FIELD OF THE INVENTION
The present invention relates to novel process for the preparation of amorphous and crystalline polymorphic forms of Valganciclovir hydrochloride.
BACKGROUND OF THE INVENTION
Valganciclovir hydrochloride brand name is Valcyte. It is hydrochloride salt of the L-valyl ester of ganciclovir that exist as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV). Valganciclovir hydrochloride is a white to off-white crystalline powder The chemical name for Valganciclovir hydrochloride is L-valine, 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propanyl ester monohydrochloride. The chemical structure of Valganciclovir hydrochloride is shown as formula-I

European Patent No. 375329 discloses ester prodrug of ganciclovir i.e. Valganciclovir and its physiologically acceptable salts thereof having advantageous bioavailability when administered by an oral route. However, this patent does not teach about the process for the preparation of Valganciclovir.
U.S Patent Nos. 5,700,936 describes process for the preparation of Valganciclovir, wherein ganciclovir is reacted with N-Boc-VaVme-NCA (N-Boc-Valine-N-carboxy

anhydride) to give protected ganciclovir and this intermediate ((N-Z-Valine)-ganciclovir) is subjected to hydrogenation in presence of palladium hydroxide on carbon under hydrogen pressure to give mono L-valyl ester of ganciclovir, i.e. Valganciclovir, which is crystalline.
WO 97/27194 describes process for the preparation of Valganciclovir, wherein silylated ganciclovir is reacted with Z-Valine NCA (Z-valine N-carboxy anhydride). This process takes 3-4 days to complete at room temperature.
US 2007/0129385 Al discloses the process for the preparation of amorphous Valganciclovir hydrochloride by using spray drying technique. This application also discloses the conversion of crystalline to amorphous Valganciclovir hydrochloride. This application also discloses process for the preparation of amorphous Valganciclovir hydrochloride form a mixture of crystalline and amorphous Valganciclovir by using spray drying or vacuum distillation techniques.
According to prior art process, amorphous Valganciclovir hydrochloride is prepared by using spry drying and vacuum drying techniques, which does not give consistent amorphous product it contains other crystalline peaks.
U.S. Patent No. 6,083,953 claims crystalline Valganciclovir hydrochloride as a product and discloses a process for preparing crystalline Valganciclovir hydrochloride, where as Valganciclovir hydrochloride is dissolved in water and the resulting solution is treated with isopropyi alcohol to give crystalline Valganciclovir hydrochloride.
Amorphous Valganciclovir hydrochloride is prepared as per the prior art process contaminated with crystalline Valganciclovir hydrochloride Therefore, there is a need to develop a process for preparation of amorphous Valganciclovir hydrochloride with out contamination of other polymorphic form. According to our polymorphic study in different solvents and different parameters, we found out the efficient process for the preparation of amorphous Valganciclovir hydrochloride.

