in varying proportions, or any other suitable solvents.

The purification may be carried out at suitable temperatures less than about 150⁰C, or less than about 100⁰C, or less than about 60°C, or less than about 40°C, or any other suitable temperatures. Suitable times for completing the purification 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 thus obtained may be recovered by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a residue or a solid. When it is in the form of a solid, it may be in the form of a crystalline compound, a solvate, an amorphous compound or a mixture thereof. The 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 150⁰C, or less than about 120°C, or less than about 100°C, or less than about 60°C, or 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 desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer. Valganciclovir or its salt of the present invention is substantially free of metal contaminants. The metal contaminants include but are not limited to: palladium, nickel, cobalt, and any other metals. "Substantially free of metal contaminants" as used herein unless otherwise defined refers to a content less than about 50 ppm (parts per million), or less than about 40 ppm, or less than about 30 ppm, or less than about 20 ppm, or less than about 10 ppm, or less than about 5 ppm, or less than about 2 ppm, or less than about 1 ppm.

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.

EXAMPLE 1 : PREPARATION OF IMIDAZOLE-1 -SULFONYLAZIDE.

Sodium azide (65.0 g) and acetonitrile (1 L) are charged into a round bottom flask and cooled to 0 to 5^CC. A solution of sulfonyl dichloride (80.5 mL) is added slowly. The mixture is heated to 25 to 28°C and stirred for 17 hours. The mixture is cooled to 2°C and imidazole (129.5 g) is added over 30 minutes. The mixture is heated to 25 to 28°C and stirred for about 4 hours. The mixture is diluted with ethyl acetate (2 L) and washed with water (2^χ2 L). The organic layer is separated and washed with a saturated solution of sodium bicarbonate (2^χ2 L). The organic layer is dried over sodium sulfate and cooled to 5°C. Ethanol (375 mL) is placed into a round bottom flask and cooled to 0 to 5°C. Acetyl chloride (106.5 mL) is added to the ethanol over about 15 minutes. This solution is added to the organic layer through a dropping funnel over about 20 minutes. The mixture is stirred for about 50 minutes. The formed solid is filtered, washed with ethyl acetate (3*500 mL), and dried at about 52°C under vacuum for about 1 hour to afford the title compound (Yield: 1 15 g).

EXAMPLE 2: PREPARATION OF 2-(S)-AZIDO-3-METHYLBUTANOIC ACID (Formula Xl).

L-valine (1.8 g), potassium carbonate (4.7 g), and imidazole-1 -sulfonyl azide (3.9 g) in methanol (16 mL) are charged into a round bottom flask and stirred at 25°C for about 10 minutes. Copper (II) sulfate pentahydrate (18 mg) is added. The mixture is warmed to 25-30°C and stirred for about 15 hours. The solvent is distilled under vacuum. Water (1 1 ml.) is added to the residue. The mixture is extracted with ethyl acetate (3x10 ml_). The solvent is evaporated at 40 to 42°C to afford the title compound. (Yield: 2.8 g).

EXAMPLE 3: PREPARATION OF 2-(S)-AZIDO-3-METHYLBUTANOIC ACID.

L-Valine (50.0 g), potassium carbonate (129.2 g) and methanol (450 ml_) are charged into a round bottom flask and cooled to 0-5⁰C. Copper (II) sulfate pentahydrate (500 mg) is added, followed by imidazole-1 -sulfonyl azide (107.0 g) and the resulting suspension is warmed to 25-30⁰C and stirred for about 17 hours. The solvent is distilled under reduced pressure. Water (1 .0 L) is added to the residue and the pH is adjusted to 2 with concentrated HCI (160 mL) at 0-5⁰C. The mixture is extracted with ethyl acetate (3><350 mL). The organic layer is dried over sodium sulfate (10.0 g) and solvent is evaporated at 40-42°C, to afford the title compound. (Yield: 85 g).

EXAMPLE 4: PREPARATION OF 2-(S)-AZIDO-3-METHYLBUTANOIC ACID.

Sodium azide (130 g) and toluene (1 .3 L) are charged into a round bottom flask and cooled to about 0°C. Sulfuryl chloride (162 mL) is slowly added over about 30 minutes and the mixture is stirred for 21 hours at room temperature.

Imidazole (245 g) is added in portions at about 0°C and stirred for another 2 hours at room temperature. The reaction is quenched by adding ice-cold water (3 L) and the organic layer is separated. The aqueous layer is washed with toluene (500 mL). The organic layers are combined and washed with saturated aqueous sodium bicarbonate (2.5 L) solution and then with brine (2.5 L). The organic layer is cooled to O⁰C and pH is adjusted to about 2 by drop-wise addition of ice-cold aqueous HCI (125 mL cone. HCI in 500 mL ice-cold water). The aqueous layer is separated and added drop-wise to the stirred mixture of L-valine (137 g), potassium carbonate (354.2 g) and copper sulphate pentahydrate (200 mg) in water (1 .5 L), at about 0⁰C. The mixture is allowed to rise to room temperature and is stirred for about 14 hours. The mixture is washed twice with ethyl acetate (2^χ1.5 L). The aqueous layer is cooled to about 0⁰C and pH is adjusted to about 2 by drop-wise addition of cone. HCI (450 mL). Ethyl acetate (2 L) is added to the aqueous layer at room temperature. The layers are separated. The aqueous layer is washed with ethyl acetate (2 L). The organic layers are combined and washed with brine (1 .5 L). The organic layer is dried over anhydrous sodium sulfate Na₂SO₄ (100 g), filtered, and washed with ethyl acetate (500 mL). The solvent is evaporated at about 50⁰C to afford the title compound. (Yield: 134 g).

