The following specification describes the nature of the invention

IMPROVED PROCESS FOR PREPARATION OF VALGANCICOVIR HYDROCHLORIDE

INTRODUCTION
The application relates to improved processes for preparing valganciclovir hydrochloride.
Valganciclovir (I) has a chemical name L-valine 2-[(2-amino-1 6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester.

Valganciclovir hydrochloride is represented by Formula II. Valganciclovir is a mono-L-valyl ester (prodrug) of the antiviral compound ganciclovir (III). Valganciclovir hydrochloride 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.

The structure of valganciclovir (I) is shown below.

The structure of valganciclovir hydrochloride (II) is shown below.

The structure of ganciclovir (III) is shown below.

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 of the application involves use of preparative reverse phase HPLC column which makes the process unsuitable for commercial scale manufacturing.

U.S. Patent No. 5 700 936 describes processes for preparing the compound 2-(2-amino-1 6-dihydro-6-oxo-purin-9-yl) methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt or diastereomer thereof comprising: hydrolyzing a compound of Formula IV:

wherein P1 is hydrogen or an amine-protecting group and P2 is an amine-protecting group; to form a compound of Formula V:

in the presence of an amine in a nonpolar aprotic solvent; and deprotecting the compound of Formula V to 2-(2-amino-1 6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate or a pharmaceutically acceptable salt thereof; optionally followed by converting 2-(2-amino-1 6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-1-propanyl-L-valinate into a pharmaceutically acceptable salt thereof; or separating 2-(2-amino-1 6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxy-propanyl-L-valinate into its (R) and (S) diastereomers.

There remains a need to provide improved processes for preparing valganciclovir and pharmaceutically acceptable salts thereof which are simple cost-effective commercially viable sustainable environmentally friendly and avoid multiple protection-deprotection steps.

SUMMARY
In one aspect the application provides improved process for preparing valganciclovir hydrochloride embodiments comprising one or more of the following steps individually or in the sequence recited:

a) reacting the compound of Formula III with a compound of Formula VI to obtain a compound of Formula VII:

wherein P1 is hydrogen or an amine-protecting group;

b) partially hydrolyzing a compound of Formula VII to obtain a compound of Formula VIII:

wherein P1 is as defined above;

c) optionally purifying the compound of Formula VIII; and

d) converting a compound of Formula VIII to valganciclovir of Formula I or valganciclovir hydrochloride of formula II.

DETAILED DESCRIPTION

In one aspect the application provides methods 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 the compound of Formula III with
a compound of Formula VI to obtain a compound of Formula VII:

wherein P1 is hydrogen or an amine-protecting group;

b) partially hydrolyzing a compound of Formula VII to obtain a compound of Formula VIII:

wherein P1 is as defined above;

c) optionally purifying the compound of Formula VIII; and

d) converting a compound of Formula VIII to valganciclovir of Formula I or a salt thereof.
Step a) involves reacting the compound of Formula III with a compound of Formula VI to obtain a compound of Formula VII. Step a) may be carried out in presence of one or more suitable base. Suitable bases which may be used in step a) include but are not limited to organic bases inorganic bases or resins such as for example: aliphatic amines e.g. triethylamine tributylamine N-methylmorpholine N N-diisopropylethylamine N-methylpyrrolidine or the like; aromatic amines e.g. pyridine N N-dimethylaminopyridine or the like; alkali metal carbonates e.g. sodium carbonate potassium carbonate or the like; alkali metal bicarbonates e.g. sodium bicarbonate potassium bicarbonate or the like; alkali metal hydroxides e.g. sodium hydroxide potassium hydroxide or the like; ammonia; resins bound to ions such as sodium potassium lithium calcium magnesium or the like; any mixtures thereof; or any other suitable bases; either alone or as their aqueous solutions.
Step a) may be carried out in the presence of one or more suitable catalyst. Suitable catalysts which may be used in step b) include but are not limited to triethylamine pyridine diisopropylethylamine