OBJECT OF THE INVENTION
The main object of the present invention is to provide novel process for the preparation of amorphous Valganciclovir hydrochloride and its pharmaceutically acceptable salts
thereof.
Yet another object of the present invention is to provide the process for preparation of crystalline Valganciclovir hydrochloride from amorphous Valganciclovir hydrochloride.
Yet another object of the present invention is to provide novel process for the purification of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)-methoxy-3 -hydroxy-1 -propyl-N(benzyloxy-carbonyl)-L-valinate i.e., monoprotected Valganciclovir intermediate.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide novel process for the preparation of amorphous Valganciclovir hydrochloride, wherein the amorphous form is isolated from the solvent and avoided the spray drying techniques.
Another object of the present invention is to provide process for the preparation of crystalline Valganciclovir hydrochloride form from amorphous Valganciclovir hydrochloride, whereas amorphous Valganciclovir hydrochloride is exposed to the humidity to get crystalline Valganciclovir hydrochloride.
Another object of the present invention is to provide novel process for the purification of 2-{2-amino-l,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propyl-N-(benzyloxy-carbonyl)-L-va!inate i.e. protected Valganciclovir, which is purified in a solvent or mixture of solvents to give pure intermediate.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an X-ray powder diffraction (XRD) pattern of amorphous form of
Valganciclovir hydrochloride.
Fig. 2 is an X-ray powder diffraction (XRD) pattern of pure mono-protected
Valganciclovir intermediate
Fig. 3 is an X-ray powder diffraction (XRD) pattern of crystalline Valganciclovir
Hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates process for the preparation of 2-(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propyl-L-valinate (Valganciclovir). Ganciclovir is reacted with halosilane to give a silylated ganciclovir intermediate, which is further reacted with Z-valine NCA to give protected Valganciclovir hydrochloride. It is subjected to hydrogenation reaction under hydrogen pressure in alcoholic solvent followed by work up-to give amorphous Valganciclovir hydrochloride.
Process for the preparation of amorphous Valganciclovir, which comprising the steps of:
a) converting ganciclovir to N-benzyloxycarbonyl-L-valinate ester of ganciclovir
b) deprotection of N-benzyloxycarbonyl-L-valinate ester of ganciclovir by hydrogenation
c) isolating Valganciclovir hydrochloride
d) dissolving Valganciclovir hydrochloride in polar solvent
e) adjusting pH of step (d) with acid 0-4 ,and isolating
f) removing solvent under reduced pressure ,
g) adding another solvent,
h) isolating Valganciclovir hydrochloride under anhydrous conditions
i) drying at 50 -110°C under reduced pressure in anhydrous conditions
j) isolating amorphous Valganciclovir hydrochloride under anhydrous conditions
and k) storing amorphous Valganciclovir hydrochloride under anhydrous conditions

According to the present invention, Valganciclovir hydrochloride is dissolved in a solvent is selected from methanol, ethanol, N,N-dimethylformamide & dimethyl sulphoxide mixtures thereof; the preferred solvent is methanol, resulting solution pH is adjusted to 0 to 4.0 and preferred pH is between 1.0 to 2.5. The acid is selected from hydrochloric acid, acidic resulting solution is distilled off completely under reduced pressure under anhydrous conditions, then added another solvent is selected from hydrocarbons such as hexane, heptane, pentane, cyclohexane, t-buty] methyl ether, toluene other solvents such as acetone, ethyl acetate, isopropyl alcohol, methylene chloride, chloroform , acetronitrile etc or mixtures thereof; the preferred another solvent is , heptanes, isopropyl alcohol cyclohexane or ethyl acetate or mixtures thereof
The separated solid is filtered and washed the compound with solvent under anhydrous condition to give Valganciclovir hydrochloride; it is subjected to drying temperature between 50 to 110° C and under reduced pressure. The preferred drying temperature is between 70 to 90°C. The drying is also carried out under anhydrous condition and the obtained solid is stored under anhydrous condition.
According to our invention, obtained Valganciclovir hydrochloride does not contain the crystalline peaks.
Another embodiment of the present invention is process for the preparation of amorphous Valganciclovir which comprising the steps of:
a) dissolving Valganciclovir hydrochloride in polar solvent,
b) optionally adjusting pH 0 to 4,
c) adding an anti solvent and
d) isolating Valganciclovir hydrochloride.
According to present invention, Valganciclovir hydrochloride is dissolved in a polar solvent is selected from, methanol, ethanol, n-propanol, isopropanol, n-butanol, where as N, N-dimethylformamide, acetronitrile, dimethyl sulphoxide or mixtures thereof;