EXAMPLE 5: PREPARATION OF 2-(S)-AZIDO-3-METHYLBUTANOIC ACID.

Sodium azide (104 g) and ethyl acetate (1 .56 L) are charged into a round bottom flask and cooled to about 0-5⁰C. Sulfuryl chloride (129 mL) is slowly added to the suspension over about 15-20 minutes and the mixture is stirred for 18-20 hours at room temperature. Imidazole (200 g) is added in portions to the mixture at about 0-5⁰C and stirred for another 3-4 hours at room temperature. 5% aqueous Na₂CO₃ solution (800 mL) is added at 0-5⁰C and the organic layer is separated. The organic layer is washed with brine (800 mL), cooled to 0-5⁰C and pH is adjusted to about 2 with aqueous HCI. The aqueous layer is separated and added to a stirred mixture of L-valine (109.6 g), potassium carbonate (283.3 g), and copper sulphate pentahydrate (200 mg) in water (1 .1 L) at about 0-5⁰C. The mixture is allowed to attain room temperature and is stirred for about 14 hours. The mixture is washed twice with ethyl acetate (2^χ600 mL). The aqueous layer is cooled to about 0-5⁰C and pH is adjusted to about 2 with cone. HCI. Ethyl acetate (400 mL) is added to the aqueous layer at room temperature. The layers are separated and the organic layer is washed with brine (500 mL). The solvent is distilled at about 50°C to afford the title compound. (Yield: 101 g).

EXAMPLE 6: PREPARATION OF N-TRITYL-2-(2-AMINO-1 ,6-DIHYDRO-6-OXO- PURIN-9-YL)METHOXY-3-TRITYLOXY-PROPAN-1 -OL (Formula VIII).

To a slurry of ganciclovir (61 .5 g), 4-dimethylaminopyridine (142.5 mg), and triethylamine (130.5 g) in dimethylformamide (570 g), at 45-51 °C, is added a solution of trityl chloride (178.5 g) in dimethylformamide (570 g) over 25 minutes. The mixture is heated and stirred at 51 -53°C for about 9 hours. The mixture is cooled to about 10°C, then is filtered and washed with dimethylformamide (150 g). The filtrate is warmed to 20⁰C and water is added in two portions (1350 mL and 900 mL). The water is decanted. Ethyl acetate (1500 mL) is added to the obtained gummy compound and stirred overnight at room temperature. The solid is filtered, washed with ethyl acetate (100 ml_), and dried at 54°C to afford the title compound. (Yield: 76.0 g).

EXAMPLE 7: PREPARATION OF N-TRITYL-2-(2-AMINO-1.6-DIHYDRO-6-OXO- PURIN-9-YL)METHOXY-3-TRITYLOXY-1 '-PROPANYL-2'-(S)-AZIDO-3'- METHYLBUTANOATE (Formula XII).

To a solution of N.N'-dicyclohexylcarbodiimide (0.7 g) in dichloromethane (80 mL) at 0⁰C is added a solution of 2-(S)-azido-3-methylbutanoic acid (0.93 g) in dichloromethane (40 ml) and the mixture is stirred for about 30 minutes. The obtained dicyclohexyl urea is filtered and reserved for further reaction. N-trityl-2- (2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3-trityloxy-propan-1 -ol (2.0 g) in dimethylformamide (40 mL) is charged into a round bottom flask, followed by addition of 4-dimethylaminopyridine (35.0 mg) and triethylamine (0.35 g) at about 26°C. The dicyclohexyl urea is added about 26°C and the mixture is stirred for about 17 hours. Water (50 mL) is added and the layers are separated. Solvent from the organic layer is evaporated at 38°C. Ether (20 mL) is added to the residue and stirred for about 2 hours. The solid is filtered and dried at 50⁰C for about 1 hour to afford the title compound. (Yield: 1 .7 g).

EXAMPLE 8: PREPARATION OF 2-(2-AMINO-1 ,6-DIHYDRO-6-OXO-PURIN-9- YL)METHOXY-1 ,3-BIS-i '-PROPYL-(2'S)-AZIDO-3'-METHYLBUTANOATE (Formula XIV).

