FIELD OF INVENTION

The present invention relates to an improved process for the preparation of pure 2- [(2-acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-l -benzyloxy-3- chloropropane (N-acetyl chlorobenzyl ganciclovir) of formula (III), and

2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-y])methoxy]-3-benzyloxypropan-l-o] (monobenzyl Ganciclovir) of formula (XIII).

The compounds of formulae (III) & (XIII) are key intermediates in the preparation of Valganciclovir hydrochloride of formula I and Ganciclovir of formula II.

The present invention relates to an invention disclosed in our co-pending application IN 2681/CHE/2009, wherein present invention is an improvement for the preparation of 2-[(2-amino-1,6-dihydro-6-oxo-9h-purin-9-yl)methoxy]-3- benzyloxypropan-l-ol (monobenzyl Ganciclovir) of formula (XIII).

BACKGROUND OF THE INVENTION

9-(2-Hydroxy-l-hydroxymethyl)ethoxy]methyl]guanine is genetically known as Ganciclovir (II)].

Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine, which inhibits replication of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV) and herpes simplex virus (HSV) in human. Ganciclovir is marketed under the name Cytovene®. It has been indicated for the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS) and also indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease.

Ganciclovir has a relatively low rate of absorption when administered orally and must be used at high dosages when administered by that route

L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester monohydrochloride is generically known as Valganciclovir (I).

Valganciclovir (la) is a mono-L-valyl ester (prodrug) of the antiviral compound Ganciclovir (II), which exists as a mixture of two diastereomers. After the oral administration, both diastereomers are rapidly converted to Ganciclovir (II) by intestinal and hepatic esterases.

Valganciclovir hydrochloride (I) is marketed in the US under the name Valcyte®. It has been approved for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) and also indicated for the prevention of cytomegalovirus (CMV) disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [(D+/R-)]) .
Roche disclosed Ganciclovir (II) in US 4,355,032. US '032 also discloses a process for the preparation of Ganciclovir by reacting Guanine (IV) with acetic anhydride and recrystallized from DMSO to produce 9-acetyl-2-acetylamino-l,9-dihydro-6H- purin-6-one (IVa), which is farther condensed with 2-0-acetoxymethyl-l,3-di-0- benzylglycerol (V) in presence of bis(p-nitrophenyl)phosphate to produce a compound of formula (VI). Compound (VI) is hydrogenated by palladium hydroxide on carbon in presence of methanol and recrystallized from methanol/ethyl acetate to produce compound (VII), which is further treated with methanolic ammonia and recrystallized from methanol to produce Ganciclovir (II). The process is shown in Scheme I.

The above process involves the use of expensive bis(p-nitrophenyl)phosphate. Hence, the above process is not suitable for commercial scale synthesis of 2-[(2- acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -benzyloxy-3- chloropropane (N-acetyl chloro benzyl ganciclovir) (III).

Various mono and diacyl esters of Ganciclovir are disclosed in J. Pharm. Sci. 1987, 76 (2), 180-184. The preparation of these esters is also mentioned in this article. However, L-valyl ester of Ganciclovir and its process of preparation is not discussed in this article. The process is shown in Scheme II.

wherein, R represents methyl, ethyl, propyl, butyl, t-butyl, n-pentyl, CH3OCH2-, CH3-(CH2)14.

SCHEME-II

EP 0 375 329 B1 generically discloses ester prodrugs of Ganciclovir including Valganciclovir. However, EP '329 does not disclose the utility as well as process for the preparation of Valganciclovir.

Roche specifically disclosed crystalline Valganciclovir hydrochloride (I) in US 6,083,953. US '953 also discloses a process for the preparation of Valganciclovir hydrochloride (I), by reacting benzyloxymethyloxirane (VIII) with paraformaldehyde in dichloromethane to provide chloromethyl ether intermediate (IX) followed by reaction with potassium acetate in acetone to produce (l-chloro-2- acetoxymethoxy-3-benzyloxy)propane (X). Compound (X) is further reacted with persilylated guanine to produce chloro benzyl ganciclovir (XI) along with its N-7 isomer, which is further reacted with potassium acetate and DMF to produce monoacetyl monobenzyl ganciclovir (XII), which is treated with ammonia in methanol to produce monobenzyl ganciclovir (XIII). Compound (XIII) is then reacted with N-(benzyloxycarbonyl)-L-valine to produce compound (XIV), which is further converted to Valganciclovir hydrochloride (I) by reacting with Pd/C and crystallized from isopropanol. The process is shown in scheme-Ill.