According to our present invention, Valganciclovir hydrochloride is dissolved in polar solvent to get clear solution, resulting solution pH is adjusted to between 0 to 4 by using hydrochloric acid or water then anti solvent is added to the clear solution. The anti solvent is selected from lower alkanols, nitriles, ethers, esters, hydrocarbons, amides, ketones and chlorinated solvents. Lower alkanol is preferably selected from ethanol, isopropyl alcohol etc. Nitrile is preferably selected from acetonitrile. Ether is mainly selected from tetrahydrofuran. Ester is mainly selected from methyl acetate, ethyl acetate. Hydrocarbons are selected from cyclopentane, cyclohexane, Amides are preferably selected from N,N-dimethyl formamide, N,N-dimethyl acetamide etc. Ketone is preferably selected from acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Chlorinated solvent is preferably methylene chloride.
According to our present invention, Valganciclovir hydrochloride is dissolved in polar solvent to get clear solution, and then anti solvent is added to the clear solution. The anti solvent is added slowly at -10 to 50°C over a period of 5 minutes to 24 hrs. The separated solid is filtered, dried under anhydrous condition at temperature between 50 to 110° C and under reduced pressure. The preferred drying temperature is between 70 to 90°C. The drying is also carried out under anhydrous condition and the obtained solid is stored under anhydrous condition.
In yet another embodiment of the present invention provides process for preparation of crystalline Valganciclovir hydrochloride form amorphous Valganciclovir hydrochloride.
The crystalline Valganciclovir hydrochloride can be prepared from amorphous Valganciclovir hydrochloride. For example, the amorphous form is exposed to more than 75% humidity by any of conventional techniques.
Another embodiment of the present invention is to provided process for purification of protected Valganciclovir hydrochloride comprises
a) treating protected Valganciclovir chloride in one or two solvents,
b) heating to higher temperature.

c) cooling ana
d) isolating the pure protected Valganciclovir hydrochloride.
According to our present invention a improved process for preparation of 2-(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propyl-N(benzyloxy-carbonyI)-L valinate (protected Valganciclovir hydrochloride) is carried out by reacting silylated ganciclovir with Z-Valine NCA (Z-valine N-carboxy anhydride) presence of base in suitable solvent at 40 to 120°C, preferably this reaction is carried out in N,N-dimethyl acetamide at 40 to 80°C for about 6 hrs to provide high yield, purity & chiral selectivity.
The protected Valganciclovir hydrochloride is treated with a solvent. The solvent group is selected from amides, ethers, ketones, lower alkanols and nitriles. Amide is preferably selected from N,N-dimethyl formamide, N,N-dimethyl acetamide etc. ether is preferably from tetrahydrofuran. Ketone is preferably selected from acetone, methyl ethyl ketone, methyl isobutyl ketone etc. Lower alkanol is preferably selected from methanol, ethanol, isopropyl alcohol etc. Nitrile is preferably selected from acetonitrile or mixtures thereof;
The protected Valganciclovir hydrochloride is dissolved in water & a solvent selected from N, N-dimethyl formamide, N, N-dimethyl acetamide preferably N,N'-dimethyl formamide to get clear solution at temperature between 60 to 100°C. The resulting solution is cooled to lower temperature 0 to 10°C. The separated solid is filtered and washed with solvent to give pure protected Valganciclovir hydrochloride.
According to the present invention, the above obtained intermediate is having the good purity as compared to the prior art. This intermediate is directly is used for deprotection reaction to give pharmaceutically acceptable grade, with out performing another ptirification steps with improved yield.