1 8-diazabicyclo[5.4.0]undec-7-ene (DBU) 1 4-diazabicyclo[2.2.2]octane (DABCO) 1-methylmorpholine 1-methyl piperidine 1 5-diazabicyclo[4.3.0]non-5-ene N N-dimethylpiperazine N N-dimethyl aniline 4-(dimethylamino)-pyridine (DMAP) hexamethylenetetramine (HMTA) tetra methylethylenediamine (TMEDA) collidine 2 3 5 6-tetramethylpyridine (TEMP) or the like. Step a) may be carried out in presence of one or more suitable coupling agent. Suitable coupling agents which may be used include but are not limited to N-hydroxy benzotriazole (HOBT) 4 5-dicyanoimidazole dicyclohexylcarbodiimide (DCC) dicyclopentylcarbodiimide diisopropylcarbodiimide 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride 1 1’-carbonyldiimidazole cyclohexylisopropyl carbodiimide (CIC) bis[[4-(2 2-dimethyl-1 3-dioxolyl)]- methyl]carbodiimide N N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl) an acid chloride ethyl chloroformate or the like.
Step a) may be carried out in one or more suitable solvent. Suitable solvents which may be used include but are not limited to an alcohol e.g. methanol ethanol isopropyl alcohol 1-propanol 1-butanol 2-butanol or the like; a ketone e.g. acetone ethyl methyl ketone methyl isobutyl ketone or the like; a hydrocarbon e.g. toluene xylene hexanes heptanes cyclohexane or the like; a halogenated hydrocarbon e.g. dichloromethane ethylene dichloride chloroform or the like; an ester e.g. ethyl acetate n-propyl acetate n-butyl acetate t-butyl acetate or the like; an ether e.g. diethyl ether diisopropyl ether methyl t-butyl ether tetrahydrofuran dioxane or the like; a polar aprotic solvent e.g. N N-dimethylformamide N N-dimethylacetamide dimethylsulfoxide sulfolane N-methylpyrrolidone or the like; a nitrile e.g. acetonitrile propionitrile or the like; water; or any mixtures thereof.
Suitable temperatures for the reaction of step a) are less than about 100°C less than about 80°C less than about 60°C less than about 40°C less than about 20°C less than about 0°C or any other suitable temperatures.
Suitable times for completing the reaction in step a) depend on the temperature and other conditions and may be generally less than about 30 hours less than about 20 hours less than about 10 hours less than about 5 hours less than about 2 hours less than about 1 hour or any other suitable times. Longer times also are suitable.

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 or the like at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C less than about 60°C less than about 40°C or any other suitable temperatures at atmospheric pressure or under reduced pressure and in the presence or absence of an inert atmosphere such as nitrogen argon neon or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product such as for example about 1 to about 15 hours or longer. Optionally 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 VII to obtain a compound of Formula VIII. Step b) may be carried out in the presence of one or more 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 or the like; organic bases such as for example triethylamine n-propylamine pyridine N-methylmorpholine diisopropylamine or diisopropylethylamine or the like; resins including but not limited to ion exchange resins such as resins bound to metal ions including lithium sodium potassium or 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 one or more suitable solvent. Suitable solvents include but are not limited to: hydrocarbon solvents including toluene xylene hexanes heptanes cyclohexane or the like; halogenated hydrocarbon solvents including dichloromethane ethylene dichloride chloroform or the like; alcohol solvents including methanol ethanol isopropyl alcohol 1-propanol 1-butanol 2-butanol or the like; ketone solvents including acetone ethyl methyl ketone methyl isobutyl ketone or the like; ester solvents including ethyl acetate n-propyl acetate n-butyl acetate t-butyl acetate or the like; ether solvents including diethyl ether diisopropyl ether methyl t-butyl ether tetrahydrofuran dioxane or the like; polar aprotic solvents including
N N-dimethylformamide N N-dimethylacetamide dimethylsulfoxide sulfolane N-methylpyrrolidone or the like; nitrile solvents including acetonitrile propionitrile or the like; water; any mixtures thereof; or any other suitable solvents.

Suitable temperatures for the reaction of step b) may be less than about 100°C less than about 80°C less than about 60°C less than about 40°C less than about 20°C less than about 0°C or any other suitable temperatures. Suitable times for completion of hydrolysis in step b) depend on the temperature and other conditions and may be generally less than about 30 hours less than about 24 hours less than about 20 hours less than about 10 hours less than about 5 hours less than about 1 hour less than about 30 minutes or any other suitable times.

Optionally step b) may afford valganciclovir and pharmaceutically acceptable salts thereof by employing a suitable combination of reagent and solvent including for example employing a base which performs partial hydrolysis of compound of Formula VII as well as removal of protecting group P1.