The major disadvantage with the above process is that persilylation of guanine and its subsequent reaction with (l-chloro-2-acetoxymethoxy-3-benzyloxy)propane (X) to produce chloro benzyl ganciclovir (XI) involves longer reaction time and low yield due to the formation of undesired impurities, which requires chromatographic purification. Further, the above process involves the use of expensive trimethylsilyl trifluoromethane sulfonate, which is not suitable for the commercial production of chloro benzyl ganciclovir (XI).

US 5,756,736 discloses a process for the preparation of Valganciclovir, by reacting Ganciclovir (II) with a trityl halide to produce a compound (XV) with trityl protection at one of the aliphatic hydroxyl groups and at the 2-amino moiety of the guanine group of Ganciclovir, which is further reacted with L-valine derivative, to produce an N,O-bistrityl-monovaline ester of Ganciclovir (XVI), followed by the removal of the protecting groups to produce Valganciclovir hydrochloride (I). The process is shown in scheme IV.

Wherein, X is bromo or chloro, P3 is an amino-protecting group and A is a carboxy- activating group.

SCHEME-IV

Further, US 6,040,446 discloses an alternative process for the preparation of Valganciclovir, which involves the condensation of a silylated guanine compound (IVb) with a substituted glycerol derivative (XVII) to produce mono-hydroxy protected Ganciclovir (XVIII), which is further reacted with L-valine derivative followed by the removal of protecting groups to produce Valganciclovir hydrochloride (I). The process is shown in scheme V.

Wherein, Z1, Z2, and Z3 are independently silyl group; Y1 and Y2 are aralkyloxy, or one of Y1 and Y2 is halo or acyloxy, Z is a leaving group selected from acyloxy, benzoyloxy, halo, mesyloxy or tosyloxy.

SCHEME-V

Hence, there is a need to develop a process, which provides 2-[(2-acetylamino-l,6- dihydro-6-oxo-9H-purin-9-y l)methoxy] -1 -benzyloxy-3 -chloropropane (N-acetyl chloro benzyl ganciclovir) of Formula (III), monobenzyl Ganciclovir of Formula (XIII) using commercially available, less expensive reagents and easy to handle at industrial scale
.
The present invention is specifically directed towards a purification process, which reduces the unwanted regio- isomer (N-7 isomer of N-acetyl chloro benzyl ganciclovir (IIIa) and an undesired homologue of N-acetyl chloro benzyl ganciclovir (XXI) to a pharmaceutically acceptable limit, which in turn used as such in the preparation of Valganciclovir.

The present invention is also directed towards a purification of monobenzyl ganciclovir (XIII), which reduces the impurities to obtain pure monobenzyl ganciclovir (XIII).

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and effective process for the preparation of 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9- yl)methoxy]-3-benzyloxypropan-l-ol (monobenzyl Ganciclovir) of formula (XIII) and its use in the preparation of Valganciclovir hydrochloride (I).

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of 2-[(2- amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-benzyloxypropan-1 -ol (monobenzyl Ganciclovir) of formula (XIII),

which comprises:

(i) condensing 9-acetyl-2-acetylamino-l,9-dihydro-6H-purin-6-one of formula (IV a),

with (2RS)-(l-chloro-2-acetyloxymethoxy-3-benzyloxy)propane of formula (X),

in the presence of an acid catalyst in a solvent to produce a mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa),

(ii)
treating the mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) with a solvent or/and a solvent mixture or/and treating with acid to produce pure N-acetyl chloro benzyl ganciclovir of formula (III) or its acid addition salt;

(iii) reacting compound of formula (III) or its acid addition salt with an alkali acetate in the presence of an acid in a solvent to produce a mixture of 2-[(2-acetylamino-l,6-dihydro-6-oxo-9H-purin-9- yl)methoxy]-l-acetyloxy-3-benzyloxypropane (diacetyl monobenzyl ganciclovir) (XXII) and 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9- yl)methoxy]-1 -acetyloxy-3-benzyloxypropane (monoacetyl monobenzyl ganciclovir) (XII);