To a solution of ganciclovir (50.0 g) in DMSO (500 mL) is added HOBT (26.5 g) and triethanolamine (20.0 g) at 25-30⁰C. 2-(S)-azido-3-methylbutanoic acid (98.0 g) dissolved in DMSO (20 mL) and DCC (121 .0 g) dissolved in DMSO (150 mL) are added at 20-25⁰C. The mass is maintained at 25-30⁰C for 2-2.5 hours. The mass is filtered and washed with DMSO (80 mL). The filtrate is added to water (4.5 L) and stirred for 30-45 minutes at 25-35°C. The solid is filtered and washed with water (0.5 L), then dried to afford the title compound. (Yield: 88.0 g). (Purity by HPLC: 96.96%; Ganciclovir of formula III: 0.76%; Compound of Formula XIII: 0.52%; Dicyclohexyl urea: 3.74%). EXAMPLE 9: PREPARATION OF 2-(2-AMINO-1 , 6-DIHYDRO-6-OXO-PURIN-9- YL)-METHOXY-3-HYDROXY-1 -PROPANYL-(2'S)-AZIDO-3'-METHYL BUTANOATE (Formula XIII).

To a solution of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-1 ,3-bis- 1 '-propyl-(2'S)-azido-3'-methylbutanoate (5.0 g) in methanol (150 ml.) is added ammonium acetate (15.2 g) at 25-30⁰C. The mixture is maintained for 48 hours at 25-30°C. The solvent is distilled to afford a residue, which is dried to afford the title compound. (Yield: 2.96 g). (Purity by HPLC: 71.59%; Ganciclovir of Formula III: 17.1 %; Compound of Formula XIV: 10.96%; Diastereomeric ratio: 51 .79:48.20).

EXAMPLE 10: PREPARATION OF 2-(2-AMINO-1 , 6-DIHYDRO-6-OXO-PURIN-9- YL)-METHOXY-3-HYDROXY-1 -PROPANYL- (2'S)-AZI DO-3'-M ETHYL BUTANOATE.

To a solution of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-1 ,3-bis- 1 '-propyl-(2'S)-azido-3'-methylbutanoate (50.0 g) in methanol (750 mL) is added N,N-diisopropylethylamine (12.8 g) and the mixture is maintained for 10-15 hours at 25-30⁰C. Acetic acid is added, stirred for 30 minutes and 90% of the methanol is distilled. Cyclohexane (500 mL) is added to the residue and azeotropic distillation of methanol and cyclohexane is performed. The residue is filtered and the solid is washed with cyclohexane (50 mL) and dried. The dried material is added to a mixture of n-butanol (555 mL) and water (925 mL) and refluxed for 20- 30 minutes. The mixture is cooled to 25-30⁰C, filtered and washed with water (35 mL) to afford a wet solid material. The above operation is repeated with the wet solid material. The solid is dried at 50-60°C. Dried material is added to methanol (495 mL), refluxed for 30-45 minutes, cooled to 25-30°C, maintained for 14-15 hours at 25-30°C, and filtered to afford a wet solid. This operation is repeated twice with obtained wet solid. The solid obtained is washed with cyclohexane (15 mL) and dried to afford the title compound. (Yield: 8.4 g). (Purity by HPLC: 99.21 %; Ganciclovir of Formula III: 0.393%; Dicyclohexyl urea: Not detected; Compound of Formula XIV: 0.063%, Diastereomeric ratio : 51 .71 :48.29). EXAMPLE 1 1 : PREPARATION OF 2-(2-AMINO-1 , 6-DIHYDRO-6-OXO-PURIN-9-

YL)METHOXY-3-HYDROXY-1 '-PROPANYL-2'-(S)-AZIDO-3"-

METHYLBUTANOATE.

To a solution of N-trityl-2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3- trityloxy-1 '-propanyl-2'-(S)-azido-3'-methylbutanoate (2.0 g) in dichloromethane (4 mL) at 15 to 16°C, is added a solution of trifluoroacetic acid (8 mL) in dichloromethane (8 mL) over about 10 minutes and the mixture is stirred for about 3 hours. Methyl t-butyl ether (25 mL) and n-hexane (100 mL) are added and the mixture is stirred for about 20 minutes. The methyl t-butyl ether and n-hexane layer is decanted and dichloromethane (15 mL) is added to the residue. The solvent is evaporated at 35 to 40°C. Methyl t-butyl ether (30 mL) and n-hexane (30 mL) are added to the residue and stirred for about 90 minutes at 25°C. The obtained solid is filtered, washed with a mixture of methyl t-butyl ether (10 mL) and n-hexane (10 mL) and dried under vacuum at 25°C to afford the title compound. (Yield: 0.545 g).

EXAMPLE 12: PREPARATION OF 2-(2-AMINO-1 , 6-DIHYDRO-6-OXO-PURIN-9-

YL)METHOXY-3-HYDROXY-1 '-PROPYL-2'-(S)-AZIDO-3'-M ETHYLBUTANOATE.