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 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 or the like at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C less than about 120°C less than about 100°C less than about 60°C less than about 40°C or any other suitable temperatures at atmospheric pressure or under reduced pressure and in the presence or absence of an inert atmosphere such as nitrogen argon neon or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product such as for example about 1 to about 15 hours or longer. The resulting solid may be crystalline or amorphous in nature.
Step c) optionally involves 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 column chromatography or by a combination of these procedures or any other suitable techniques. The precipitation may be achieved by crystallization such as by cooling a solution or by adding an anti-solvent to a solution of the product 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: hydrocarbon solvents (e.g. hexanes heptanes cyclohexane toluene xylenes or the like); ether solvents (e.g. diethyl ether diisopropyl ether methyl t-butyl ether or the like); or any other suitable anti-solvents.
Suitable solvents for purification include but are not limited to: water acetic acid hydrocarbon solvents including hexanes heptanes cyclohexane toluene xylenes or the like halogenated hydrocarbon solvents including dichloromethane ethylene dichloride chloroform or the like; alcohol solvents including methanol ethanol 1-propanol 2-propanol 1-butanol 2-butanol or the like; ketone solvents including acetone ethyl methyl ketone methyl isobutyl ketone or the like; ester solvents including ethyl acetate n-propyl acetate n-butyl acetate t-butyl acetate or the like; ether solvents including diethyl ether diisopropyl ether methyl t-butyl ether tetrahydrofuran dioxane or the like; polar aprotic solvents including N N-dimethylformamide N N-dimethylacetamide dimethylsulfoxide sulfolane N-methylpyrrolidone or the like; nitrile solvents including acetonitrile propionitrile or the like; any mixtures thereof; or any other suitable solvents.

Suitable resins may be used for column purifications include but not limited to Sepabeads SP207 ADS 551 SL-668 PVC resinB10 hydrophobic silicon dioxide and MMJ-106MQ or any other suitable resins.

Purification may be carried out at suitable temperatures less than about 100°C less than about 80°C less than about 60°C less than about 40°C less than about 30°C less than about 20°C 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 less than about 24 hours less than about 20 hours less than about 10 hours less than about 5 hours less than about 1 hour less than about 30 minutes or any other suitable times.

Unreacted compound of formula VII present in compound of formula VIII may be separated by following the step (c) and reused for the step (b).

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 or the like at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C less than about 120°C less than about 100°C less than about 60°C less than about 40°C or any other suitable temperatures at atmospheric pressure or under reduced pressure and in the presence or absence of an inert atmosphere such as nitrogen argon neon or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product such as for example about 1 to about 15 hours or longer.

Step d) involves converting a compound of Formula VIII to valganciclovir or a salt thereof. Step d) may be carried out using any suitable deprotection technique including for example catalytic hydrogenation using hydrogen gas in the presence of a metal including Raney nickel palladium on carbon or the like; or hydrolysis using an acid or base; or any other suitable deprotection agents known in the art. Optionally catalytic hydrogenation may be carried out in the presence of one or more 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.

Optionally the product obtained in step d) may be further purified using purification techniques known in the art for example using column chromatography or various types of isolation methods including precipitation adding an anti-solvent to a solution or the like in order to achieve a diastereomeric ratio of valganciclovir or its salt in the range of (45:55) to (55:45).

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. DMSO is dimethylsulfoxide and HPLC is high-pressure liquid chromatography. The term "reacting" is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place.

An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcohol solvents” include but are not limited to methanol ethanol 2-nitroethanol 2-fluoroethanol 2 2 2-trifluoroethanol hexafluoroisopropyl alcohol ethylene glycol 1-propanol 2-propanol (isopropyl alcohol) 2-methoxyethanol 1-butanol 2-butanol i-butyl alcohol t-butyl alcohol 2-ethoxyethanol diethylene glycol 1- 2- or 3-pentanol neo-pentyl alcohol t-pentyl alcohol diethylene glycol monomethyl ether diethylene glycol monoethyl ether cyclohexanol benzyl alcohol phenol glycerol C1-6alcohols or the like.
“Amine-protecting group” refers to a radical when attached to a nitrogen atom in a target molecule is capable of surviving subsequent chemical reactions applied to the target molecule i.e. hydrogenation reaction with acylating agents alkylation etc. The amine-protecting group can later be removed. Amine protecting groups include but are not limited to fluorenylmethoxycarbonyl (FMOC) tert-butoxycarbonyl (t-BOC) benzyloxycarbonyl (Z) those of the acyl type (e.g. formyl benzoyl trifluoroacetyl p-tosyl aryl- and alkylphosphoryl phenyl- and benzylsulfonyl o-nitrophenylsulfenyl o-nitrophenoxyacetyl) and of the urethane type (e.g. tosyloxyalkyloxy- cyclopentyloxy- cyclohexyloxy- 1 1-dimethylpropyloxy 2-(p-biphenyl)-2-propyloxy- and benzylthiocarbonyl). Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule.