(iv) treating the mixture of diacetyl monbenzyl ganciclovir (XXII) and monoacetyl monobenzyl ganciclovir (XII) with a base in the presence of a solvent to produce crude monobenzyl Ganciclovir (XIII);

(v) treating the crude monobenzyl Ganciclovir with an acid to obtain an acid addition salt of monobenzyl Ganciclovir;

(vi) treating the acid addition salt of monobenzyl Ganciclovir with a base in the presence of a solvent to produce an alkali salt of monobenzyl Ganciclovir;

(vii) neutralization of the alkali salt of monobenzyl Ganciclovir with an acid to produce pure monobenzyl Ganciclovir (XIII).

In another embodiment, the present invention also relates to the use of above 2-[(2- acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] -1-benzyl oxy-3- chloropropane (N-acetyl chloro benzyl ganciclovir) of Formula (III) and 2-[(2- amino-l,6-dihydro-6-oxo-9h-purin-9-yl)methoxy]-3-benzyloxypropan-l-ol (monobenzyl Ganciclovir) of formula (XIII) to produce Valganciclovir hydrochloride (I).
In another embodiment, the present invention also relates to the use of above 2-[(2- acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -benzyloxy-3- chloropropane (N-acetyl chloro benzyl ganciclovir) of Formula (III) and 2-[(2- amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-benzyloxypropan-l-ol (monobenzyl Ganciclovir) of formula (XIII) to produce Ganciclovir (II).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of 2-[(2- acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -benzyloxy-3- chloropropane (N-acetyl chloro benzyl ganciclovir) of Formula (III).
9-Acetyl-2-acetylamino-l,9-dihydro-6H-purin-6-one of formula (IVa) is condensed with (2RS)-(l-chloro-2-acetyloxymethoxy-3-benzyloxy)propane of formula (X) in presence of an acid catalyst in a suitable organic solvent to produce a mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa).
The suitable organic solvents for the above reaction include but are not limited to N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane. The acid catalyst is selected from p-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid.
The reaction may be performed at a temperature ranging from about 50°C to about 150°C. More preferably the reaction is carried out at a temperature of about 100°C to 120°C. The reaction time is about 1 to about 10 hours, more preferably about 2 to about 4 hours. After completion of the reaction, the reaction mass is cooled to 10°C to about 30°C and aqueous solution of sodium chloride followed by solvent is added to extract the mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) from the reaction mass. Aqueous layer is extracted further with organic solvent and the combined organic layer containing mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) is treated with carbon and solvent is removed either by distillation or under reduced pressure.
The solvent used for extraction is selected from ethyl acetate, methylene chloride, chloroform.
According to one embodiment, the residue containing a mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) is treated with solvent at a temperature of about 30 to about 100°C, more preferably at 40-60°C for about 0.5 hrs to 3 hrs, which is further cooled to 10°C to about 30°C. The precipitated product is filtered, followed by washing with a solvent and dried the product to produce crude N-acetyl chloro benzyl ganciclovir (III).
The solvent used in the above isolation is selected from toluene, isopropyl alcohol or mixtures there of.
Crude N-acetyl chloro benzyl ganciclovir (III) is slurried from a solvent mixture, which is selected from toluene/ethanol, toluene/isopropyl alcohol to produce pure N- acetyl chloro benzyl ganciclovir (III). The slurry is performed at a temperature of 30°C to about 100°C, more preferably 40 to 60°C. Pure N-acetyl chloro benzyl ganciclovir (III) is isolated by techniques well known in the art, such as filtration, and optionally dried.