To a slurry of ganciclovir (49.4 g) in DMSO (720 mL) is added HOBT (26 g) followed by triethylamine (19.4 g) and the resulting solution is cooled to 10-15⁰C. 2-(S)-azido-3-methylbutanoic acid (42 g) in DMSO (480 mL) is added and the mixture is stirred for 10 minutes. Dicyclohexylcarbodiimide (47.8 g) dissolved in DMSO (320 mL) is added and the mixture is slowly warmed to room temperature and stirred for about 2 hours. The mixture is filtered. The filtrate is added to chilled water (8.25 L) and stirred for 10 minutes, then the mixture is slowly warmed to room temperature and filtered. Water (1.0 L) is added to the wet solid followed by stirring for about 10 minutes. The slurry is filtered and the solid is dried under reduced pressure for about 20 hours. The solid is charged into a round bottom flask containing a 1 :1 mixture of water and n-butanol (1000 mL) and warmed slowly to reflux for about 25 minutes. The resulting solution is slowly cooled to room temperature and the formed solid is filtered. The solid is added to a 1 :1 mixture of water and n-butanol (800 mL) and refluxed for about 40 minutes, then the mixture is slowly cooled to room temperature and formed solid is filtered. The solid is added to a 1 :1 mixture of water and n-butanol (600 ml.) and refluxed for about 30 minutes, then the mixture is slowly cooled to room temperature and formed solid is filtered. The solid is added to a 1 :1 mixture of water and n-butanol (600 ml.) and refluxed for about 40 minutes, then the mixture is slowly cooled to room temperature and formed solid is filtered. The solid is dried under reduced pressure for about 3 hours to afford the title compound. (Yield: 20 g).

EXAMPLE 13: PREPARATION OF VALGANCICLOVIR FREE BASE (Formula I). To a solution of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3- hydroxy-1 '-propanyl-2'-(S)-azido-3'-methylbutanoate (1 .12 g) in ethanol (30 mL) at 25°C is added Raney nickel (4 g) in ethanol (30 mL) and the mixture is heated to reflux and stirred for about 30 minutes. The mass is filtered through diatomaceous earth and washed with ethanol (2*30 mL). The solvent is evaporated from the filtrate at 35°C. lsopropanol (10 mL) is added to the residue. The solvent is evaporated from the mixture and the solid is dried under vacuum at 35°C for about 90 minutes to afford the title compound. (Yield: 0.9 g).

EXAMPLE 14: PREPARATION OF VALGANCICLOVIR ACETATE SALT. To a mixture of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3- hydroxy-1 '-propanyl-2'-(S)-azido-3'-methylbutanoate (0.25 g) and zinc dust (0.75 g) in a round bottom flask is added acetic acid (15 mL) slowly, and the suspension is stirred at 25°C for 1 hour. The mixture is filtered and the solid is washed with acetic acid (5 mL). The solvent is evaporated to dryness at 30⁰C and the residue is co-distilled with isopropanol (3^χ15 mL) to dryness at 25°C, to afford the title compound. (Yield 0.210 g).

EXAMPLE 15: PREPARATION OF VALGANCICLOVIR ACETATE SALT.

2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1 '-propanyl-2'- (S)-azido-3'-methylbutanoate (2.0 g) and zinc dust (6 g) are charged into a round bottom flask and cooled to 20-25⁰C. A solution of acetic acid (20 mL) and isopropanol (80 mL) is slowly added and the resulting suspension is stirred for about an hour. The mixture is filtered and washed with acetic acid (10 mL). The solvent is evaporated to dryness at 30°C and the residue is suspended in acetone (30 mL) and stirred for about an hour. The solid is filtered, washed with acetone (15 mL), and dried under reduced pressure to afford the title compound. (Yield: 2.2 g).

EXAMPLE 16: PREPARATION OF VALGANCICLOVIR ACETATE SALT.

2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1 '-propanyl-2'- (S)-azido-3'-methylbutanoate (10.0 g) and zinc dust (30 g) are charged into a round bottom flask and cooled to 5-10⁰C. A solution of acetic acid (100 mL) in isopropanol (400 mL) is slowly added and the resulting suspension is stirred at 25- 30⁰C for about 45 minutes. The mixture is filtered through flux calcined diatomaceous earth and washed with a mixture of acetic acid (10 mL) and isopropanol (40 mL). The solvent is evaporated to dryness at 35°C and the residue is suspended in acetone (200 mL) and stirred for 30 minutes. The solid is filtered, washed with acetone (50 mL), and dried under reduced pressure. The solid is suspended in water (50 mL) and stirred for 5 minutes at about 5°C.

Acetone (330 mL) is added to the suspension and stirred for about 5 minutes. The mixture of water and acetone is decanted and the mixture is warmed to room temperature. Acetone (330 mL) is added to the mixture and stirred for about 25 minutes. The solid is filtered, washed with acetone (40 mL), and dried under reduced pressure to afford the title compound. (Yield: 7.1 g).

EXAMPLE 17: PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE SALT (Formula II).

Acetic acid (6 mL) is slowly added to a suspension of valganciclovir acetate (6.0 g) in ethanol (120 mL) at about 28°C. The resulting solution is stirred for about 10 minutes. 4% HCI (0.68 g) in ethyl acetate (17 mL) is added to the solution and stirred for about 45 minutes. The solid is filtered, washed with ethanol (30 mL), and dried under reduced pressure. The solid is suspended in methanol (12 mL) and stirred for about 45 minutes. The methanol layer is decanted. Ethanol (12 mL) is added to the residue followed by methyl t-butyl ether (36 mL). The precipitated solid is filtered, washed with methyl t-butyl ether (18 mL), and dried under reduced pressure to afford the title compound. (Yield: 1 .0 g). EXAMPLE 18: PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE SALT.