Examples of an amine-protecting agent include but are not limited to C1-C6 aliphatic acid chlorides or anhydrides C6-C14arylcarboxylic acid chlorides or anhydrides t-butyl chloroformate di-tert-butyl dicarbonate butoxycarbonyloxyimino-2-phenylacetonitrile t-butoxycarbonyl azide t-butyl fluoroformate fluorenylmethoxycarbonyl chloride fluorenylmethoxycarbonyl azide fluorenylmethoxycarbonyl benzotriazol-1-yl (9-fluorenylmethoxycarbonyl)succinimidyl carbonate fluorenylmethoxycarbonyl pentafluorophexoxide trichloroacetyl chloride methyl- ethyl- trichloromethyl- chloroformate and other amine protecting agents known in the art. Examples of such known amine-protecting agents are found in pages 385-397 of T. W. Green P. G. M. Wuts “Protective Groups in Organic Synthesis Second Edition” Wiley-Interscience New York 1991.

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: hydrocarbon solvents e.g. hexanes heptanes cyclohexane toluene xylenes or the like; ether solvents e.g. diethyl ether diisopropyl ether methyl t-butyl ether or the like; or any other suitable anti-solvents.

An “ester solvent” is an organic solvent containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “Ester solvents” include but are not limited to ethyl acetate n-propyl acetate n-butyl acetate isobutyl acetate t-butyl acetate ethyl formate methyl acetate methyl propanoate ethyl propanoate methyl butanoate ethyl butanoate C3-6esters or the like.

An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include but are not limited to diethyl ether diisopropyl ether methyl t-butyl ether glyme diglyme tetrahydrofuran 1 4-dioxane dibutyl ether dimethylfuran 2-methoxyethanol 2-ethoxyethanol anisole C2-6ethers or the like.

A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include but are not limited to dichloromethane 1 2-dichloroethane trichloroethylene perchloroethylene 1 1 1-trichloroethane 1 1 2-trichloroethane chloroform carbon tetrachloride or the like.

“Hydrocarbon solvent” refers to a liquid hydrocarbon which may be linear branched or cyclic. It may be saturated unsaturated or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include but are not limited to n-pentane isopentane neopentane n-hexane isohexane 3-methylpentane 2 3-dimethylbutane neohexane n-heptane isoheptane 3-methylhexane neoheptane 2 3-dimethylpentane 2 4-dimethylpentane 3 3-dimethylpentane 3-ethylpentane 2 2 3-trimethylbutane n-octane isooctane 3-methylheptane neooctane C5-C8aliphatic hydrocarbons cyclohexane methylcyclohexane ligroin petroleum ethers benzene toluene ethylbenzene m-xylene o-xylene p-xylene indane naphthalene tetralin trimethylbenzene C6-C10aromatic hydrocarbons or mixtures thereof.

A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include but are not limited to acetone ethyl methyl ketone diethyl ketone methyl isobutyl ketone C3-6ketones or the like.

A “nitrile solvent” is an organic solvent containing a cyano -(C=N) bonded to another carbon atom. “Nitrile solvents” include but are not limited to acetonitrile propionitrile C2-6nitriles or the like.

A “polar aprotic solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents such as hexamethyl phosphoramide (HMPA) and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents such as nitromethane nitroethane nitropropane and nitrobenzene; ester-based organic solvents such as ?-butyrolactone ethylene carbonate propylene carbonate butylene carbonate dimethyl carbonate and propiolactone; pyridine-based organic solvents such as pyridine and picoline; sulfone-based solvents such as dimethyl sulfone diethyl sulfone diisopropylsulfone 2-methylsulfolane 3-methylsulfolane 2 4-dimethyl-sulfolane 3 4-dimethyl sulfolane 3-sulfolene and sulfolane; and nitrile-based organic solvents such as acetonitrile propionitrile and benzonitrile. These organic solvents may be used alone or two or more of these may be combined appropriately.