It has been observed that N-acetyl chloro benzyl ganciclovir (III) isolated by the above process having N-7-isomer of N-acetyl chloro benzyl ganciclovir (IIIa) less than 0.5% and homologue of N-acetyl chloro benzyl ganciclovir less than 4%.
According to another embodiment, the residue containing a mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) is treated with a solvent mixture selected from toluene/isopropanol, toluene/butanol, at a temperature of about 30°C to about 100°C, more preferably 40 to 60°C followed by cooling to a temperature of about 10°C to about 30° for about 5 to about 20 hrs, more preferably 14 to 16 hrs. The product obtained is filtered and dried to produce crude N-acetyl chloro benzyl ganciclovir (III).
Crude N-acetyl chloro benzyl ganciclovir (III) is treated with an acid in a solvent to produce acid addition salt of N-acetyl chloro benzyl ganciclovir (III). The salt formation is performed at a temperature of about 30°C to about 100°C, more preferably 40 to 60°C followed by cooling to a temperature of about 10°C to about 30° for about 1 to about 8 hrs, more preferably 2 to 3 hrs.
The acid used to prepare acid addition salt is selected from hydrochloric acid,' hydrobromic acid. The solvent used in the salt formation is selected from methanol, ethanol, isopropanol, toluene, 1-butanol, acetone, ethyl acetate or mixtures there of.
It has been observed that N-acetyl chloro benzyl ganciclovir (III) isolated by the above process having N-7-isomer of N-acetyl chloro benzyl ganciclovir (IIIa) less than 0.1% and homologue of N-acetyl chloro benzyl ganciclovir less than 0.8%.
According to an another embodiment, the residue containing a mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) is treated with an acid in a solvent to produce acid addition salt of N-acetyl chloro benzyl ganciclovir (III). The salt formation is performed at a temperature of about 30°C to about 100°C,
more preferably at about 40 to 60°C, followed by cooling to a temperature of about 10°C to about 30° for about 1 to about 8 hrs, more preferably 2 to 3 hrs.
The acid used to prepare acid addition salt is selected from hydrochloric acid, hydrobromic acid. The solvent used in the salt formation is selected from methanol, ethanol, isopropanol, toluene, 1-butanol, acetone, ethyl acetate or mixtures there of.
The product obtained is further purified in a solvent mixture to produce pure acid addition salt of N-acetyl chloro benzyl ganciclovir (III).
It has been observed that N-acetyl chloro benzyl ganciclovir (III) isolated by the above process having N-7-isomer of N-acetyl chloro benzyl ganciclovir (IIIa) less than 0.1% and homologue of N-acetyl chloro benzyl ganciclovir less than 0.5%.
According to an another embodiment, 2-[(2-acetylamino-l,6-dihydro-6-oxo-9H- purin-9-yl)methoxy]-3-benzyloxy-l-chloropropane or its acid addition salt (N-acetyl chloro benzyl ganciclovir) of formula (III) is reacted with an alkali acetate in the presence of an acid in a suitable organic solvent to produce a mixture of 2-[(2- acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -acetyloxy-3- benzyloxypropane (diacetyl monobenzyl ganciclovir) (XXII) and 2-[(2-amino-l,6- dihydro-6-oxo-9H-purin-9-yl)methoxy]-l-acetyloxy-3-benzyloxypropane (monoacetyl monobenzyl ganciclovir) (XII).
The alkali acetate used in the above reaction is selected from sodium acetate, potassium acetate. The acid used in the above reaction is selected from acetic acid, formic aid, methane sulfonic acid or mixtures there of.
The suitable organic solvents for the above reaction include but are not limited to N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane or mixtures there of.
The reaction may be performed at a temperature ranging from about 95°C to about 120°C. More preferably the reaction is carried out at a temperature of about 100°C to 115°C. After completion of the reaction, the reaction mass is cooled to 20°C to about 30°C, filtered and the filtrate is concentrated at about 50-100°C, more preferably at 60-82°C under reduced pressure.