Acetic acid (7 mL) is added to a suspension of valganciclovir acetate (7.0 g) in isopropanol (140 mL) at about 20°C. Thfluoroacetic acid (7 mL) is added to the suspension and stirred for about 5 minutes. The resulting solution is filtered through flux calcined diatomaceous earth and the solid is washed with isopropanol (10 mL). To the filtrate is added 4% HCI in isopropanol (14 mL) and stirred for 30 minutes. The precipitated solid is filtered, washed with isopropanol (20 mL), and dried under reduced pressure to afford the title compound. (Yield: 4.0 g).

EXAMPLE 19: PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE SALT.

To a solution of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)-methoxy-3- hydroxy-1-propanyl-(2'S)-azido-3'-methyl butanoate (30.0 g) in methanol (600 mL) in an autoclave vessel is added aqueous HCI (9.6 mL) and 10% Pd on carbon (50% wet, 3.0 g), and hydrogen pressure of 4 kg/cm² is maintained for 2-3 hours at 25-30^cC. Catalyst is filtered and washed with methanol (150 mL). The filtrate is treated with resin (Tulsion™ CH-97, a crosslinked polystyrene resin with methylenethiol functional groups) at 25-30^°C. The mixture is treated with carbon (3 g), filtered, and the solid is washed with methanol (150 mL) at 25-30⁰C. Methanol is distilled below 40⁰C to a minimal volume. Water is added to make the volume up to 2.4 times by volume based on input. The mixture is washed with toluene (3^χ60 mL) and n-butanol (2^χ60 mL) at 25-30°C. lsopropyl alcohol (120 mL) is added to the aqueous layer and stirred for 2-3 hours for solid formation at 25- 30⁰C. lsopropyl alcohol (210 mL) is added and stirred for 14-15 hours at 25-30°C. n-Heptane (150 mL) is added and maintained for one hour at 0-5°C. Solid is filtered at -10 to -15°C, washed with isopropanol and dried under vacuum at 40- 50°C. The solid is added to water (34.5 mL) and the solution is washed with n- butanol (2^χ46 mL) at 25-30°C. lsopropyl alcohol (480 mL) is added to the aqueous layer and stirred for solid formation. The mixture is cooled to -10 to -15°C and maintained for one hour. The solid is filtered, washed with chilled isopropyl alcohol (46 mL) and dried under vacuum at 45-50°C. This operation is repeated with obtained solid for further purification to afford the title compound. (Yield: 18.0 g). (Purity by HPLC: 99.55%; guanine of formula XIX: 0.01 %; ganciclovir of Formula III: 0.21 %; isovalganciclovir of formula (XXI): 0.03%; diester of Formula XX: 0.02%; Palladium content by atomic absorption spectroscopy: Not detected; diastereomeric ratio: 51 .81 :48.18).

EXAMPLE 20: PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE SALT.

To a solution of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)-methoxy-3- hydroxy-1-propanyl-(2'S)-azido-3'-methyl butanoate (5.0 g) in methanol (100 mL) in an autoclave vessel is added aqueous HCI (1 .6 mL) and 10% Pd on carbon (50% wet, 0.5 g), and hydrogen pressure of 4 kg/cm² is maintained for 2-3 hours at 25-30°C. The reaction is filtered through a flux calcined diatomaceous earth bed and the solid is washed with methanol (25 mL). The filtrate is treated with resin (Tulsion CH-97, 60 mL) at 25-30⁰C. The mixture is treated with carbon (0.5 g), filtered, and the solid is washed with methanol (25 mL) at 25-30⁰C. Methanol is distilled under vacuum at below 40⁰C until a minimal volume remains. Water (5 mL) is added and stirred for 15-20 minutes at 25-30°C. The solution volume is adjusted to 12 mL with water. The mixture is washed with toluene (3^χ10 mL) and n-butanol (2^χ10 mL) at 25-30⁰C. lsopropyl alcohol (30 mL) is added to the aqueous layer and stirred for 2-3 hours for solid formation at 25-30⁰C. lsopropyl alcohol (25 mL) is added and stirred for 14-15 hours at 25-30°C. Cyclohexane (25 mL) is added and maintained for one hour at 0-5°C, then one hour at -10 to -15°C. Solid is filtered at -10 to -15°C, washed with chilled isopropanol (10 mL) and vacuum dried at 40-50⁰C. The solid is added to water (7 mL) and stirred for 30 minutes at 25-30°C. The aqueous layer is washed with n-butanol (2x9 mL) at 25- 30°C. lsopropyl alcohol (18 mL) is added and maintained for 15-30 minutes at 25- 30°C. lsopropyl alcohol (77 mL) is added and maintained for one hour at -10 to - 15°C. The solid is filtered, washed with chilled isopropyl alcohol (9 mL) and dried under vacuum at 40-50°C. The above operation is repeated with obtained solid for purification to afford the title compound. (Yield: 3.56 g). EXAMPLE 21 : PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE SALT.