“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. “Amine-protecting group” means a protecting group that preserves a reactive amine group that otherwise would be modified by certain chemical reactions. Useful amine protecting groups include but are not limited to: benzyloxycarbonyl (Cbz) tert-butyloxycarbonyl (BOC) 9-fluorenylmethoxycarbonyl (FMOC) trifluoroacetyl benzyl trityl formyl or the like.

“Suitable coupling agent" refers to a compound molecule or substance capable of activating carboxylic acids with respect to nucleophilic attack. In some embodiments the suitable coupling agents are capable of activating carboxylic acids where the attacking nucleophile is an amine or alcohol resulting in amide or ester formation. Non-limiting examples of such suitable coupling agents include carbodiimide compounds (e.g.

N N""-dicyclohexylcarbodiimide (DCC) N N’-diisopropylcarbodiimide (DIC) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) or the like). Carbodiimide compounds may be either used alone or in combination with HOAt HOBt or HODhbt. Further examples of suitable coupling agents include alkyl chloroformate compounds (e.g. ethyl chloroformate isobutyl chloroformate or the like) that are generally used with a tertiary amine like triethyl amine diethyl azodicarboxylate (DEAD) with triphenylphosphine (the Mitsunobu reaction) various chlorosilanes chlorosulfonyl isocyanate

N N""-carbonyldiimidazole (CDI) phosphonium reagents (e.g. BOP AOP PyBOP PyAOP BroP PyBroP CF3-NO2-PyBOP or the like) in situ acid fluoride generators (e.g. TFFH BTFFH DAST cyanuric fluoride or the like) aminium reagents (e.g. HBTU HATU HBPyU HAPyU or the like) phosphinyls (e.g. DPPA DEPC or the like) pentafluorophenyl active ester generators (e.g. PfTU PfPyU FDPP PFP-trifluoroacetate FPFOH plus DCC or the like) mixed carbon anhydrides (e.g. EEDQ IIDQ or the like) CIP and BOP-Cl.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C 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 ” or 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.

Certain specific aspects and embodiments of the present disclosure will be explained in more detail with reference to the following examples which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present disclosure.

EXAMPLES
EXAMPLE 1: PREPARATION OF BIS-(Cbz-L-VALYL)-ESTER OF GANCICLOVIR (FORMULA VII).

To a solution of ganciclovir (10.0 g) in DMSO (80 mL) is added Cbz-L-valine (29.5 g) 4-(dimethylamino)-pyridine (DMAP) (400 mg) and dicyclohexylcarbodiimide (DCC) (24.2 g) at 25-30°C. The mass is maintained at 25-30°C for 5-6 hours. The mass is filtered and washed with DMSO (20 mL). The filtrate is added to 10% sodium chloride solution (200 mL) and ethyl acetate (70 mL). The organic layer is separated and aqueous layer is washed with ethyl acetate (30 mL). The combined organic layer is washed with 20% sodium chloride solution (100 mL).

Cyclohexane (300 mL) is added to the organic layer and the mixture is maintained for 12-14 hours at 25-30°C. The formed solid was collected by filtration washed with cyclohexane (50 mL) and dried to afford the title compound. Yield: 26.5 g. Purity by HPLC: 98.87%; mono-(Cbz-L-valyl)-ester of Formula VIII: 0.58%.