Example 1
Preparation of 2-(2-ainmo-l,6-diliydro-6-oxo-purin-9-yI)-methoxy-3-hydroxy-l-propyl-N-(benzyloxycarbonyl)-L-valinate (protected Valganciclovir)
To a suspension of 2-{2-amino-l,6-dihydro-6-oxo-purin-9-yl)-methoxy-l,3-propanediol (ganciclovir,lOOg) in N,N-dimethyl formamide (300ml) at -5 to 5°C under the nitrogen atmosphere trimethylsilyl chloride (52g) was added. After complete addition, the reaction mixture was stirred for 3 hrs at -5 to 5°C. To this solution, imdiazole (40g) was added at -10 to 15°C under nitrogen atmosphere and stirred for approximately 30 min to an hour at -10 to 15°C. After stirring for 30 min to an hour, Z-vaUne NCA (lOOg) was added at -5 to 10°C and temperature was raised to 20 to 30°C and then 40 to 80°C, this reaction mixture was maintained at 40 to 80°C for reaction is complete . The reaction mixture was cooled to 25 to 35C and methylene chloride (lOOOml) was slowly added followed by dilute HCl (700ml) at such a rate that the internal reaction temperature must be below 30°C. The reaction mixture was stirred for 30 min at 25 to 35°C. The stirring was stopped and the layers were allowed to separate. The organic layer was stored. The aqueous layer was washed with 300m] methylene chloride and cooled to 5 to 10°C. The above methylene chloride layer was stored. The aqueous layer was made basic at pH 1 to 2 with 20% ammonia solution at 5 to 25°C, After pH adjustment, the aqueous layer was cooled to 5 to 10°C and stirred for an hour. After an hour, the precipitate was filtered and washed with water (500ml) and then solid suck dried. Above stored organic layers was combined and extracted twice with aq methanolic HCl (1700mt) and once with aq methanolic HCl (600ml). Above extracted aqueous and aq methanolic HCl layers was combined and collected solid was added. This solution was stirred till it became clear. After getting clear solution, it was extracted with aq methanolic HCl thrice and then the both layers were separated.
The aqueous and aq methanolic HCl layers was combined and cooled to 5 to 10°C. This combined layer was made basic at pH 5 to 6 by using ammonia solution. The resulting solution was stirred for an hour at 20 to 25°C and filtered. The precipitate was washed with (500ml) water and dried at 50 to 60°C. The solid product, 2-(2-amino-l,6-dihydro-

6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propyl-N-{benzyloxycarbonyl)-L-valinate (protected Valganciclovir) with dry weight 80 gm. Purity & chiral purity above 99%.
Example 2
Purification of protected Valganciclovir
The above dry product was charged in acetone (200ml) followed by water (200ml) and the reaction mixture was heated to reflux for half an hour. After reflux, the reaction mixture was cooled to room temperature and further it was cooled to 10 to 15°C. The precipitate was filtered and washed with acetone: water (1:1, 200 ml).The product was dried at 55°C till constant weight. Dry wt = 95g . Purity above 99%.
Example 3
Preparation of amorphous 2-(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-1-propyl-L-valinate hydrochloride (Valganciclovir hydrochloride)
To a mixture 2-(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-raethoxy-3-hydroxy-l-propyl-N-(benzyloxycarbonyl)-L-valinate (lOOg) in methanol (1300ml) water (450ml) and concentrated HCl (30ml) and palladium on carbon (5gm) followed by was treated with H2 gas for 3 to 12 hrs at 20 to 40°C till the completion of reaction. When the reaction was completed the reaction mixture was filtered through hyflow bed and washed with methanol (200ml). The filtrate was concentrated under vacuum till dryness. Water (200ml) was added and the aqueous layer was washed with ethyl acetate (200ml) twice and isopropyl alcohol (1400ml) was added in the 2 -3 hrs and the reaction mixture was stirred for 4-12 hrs at 25 to 35°C. The product was collected by filtration, washed with mixture of chilled isopropyl alcohol and water (200ml) and finally with chilled isopropyl alcohol (200ml).
The entire mass was dissolved in methanol (2000ml). The filtrate containing the product was acidified at pH 0 to 4 by dilute HCl. The organic solvent was removed fi-om the mass under reduced pressure below 50°C. To the product, ethyl acetate & cyclohexane (3 x

200ml) was added and the traces of solvent were removed by reduced pressure below 50°C. The above concentrated product was suspended in ethyl acetate & cyclohexane (1:1; 1800ml) and stirred for 1 to 2 hrs. The product was filtered and washed with ethyl acetate & cyclohexane (1:1; 200ml).
The solid product was placed in a vacuum oven and dried and stored under anhydrous conditions to get 55gm of amorphous 2-(2-amino-l,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propyl-L-valinate hydrochloride(Valganciclovir).
Example 4
Preparation of pure Valganciclovir hydrochloride by addition of anti solvent
Valganciclovir hydrochloride (lOOg) was dissolved in methanol (700ml). This solution was stirred at room temperature for 10 min and pH is adjusted to 0-4 by adding hydrochloric acid. To the above solution, isopropyl alcohol (3400ml) was added in slow manner and it was stirred for overnight till to get product. After getting product, it was filtered and washed with isopropyl alcohol (200ml). The product was dried under vacuum and stored under anhydrous conditions to get 75gm of amorphous Valganciclovir.
Example 5
Process for preparation of Crystalline Valganciclovir hydrochloride from amorphous Valganciclovir hydrochloride
Amorphous Valganciclovir hydrochloride (5g) was taken in a Petri dish. This Petri dish was placed in desiccator or chamber having saturated solution of potassium nitrate having humidity above 90%. The sample was kept for 24 hrs. The material was recovered from desiccator. Yield: 4.8 g to give crystalline Valganciclovir hydrochloride.