To a solution of 2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)-methoxy-3- hydroxy-1-propanyl-(2'S)-azido-3'-methyl butanoate (10.0 g) in methanol (200 mL) in an autoclave vessel is added aqueous HCI (3.2 mL) and 10% Pd on carbon (50% wet, 1 g), and a hydrogen gas pressure of 4 kg/cm² is maintained for 2-3 hours at 25-30⁰C. The mass is filtered through a flux calcined diatomaceous earth bed and the bed is washed with methanol (50 mL). The filtrate is treated with carbon (1 g) at 25-35°C. Carbon is filtered. To the filtrate, triphenylphophine (10 mg) is added and stirred for one hour at 25-35 C. The mixture is filtered through a flux calcined diatomaceous earth bed and the bed is washed with methanol (50 mL). Methanol is distilled from the filtrate under reduced pressure below 40⁰C. Water (10 mL) is added to the residue and distilled under reduced pressure below 40°C. The volume is adjusted with water to 24 mL. The mixture is washed with toluene (3*20 mL) and n-butanol (2x20 mL) at 25-30⁰C. lsopropyl alcohol (50 mL) is added to the aqueous layer and stirred for 2-3 hours for solid formation at 25- 30°C. lsopropyl alcohol (60 mL) is added and stirred for 14-15 hours at 25-30°C. Cyclohexane (50 mL) is added and maintained for one hour at 0-5°C, then one hour at -10 to -15°C. Solid is filtered at -10 to -15°C, washed with chilled isopropyl alcohol (20 mL) and suction dried. The solid is dried at 40-50⁰C. (Yield: 7.5 g). (Palladium content by atomic absorption spectroscopy: 20 ppm (parts per million.)

EXAMPLE 22: PREPARATION OF N₁O-BISTRITYL GANCICLOVIR (Formula VIII). Ganciclovir (50 g) and dimethylformamide (467 mL) are charged into a round bottom flask. 4-dimethylaminopyridine (0.1 156 g), and triethylamine (105 g) are added at about 29°C. The mixture is stirred and heated to about 49°C. A solution of trityl chloride (145 g) in dimethylformamide (466.5 mL) is added over about 3 hours and stirred for about 9 hours. The mixture is cooled to about 15°C and stirred for about 90 minutes. The mixture is filtered and washed with dimethylformamide (122 mL). Water is slowly added in two portions (1 100 mL and 735 mL) to the filtrate at about 20⁰C. The mixture is stirred for about 2 hours at room temperature. The mixture is filtered and the solid is dried for about 45 minutes at room temperature. The solid is washed with water (605 ml.) and further dried for about 45 minutes. Methanol (3400 ml_) is added to the wet solid and the mixture is heated to reflux for about 1 hour and further stirred at reflux for about 1 hour. The mixture is cooled to room temperature over 45 minutes. The mixture is filtered and dried for about 10 minutes. The solid is washed with methanol (500 ml_) and dried for about 30 minutes at room temperature. The solid is further dried at about 70°C for about 8 hours to afford the title compound. (Yield: 91 .7 g).

EXAMPLE 23: PREPARATION OF N,O-BISTRITYL-O-MESYL GANCICLOVIR (Formula XV).

N,O-bistritylganciclovir (25 g), triethylamine (23.5 mL) and dichloromethane (500 mL) are charged into a round bottom flask at room temperature and stirred for about 45 minutes. The mixture is cooled to about 10-15⁰C. A solution of mesyl chloride (6.54 mL) in dichloromethane (25 mL) is slowly added over 40 minutes. The mixture is stirred for about 30 minutes and water (250 mL) is added and further stirred for about 20 minutes. The layers are separated. The aqueous layer is extracted with dichloromethane (125 mL). The organic layers are combined and dried over anhydrous sodium sulfate (2.5 g). The solvent is evaporated at about 45°C under reduced pressure to afford the title compound. (Yield: 23.5 g).

EXAMPLE 24: PREPARATION OF O-MESYL GANCICLOVIR (Formula XVI)

An acetic acid and water mixture (80:20, 250 mL) is charged to N,O-bistrityl O-mesyl ganciclovir (25 g) in a round bottom flask at about 28°C and stirred for about 10 minutes. The mixture is heated to about 65°C and stirred for about 10¹/₂ hours. The mixture is cooled to about 30⁰C over 20 minutes. The mixture is filtered and the solid is washed with water (25 mL). The water is distilled at about 70⁰C under reduced pressure. Diisopropyl ether (250 mL) is added to the residue and stirred for about 40 minutes. The mixture is filtered and washed with diisopropyl ether (50 mL). The solvent is evaporated at about 30°C to afford the title compound. (Yield: 7.9 g). EXAMPLE 25: PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE.