EXAMPLE 2: PREPARATION OF MONO-(Cbz-L-VALYL)-ESTER OF GANCICLOVIR (FORMULA VIII). To a solution of bis-(Cbz-L-valyl)-ester of ganciclovir of Formula VII (100 g) in methanol (200 mL) is added n-propylamine (14.0 mL) at 24 °C. After maintaining the reaction mixture for 10 hours at 24 °C acetic acid (400 mL) was added at 12 °C and stirred for 15 minutes. The resulted reaction mixture was slowly added to the water (2.0 L) at 11 °C and maintained at 12 °C for 90 minutes. Separated solid was collected by filtration washed with water (1.0 L) and suck dried. The obtained wet compound and cyclohexane (1200 mL) was charged into flask heated to 55 °C and maintained at 55 °C for 90 minutes. Separated solid was filtered at 56 °C washed with cyclohexane (300 mL) and dried at 45 °C under reduced pressure for 4 hours to afford 57.0 g of crude mono-(Cbz-L-valyl)-ester of ganciclovir of Formula VIII compound. To a solution of the above crude compound (25 g) and methanol (1375 mL) water (281 mL) was added at 28 °C. The resultant reaction mixture was passed through the column (packed with SP-207 resin and stabilized by passing 17% aqueous methanol (400 mL)). Mono-(Cbz-L-valyl)-ester of ganciclovir of Formula VIII containing fraction was collected by passing 17% aqueous methanol as mobile phase followed by bis-(Cbz-L-valyl)-ester of ganciclovir of Formula VII containing fraction was collected by passing methanol as mobile phase. The resultant fractions were separately concentrated precipitated solid was filtered and dried at 45 °C under reduced pressure to afford 11.7 g of compound of formula VIII and 9.7 g of compound of formula VII.

EXAMPLE 3: PREPARATION OF MONO-(Cbz-L-VALYL)-ESTER OF GANCICLOVIR (FORMULA VIII). To a solution of bis-(Cbz-L-valyl)-ester of ganciclovir of Formula VII (100 g) in methanol (200 mL) is added n-propylamine (14.0 mL) at 24 °C. After maintaining the reaction mixture for 12 hours at 24 °C acetic acid (400 mL) was added at 12 °C and stirred for 15 minutes. The resulted reaction mixture was slowly added to the water (2.0 L) at 11 °C and maintained at 12 °C for 90 minutes. Separated solid was collected by filtration washed with water (1.0 L) and suck dried. The obtained wet compound and cyclohexane (1200 mL) was charged into flask heated to 57 °C and maintained at 57 °C for 90 minutes. Separated solid was filtered at 56 °C washed with cyclohexane (300 mL) and dried at 45 °C for 4 hours under reduced pressure to afford 58.0 g of title compound.

EXAMPLE 4: PREPARATION OF MONO-(Cbz-L-VALYL)-ESTER OF GANCICLOVIR (FORMULA VIII). To a solution of bis-(Cbz-L-valyl)-ester of ganciclovir of Formula VII (100 g) in methanol (200 mL) is added n-propylamine (14.0 mL) at 24 °C. After maintaining the reaction mixture for 15 hours at 24 °C acetic acid (400 mL) was added at 12 °C and stirred for 15 minutes. The resulted reaction mixture was slowly added to the water (2.0 L) at 11 °C and maintained at 12 °C for 1 hour 40 minutes. Separated solid was collected by filtration washed with water (1.0 L) and dried at 45 °C under reduced pressure for 10 hours to afford 82.8 g of crude title compound. 40 g of dry compound and cyclohexane (600 mL) was charged into flask heated to 58 °C and maintained at 58 °C for 90 minutes. Separated solid was filtered at 58 °C washed with cyclohexane (150 mL) and dried at 45 °C for 3 hours 30 minutes to afford 24.0 g of title compound.

EXAMPLE 5: PREPARATION OF MONO-(Cbz-L-VALYL)-ESTER OF GANCICLOVIR (FORMULA VIII). To a solution of bis-(Cbz-L-valyl)-ester of ganciclovir of Formula VII (100 g) in methanol (200 mL) is added n-propylamine (14.0 mL) at 24 °C. After maintaining the reaction mixture for 15 hours at 24 °C acetic acid (400 mL) was added at 12 °C and stirred for 15 minutes. The resulted reaction mixture was slowly added to the water (2.0 L) at 11 °C and maintained at 12 °C for 1 hour 40 minutes. Separated solid was collected by filtration washed with water (1.0 L) and dried at 45 °C under reduced pressure for 10 hours to afford 82.8 g of crude title compound. 40 g of dry compound and acetic acid (200 mL) was charged into flask at 28 °C and stirred for 20 minutes. The resulted reaction mixture was slowly added to the water (1.0 L) at 10 °C and maintained at 12 °C for 90 minutes. Separated solid was collected by filtration washed with water (500 mL) and suck dried. The obtained wet compound and cyclohexane (600 mL) was charged into flask heated to 58 °C and maintained at 58 °C for 90 minutes. Separated solid was filtered at 58 °C washed with cyclohexane (150 mL) and dried at 45 °C under reduced pressure for 4 hours to afford 23.1 g of title compound.