We Claim;
1. Process for the preparation of amorphous Valganciclovir hydrochloride which comprising the steps of:
a) converting ganciclovir to N-benzyloxycarbonyl-L-vaiinate ester of ganciclovir,
b) deprotection of N-benzyloxycarbonyi-L-valinate ester of ganciclovir by hydrogenation,
c) isolating Valganciclovir hydrochloride,
d) dissolving Valganciclovir hydrochloride in polar solvent
e) adjusting pH of step (d) with acid between 0-4,
f) removing solvent,
g) adding another solvent and
h) isolating and drying to give Valganciclovir hydrochloride under anhydrous conditions.
2. A process according to claim 1, wherein polar organic solvent is selected from methanol, ethanol, N,N-dimethyl formamide, dimethylsulphoxide or mixtures thereof;
3. A process according to claim 1, wherein acid is seleaed from hydrochloric acid.
4. A process according to claim 1, wherein removing the solvent is carried out under reduced pressure.
5. A process according to claim 1, wherein another solvent is selected from hexane, heptane, pentane, cyclohexane, t-butyl methyl ether, toluene acetone, ethyl acetate, isopropyl alcohol, methylene chloride, chloroform , acetronitrile or mixtures thereof;
6. A process according to claiml, wherein drying is carried temperature between 50-110° C.

7. A process according to claim 6, wherein the preferred drying is carried temperature between 70-90''C and under reduced pressure.
8. Process for the preparation of amorphous Valganciclovir hydrochloride which comprising the steps of:

a) dissolving Valganciclovir hydrochloride in polar solvent,
b) adjusting pH of step (a) with acid between 0-4,
c) removing solvent,
d) adding another solvent and
e) isolating and drying to give amorphous Valganciclovir hydrochloride under anhydrous conditions.

9. A process according to claim 8, wherein polar organic solvent is selected from methanol, ethanol, N,N-dimethyl formamide, dimethylsulphoxide or mixtures thereof;
10. A process according to claim 8, wherein acid is selected from hydrochloric acid.
11. A process according to claim 8, wherein removing the solvent is carried out under reduced pressure.
12. A process according to claim 8, wherein another solvent is selected from hexane, heptane, pentane, cyclohexane, t-butyl methyl ether, toluene acetone, ethyl acetate, isopropyl alcohol, methylene chloride, chloroform , acetonitrile, acetone
or mixtures thereof;
13. A process according to claim 8, wherein drying is carried temperature between 50-110° C under anhydrous conditions,
14. A process according to claim 13, wherein the preferred drying temperature is between 70-90° and under reduced pressure.

15. A process for the preparation of crystalline Valganciclovir hydrochloride wherein
amorphous Valganciclovir hydrochloride is exposed to humidity to give
crystalline Valganciclovir hydrochloride.
16. A improved process for preparation of 2-{2-amino-1,6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-l-propyl-N(benzyloxy- carbonyl)-L-valinate (protected Valganciclovir hydrochloride) by reacting silylated ganciclovir with Z-Valine NCA (Z-valine N-carboxy anhydride) in suitable solvent at 40 -100°C
17. A process for purifying the protected Valganciclovir hydrochloride where as Valganciclovir hydrochloride is crystallized from a solvent, water or mixtures thereof;
18. A process according claim 16, wherein solvent is selected from acetone, ethyl acetate, methanol, ethanol isopropyl alcohol, methylene chloride, chloroform , acetronitrile dimethyl formamide, dimethyl acetamide etc or mixtures thereof;