O-mesylganciclovir (5 g), L-laline (1 .76 g), sodium hydroxide (0.6 g), tetrabutylammonium bromide (0.5 g) and dimethylformamide (100 mL) are charged into a round bottom flask at about 26°C. The mixture is heated to about 93°C and stirred for about 6 hours. The mixture is cooled to room temperature. The mixture is filtered and the filtrate distilled at about 85°C under reduced pressure for about 55 minutes. The residue is cooled to about 30⁰C and purified by column chromatography (methanol-chloroform mobile phase). The fractions containing valganciclovir are combined and evaporated. The obtained solid is taken in to water (50 mL). The pH is adjusted to about 2 with 15% HCI solution (2 mL). The solution is washed with methyl ethyl ketone (3*50 mL) and then saturated with acetone (100 mL). The solid is filtered and washed with acetone (5 mL). The solid is dried at about 26°C for about 3 hours to afford the title compound. (Yield: 1 .07 g).

EXAMPLE 26: PREPARATION OF AMORPHOUS VALGANCICLOVIR HYDROCHLORIDE SALT.

2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1 '-propanyl-2'- (S)-azido-3'-methylbutanoate (3.0 g) and methanol (75 mL) are charged into a reaction vessel. Ethanolic hydrogen chloride (10.3%, 1 1 .2 mL) is added at room temperature followed by addition of 10% Pd on carbon (300 mg). The mixture is subjected to a hydrogen pressure of about 3 kg/cm² for about 2 hours at room temperature. The catalyst is filtered and the filtrate is added to methyl t-butyl ether (500 mL). The solid is filtered and dried under reduced pressure for about 40 minutes to afford the title compound. (Yield: 2.8 g). A powder X-ray diffraction pattern of the product, obtained using copper Ka radiation, is shown as Fig. 1 .

EXAMPLE 27: CONVERSION OF A COMPOUND OF FORMULA XIV TO A COMPOUND OF FORMULA III. A compound of Formula XIV (0.5 g) and ammonia solution (18% wt./v; 50 mL) are charged into a round bottom flask followed by addition of methanol (20 mL). The solution is stirred at room temperature for 5-6 hours. The solvent is distilled at 30-40°C and ethanol (20 mL) is added to the residue and stirred for 30 minutes. The mixture is filtered, washed with ethanol (10 ml_), and dried under reduced pressure to afford ganciclovir. (Yield: 0.2 g).

EXAMPLE 28: CONVERSION OF A COMPOUND OF FORMULA XIV TO A COMPOUND OF FORMULA XIII.

To a solution of a compound of Formula XIV (1 .0 g) in n-butanol (13 mL) is added thethylamine (0.8 g) and the solution is refluxed for 18-20 hours. The solution is cooled to room temperature and stirred for about 3 hours. The formed solid is filtered, washed with n-butanol, and dried under reduced pressure to afford the compound of Formula XIII. (Yield: 0.5 g).

Claims

CLAIMS:

1 . A process for preparing valganciclovir and pharmaceutically acceptable salts thereof, comprising: a) reacting a compound of Formula III or a salt thereof or a protected derivative of Formula X or a salt thereof, with 2-(S)-azido-3-methylbutanoic acid of Formula Xl or a salt thereof or an activated derivative thereof, to obtain a compound of Formula XII or a salt thereof;

FORMULA X FORMULA

FORMULA Xl FORMULA XII wherein Pi, P₂, and P₄ are individually hydrogen or a protecting group; optionally followed by one or more of the following steps: b) converting a compound of Formula XII to a compound of Formula XIII or a salt thereof;

FORMULA XIII c) converting a compound of Formula XIII to valganciclovir, or optionally converting a compound of Formula XII to valganciclovir in a single step.

2. The process of claim 1 , further comprising one or more of: i) converting valganciclovir to a salt thereof; ii) converting a salt of valganciclovir to valganciclovir; and iii) converting a first salt of valganciclovir into a second salt of valganciclovir.

3. The process of claim 1 , wherein the compound of Formula XII in step a) is N-trityl-2-(2-amino-1 ,6-dihydro-6-oxo-purin-9-yl)methoxy-3-trityloxy-1 '-propanyl-2'- (S)-azido-3'-methylbutanoate.

4. The process of claim 1 , wherein the compound of Formula XIII is prepared by reacting a compound of Formula III with 2-(S)-azido-3-methylbutanoic acid of Formula Xl.

5. The process of claim 1 , wherein a) is carried out in the presence of a base.

6. The process of claim 1 , wherein a) is carried out in the presence of an organic base, inorganic base, or resin.

7. The process of claim 1 , wherein a) is carried out in the presence of a catalyst.

8. The process of claim 1 , wherein a) is carried out in the presence of a catalyst comprising triethylamine, pyridine, diisopropylethylamine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene, 1 ,4-diazabicyclo[2.2.2]octane, 1 - methylmorpholine, 1 -methylpiperidine, 1 ,5-diazabicyclo[4.3.0]non-5-ene, N, N- dimethylpiparazine, N,N-dimethylaniline, 4-(dimethylamino)-pyridine, hexamethylenetetramine, tetramethylethylenediamine, collidine, or 2,3,5,6- tetramethylpyridine.