EXAMPLE 6: PURIFICATION OF MONO-(Cbz-L-VALYL)-ESTER OF GANCICLOVIR (FORMULA VIII).
To a solution of mono-(Cbz-L-valyl)-ester of ganciclovir of Formula VIII (25 g) and methanol (1375 mL) water (281 mL) was added at 28 °C. The resultant reaction mixture was passed through the column (packed with SP-207 resin and stabilized by passing 17% aqueous methanol (400 mL)). Mono-(Cbz-L-valyl)-ester of ganciclovir of Formula VIII containing fraction was collected by passing 17% aqueous methanol as mobile phase followed by bis-(Cbz-L-valyl)-ester of ganciclovir of Formula VII containing fraction was collected by passing methanol as mobile phase. The resultant fractions were separately concentrated precipitated solid was filtered and dried at 45 °C under reduced pressure to afford 11.7 g of compound of formula VIII and 9.7 g of compound of formula VII.

EXAMPLE 7: PREPARATION OF VALGANCICLOVIR HYDROCHLORIDE SALT. To a solution of mono-(Cbz-L-valyl)-ester of ganciclovir of Formula VIII (10 g) in methanol (200 mL) in an autoclave vessel is added aqueous HCl (2.2 mL) and 10% palladium on carbon (50% wet 1.0 g) and a hydrogen pressure of 3.0-3.5 kg/cm2 is maintained for 2 hours 30 minutes at 29°C. The mass is filtered and the collected solid is washed with methanol (20 mL). To the filtrate is added triphenylphosphine (20 mg) and charcoal. The reaction mass is maintained for 75 minutes at 28°C. The mass is filtered and the collected solid is washed with methanol (30 mL).The filtrate is evaporated below 40°C to remove methanol and the water (10 mL) is added and stirred for 15 minutes. Isopropyl alcohol (200 mL) is added to the mixture at 3°C and stirred for 3 hours. The separated solid is filtered and washed with Isopropyl alcohol (20 mL). The obtained wet compound water (15 mL) and n-propyl alcohol (30 mL) are charged into round bottom flask and stirred for 15 minutes. The resultant reaction mass is filtered and washed with mixture of water (5 mL) and n-propyl alcohol (10 mL). To the obtained filtrate n-propyl alcohol (160 mL) is added at 5°C and stirred for 2 hours 10 minutes. Separated solid is filtered washed with n-propyl alcohol (10 mL) and dried at 45°C for 17 hours under reduced pressure to afford 5.7 g of the title compound.

WE CLAIM:

1. An improved process for preparing valganciclovir hydrochloride, which includes one or more of the following steps, individually or in the sequence recited:

a) reacting the compound of Formula III with a compound of Formula VI, to
obtain a compound of Formula VII:

wherein P1 is hydrogen or an amine-protecting group;

b) partially hydrolyzing a compound of Formula VII, to obtain a compound of
Formula VIII:

wherein P1 is as defined above;

c) optionally purifying the compound of Formula VIII; and

d) converting a compound of Formula VIII to valganciclovir of Formula I or valganciclovir hydrochloride of formula II.

2. The process of claim 1, wherein the compound of formula VIII is purified using column chromatography or crystallization techniques.

3. The process of claim 2, wherein the compound of formula VIII is purified using column chromatography.

4. The process of claim 2, wherein the compound of formula VIII is purified using crystallization.

5. The process of claim 3, wherein the resin used for the purification of compound of formula VIII is Sepabeads SP207, ADS 551, SL-668, PVC resinB10, hydrophobic silicon dioxide and MMJ-106MQ.

6. The process of claim 5, wherein the resin is Sepabeads SP207.

7. The process of claim 2, wherein the solvent used for the purification of compound of formula VIII is water, hydrocarbons, halogenated hydrocarbons, alcohols, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.

8. The process of claim 7, wherein the solvent is mixture of water, alcohols or mixtures thereof.

9. The process of claim 8, wherein the solvent is water, methanol, ethanol, isopropyl alcohol, n-butanol, 2-butanol or mixtures thereof.

10. The process of claim 9, wherein the solvent is water methanol or mixture thereof.