The residue containing a mixture of diacetyl monobenzyl ganciclovir) (XXII) and monoacetyl monobenzyl ganciclovir (XII) is treated with a base in the presence of a solvent to produce crude monobenzyl Ganciclovir (XIII);

The base used in the above reaction is selected from aqueous ammonia, aqueous ammonium hydroxide and potassium hydroxide, preferably aqueous ammonia. The solvent used in the above reaction is selected from methanol, ethanol, isopropanol or mixtures there of, preferably methanol.

The reaction mass is concentrated at a temperature of about 35-60°C, preferably 40- 55° under reduced pressure. The concentrated mass is diluted with water, stirred and dried under reduced pressure to obtain crude monobenzyl ganciclovir (XIII).
Crude monobenzyl ganciclovir (XIII) is treated with an acid in a solvent to produce an acid addition salt of monobenzyl Ganciclovir. The suitable solvents include but are not limited to alcohol selected from methanol, ethanol, isopropanol or mixtures there of. The acid used to prepare acid addition salt is selected from hydrochloric acid, hydrobromic acid. The reaction mass is heated to a temperature about 30- 55°C, more preferably at about 40°C and the resulting solution is crystallized by addition of a solvent selected from ethyl acetate to produce an acid addition salt of monobenzyl Ganciclovir.

The acid addition salt of monobenzyl Ganciclovir (XIII) is treated with a base in the presence of solvent to produce an alkali salt of monobenzyl Ganciclovir (XIII).
The base used in the above reaction is selected from sodium hydroxide, potassium hydroxide, The solvent used in the above reaction is selected from ethanol, methanol, isopropanol and /or water. The salt formation is carried out at a temperature about 40-85°C, more preferably 70-75°C.

Neutralization of the alkali salt of monobenzyl ganciclovir is carried out using an aqueous acid to produce a pure monobenzyl Ganciclovir (XIII). The product is filtered, washed with water and dried at a temperature about 45-65°C, more preferably at about 50-55°C under reduced pressure.
The acid used in the above reaction is selected from hydrochloric acid, hydrobromic acid.

In another embodiment, the present invention also relates to the use of pure N-acetyl chloro benzyl ganciclovir (III) or its acid addition salt thereof and pure monobenzyl Ganciclovir (XIII) or its acid addition salt thereof to produce Valganciclovir hydrochloride (I) by the process reported in US 6,083,953.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention
.
Examples: Example -1
Preparation of 2-[2-acetyIamino-l,6-dihydro-6-oxo-9H-purin-9-yl)-methoxy]-l- benzyloxy-3-chloropropane (N-acetyl chloro benzyl Ganciclovir)
A mixture of N,N-dimethylformamide (1500ml), 9-acetyl-2-acetylamino-l,9- dihydro-6H-purin-6-one (300 g) and (2RS)-(l-chloro-2-acetyloxymethoxy-3- benzyloxy)propane (695.70 g) were added to p-toluenesulfonic acid monohydrate (15 g) and heated for 3 hr at 110-115°C. The ratio of N-9 to N-7 isomers of N-acetyl chloro benzyl ganciclovir at this stage was about 2.5:1. Reaction mass was cooled to 25° C, then 8% w/w aqueous sodium chloride solution (2100 ml) and ethyl acetate (2100 ml) were added. The mass was stirred for 20 min and the organic layer was separated. Aqueous layer was extracted with ethyl acetate (1000 ml) and the combined organic layer was washed with water (1500 ml), and then treated with carbon (30 g) at 25-27° C for 30 min. Carbon was removed by filtration and the residue was washed with ethyl acetate (300 ml). The filtrate was concentrated at 40- 50°C under reduced pressure to remove ethylacetate completely. Toluene (1200 ml) was added to the residue and stirred at 27-29°C for 16 hr. Crude N-acetyl chloro benzyl ganciclovir was filtered, washed with toluene (300 ml) and dried at 50-55°C under reduced pressure.
(Content of 7-isomer of N-acetyl chloro benzyl ganciclovir: 4.21% Homologue of N-acetyl chloro benzyl ganciclovir: 5.07%)

Crude N-acetyl chloro benzyl ganciclovir was stirred in a mixture of toluene (405 ml) and ethanol (45 ml) at 50-55°C for 1 hr, then cooled to 27°C and stirred at 27- 28° C for 2 hr. The product was filtered and washed with a mixture of toluene (135 ml) and ethanol (15 ml). The wet product was dried at 50-55°C under reduced pressure to obtain 135.20 gm of N-acetyl chloro benzyl ganciclovir. (Content of 7-isomer of chloro benzyl ganciclovir: 0.26% Homologue of N-acetyl chloro benzyl ganciclovir: 3.94%)