9. The process of claim 1 wherein a) is carried out in the presence of a coupling agent.

10. The process of claim 1 wherein a) is carried out in the presence of a coupling agent comprising N-hydroxybenzotriazole, 4,5-dicyanoimidazole, dicyclohexylcarbodiimide, dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1 - ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1 ,1 '- carbonyldiimidazole, cyclohexylisopropylcarbodiimide, bis[[4-(2,2-dimethyl-1 ,3- dioxolyl)]-methyl]carbodiimide, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride, an acid chloride, or ethyl chloroformate.

1 1 . A process for preparing valganciclovir or a salt thereof, comprising: a) reacting a compound of Formula III with 2-(S)-azido-3- methylbutanoic acid of Formula Xl, to obtain a compound of Formula XIV;

FORMULA III FORMULA Xl FORMULA XIV b) partially hydrolyzing a compound of Formula XIV, to obtain a compound of Formula XIII; and

FORMULA XIII c) converting a compound of Formula XIII to valganciclovir or a salt thereof.

12. The process of claim 1 1 , wherein a) is carried out in the presence of a base.

13. The process of claim 1 1 , wherein a) is carried out in the presence of an organic base, inorganic base, or resin.

14. The process of claim 1 1 , wherein a) is carried out in the presence of a catalyst.

15. The process of claim 1 1 , wherein a) is carried out in the presence of a catalyst comprising triethylamine, pyridine, diisopropylethylamine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene, 1 ,4-diazabicyclo[2.2.2]octane, 1 - methylmorpholine, 1 -methylpiperidine, 1 ,5-diazabicyclo[4.3.0]non-5-ene, N₁N- dimethylpiparazine, N,N-dimethylaniline, 4-(dimethylamino)-pyridine, hexamethylenetetramine, tetramethylethylenediamine, collidine, or 2,3,5,6- tetramethylpyridine.

16. The process of claim 1 1 , wherein a) is carried out in the presence of a coupling agent.

17. The process of claim 1 1 , wherein a) is carried out in the presence of a coupling agent comprising N-hydroxybenzotriazole, 4,5-dicyanoimidazole, dicyclohexylcarbodiimide, dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1 - ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1 ,1 '- carbonyldiimidazole, cyclohexylisopropylcarbodiimide, bis[[4-(2,2-dimethyl-1 ,3- dioxolyl)]-methyl]carbodiimide, N,N'-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride, an acid chloride, or ethyl chloroformate.

18. The process of claim 1 1 , wherein b) is carried out in the presence of an inorganic base, organic base, or resin.

19. The process of claim 1 1 , wherein b) is carried out in the presence of an ammonia solution, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.

20. The process of claim 1 1 , wherein b) is carried out in the presence of triethylamine, pyridine, N-methylmorpholine, N,N-diisopropylamine, or diisopropylethylamine.

21 . A process of claim 11 , wherein b) is carried out in the presence of an ion exchange resin bound to metal ions comprising lithium, sodium, or potassium.

22. A compound of Formula XII, or a salt thereof.

FORMULA XII

23. A compound of Formula XIII, or a salt thereof.

FORMULA XIII

24. A compound of Formula XIV, or a salt thereof.

FORMULA XIV

25. A compound of Formula XIV, or a salt thereof,

FORMULA XVI wherein A is an activating group.

26. Valganciclovir or its salt, having a purity at least 99% by weight, as determined by HPLC.

27. Valganciclovir or its salt, having a purity at least 99.5% by weight, as determined by HPLC.

28. Valganciclovir or its salt, containing one or more corresponding impurities at less than 1 % by weight, as determined by HPLC.

29. Valganciclovir or its salt, containing one or more corresponding impurities at less than 0.5% by weight, as determined by HPLC.

30. Valganciclovir or its salt, containing one or more corresponding impurities at less than 0.3% by weight, as determined by HPLC.

31 . Valganciclovir or its salt, containing one or more corresponding impurities at less than 0.2% by weight, as determined by HPLC.

32. Valganciclovir or its salt, containing one or more corresponding impurities at less than 0.1 % by weight, as determined by HPLC.

33. Valganciclovir or its salt of any of claims 26-32, wherein a corresponding impurity comprises: guanine impurity of Formula (XVII); ganciclovir impurity of Formula (III); mono azide ester valganciclovir of Formula (XIX); bis-azide ester valganciclovir of Formula (XIV); bis-amine ester valganciclovir of Formula (XX); dimethyl acryl ganciclovir of Formula (XVII); valaryl ganciclovir of Formula (XVIII); or isovalganciclovir impurity of Formula (XXI).

FORMULA XIX FORMULA FORMULA XIII

FORMULA XIV FORMULA XX

FORMULA XVII FORMULA XVIII

FORMULA XXI

34. Valganciclovir or its salt, substantially free of metal contaminants.

35. Valganciclovir or its salt, substantially free of palladium.

36. Valganciclovir or its salt, containing less than about 50 ppm palladium.