Example – 2

Preparation of 2-[2-acetyIamino-l,6-dihydro-6-oxo-9H-purin-9-yl)-methoxyl-l- benzyloxy-3-chloropropane hydrochloride (N-Acetyl chloro benzyl ganciclovir hydrochloride)
A mixture of N,N-dimethylformamide (800 ml), 9-acetyl-2-acetylamino-l,9- dihydro-6H-purin-6-one (200 g) and (2RS)-(l-chloro-2-acetyloxymethoxy-3- benzyloxy)propane (463.80 g) were added to p-toluenesulfonic acid monohydrate (10 g) and heated for 3 hr at 110-115° C. The ratio of N-9 to N-7 isomers of N-acetyl chloro benzyl ganciclovir at this stage was about 2.5:1. Reaction mass was cooled to 28° C, then 8% w/w aqueous sodium chloride solution (1400 ml) and ethyl acetate (1400 ml) were added. The mass was stirred for 20 min and the organic layer was separated. Aqueous layer was extracted with ethyl acetate (600 ml) and the combined organic layer was washed with water (1000 ml), and then treated with carbon (20 g) at 27-28° C for 30 min. Carbon was removed by filtration and the residue was washed with ethyl acetate (200 ml). The filtrate was concentrated at 40- 50°C under reduced pressure to remove ethyl acetate completely. Toluene (720 ml) and isopropyl alcohol (80 ml) were added to the residue and stirred at 50-55° C for 1 hr. The resulting product slurry was cooled to 26° C and stirred at 26-28° C for 16 hr. Crude N-acetyl chloro benzyl ganciclovir was filtered, washed with mixture of toluene (180 ml) and isopropyl alcohol (20 ml) and dried at 50-55°C under reduced pressure.
(Content of 7-isomer of N-acetyl chloro benzyl ganciclovir: 0.17% Homologue of N-acetyl chloro benzyl ganciclovir: 2.54%)
A mixture of crude N-acetyl chloro benzyl ganciclovir (85 g), ethanol (600 ml) and concentrated hydrochloric acid (21.86 g, 35% w/w) were stirred at 50-55° C for 45 min, then cooled to 28° C and stirred at 28-30°C for 2 hr. The product was filtered and washed with ethanol (85 ml) and dried at 50-55° C under reduced pressure to obtain l00g of N-acetyl chloro benzyl ganciclovir hydrochloride. (Content of 7-isomer of N-acetyl chloro benzyl ganciclovir: Not detected, Homologue of N-acetyl chloro benzyl ganciclovir: 0.76%)

Example – 3

Preparation of 2-[2-acetylamino-l,6-dihydro-6-oxo-9H-purin-9-yl)-methoxy]-l- benzyloxy-3-chloropropane hydrochloride (N-Acetyl chloro benzyl ganciclovir hydrochloride)
A mixture of N,N-dimethylformamide (1000 ml), 9-acetyl-2-acetylamino-l,9- dihydro-6H-purin-6-one (250 g) and (2RS)-(l-chloro-2-acetyloxymethoxy-3- benzyloxy)propane (579.80 g) were added to p-toluenesulfonic acid monohydrate (12.50 g) and heated for 3 hr at 110-115° C. The ratio of N-9 to N-7 isomers of N- acetyl chloro benzyl ganciclovir at this stage was about 2.5:1. Reaction mass was cooled to 28°C, then 8% w/w aqueous sodium chloride solution (1750 ml) and ethyl acetate (1750 ml) were added. The mass was stirred for 20 min and the organic layer was separated. Aqueous layer was extracted with ethyl acetate (830 ml) and the combined organic layer was washed with water (1250 ml), and then treated with carbon (25 g) at 25-30° C for 30 min. Carbon was removed by filtration and the residue was washed with ethyl acetate (250 ml). The filtrate was concentrated at 40- 50°C under reduced pressure to remove ethyl acetate completely, and the residual mass was co-distilled with isopropyl alcohol (250 ml). Isopropyl alcohol (1250 ml) was added to the residue and heated to 48°C, and then concentrated hydrochloric acid was added (61.0 g, 35% w/w). Clear solution of N-acetyl chloro benzyl ganciclovir hydrochloride was formed and slowly cooled to 30°C, and then the product was crystallized. The slurry was stirred at 28-30°C for 2 hr, filtered and washed with isopropyl alcohol (250 ml).

(Content of 7-isomer of N-acetyl chloro benzyl ganciclovir: 0.98% Homologue of N-acetyl chloro benzyl ganciclovir: 1.34%)g
The N-acetyl chloro benzyl ganciclovir hydrochloride was further purified from a mixture of methanol (430 ml) and isopropyl alcohol (430 ml). 120 g of N-acetyl chloro benzyl ganciclovir hydrochloride was obtained. (Content of 7-isomer of N-acetyl chloro benzyl ganciclovir: 0.02% Homologue of N-acetyl chloro benzyl ganciclovir: 0.11%).

Example – 4

Preparation of 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-benzyloxy propan-l-ol (monobenzyl Ganciclovir)
A mixture of 2-[(2-acetylamino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3- benzyloxy-l-chloropropane hydrochloride (N-acetyl chloro benzyl ganciclovir hydrochloride, 340 g), N,N-dimethylformamide (1020 ml) and potassium acetate (249 g) was stirred at 110-115°C for 34 h. The reaction mass was cooled to 28°C, filtered and the residue was washed with N,N-dimethylformamide (340 ml). The filtrate was concentrated at 60-75°C under reduced pressure to remove N,N- dimethylformamide. The residue containing a mixture of 23.72% of 2-
[(2-acetylamino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -acetyloxy-3- benzyloxypropane (diacetyl monobenzyl ganciclovir) and 63.38% of 2-[(2-amino- 1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -acetyl oxy-3-benzyl oxypropane (monoacetyl monobenzyl ganciclovir) was dissolved in methanol (2040 ml), then aqueous ammonia (1020 ml, 20% w/w) was added and stirred at 25-30°C for 24 h. Thereafter, the reaction mass was concentrated to a volume of -800 ml at 40-50°C under reduced pressure and the residue was diluted with water (1020 ml). The mass was stirred at 25-27°C for 1 h, filtered, washed with water (340 ml) and dried at 50- 55°C under reduced pressure to obtain crude monobenzyl ganciclovir (238 g). Chromatographic purity (by HPLC) 89.95%.

The crude monobenzyl ganciclovir (238 g) was suspended in methanol (1190 ml) at 25 °C, heated to 41°C and hydrochloric acid (35% w/w, 72 g) was added. The resulting clear solution was crystallized by addition of ethyl acetate (2380 ml). The product slurry was cooled to 28°C and stirred at 27-30°C for 1 h, filtered and washed with ethyl acetate (238 ml) to produce monobenzyl Ganciclovir hydrochloride (wet) (chromatographic purity (by HPLC) 96.5%) . The obtained wet solid was added to methanol (890 ml), heated to 45°C and diluted with ethyl acetate (1780 ml). The resulting slurry was cooled to 27°C, stirred at 27-30°C for 1 h, filtered, washed with ethyl acetate (180 ml) to obtain monobenzyl ganciclovir hydrochloride with chromatographic purity (by HPLC) 97.54%. This was suspended in water (600 ml) and 10% w/w aqueous sodium hydroxide solution (190 ml) was added to adjust the pH to 4.04. The slurry was filtered, washed with DM water (160 ml) and dried at 50-55°C under reduced pressure to obtain 148 g of monobenzyl Ganciclovir. Chromatographic purity (by HPLC): 97.55%.

Example – 5

Preparation of 2-((2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3- benzyloxypropan-l-ol (monobenzyl Ganciclovir)

A mixture of 2-[(2-acetylamino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3- benzyloxy-l-chloropropane hydrochloride (N-Acetyl chloro benzyl ganciclovir hydrochloride) (600 g), N,N-dimethylformamide (1800 ml), acetic acid (30 g) and potassium acetate (435 g) were stirred at 110-115°C for 42 h. The reaction mass was cooled to 26°C, filtered and the residue was washed with N,N-dimethylformamide (600 ml). The filtrate was concentrated at 60-82°C under reduced pressure (50-5 mm Hg) to remove N,N-dimethylformamide. The residue containing a mixture of 16.7% of 2-[(2-acetylamino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-l- acetyloxy-3-benzyloxypropane (Diacetyl monobenzyl ganciclovir) and 66.62% of 2- [(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -acetyloxy-3- benzyloxypropane (Monoacetyl monobenzyl ganciclovir) was dissolved in methanol (3600 ml). Aqueous ammonia (1800 ml, -20% w/w) was added to the solution and stirred at 25-30°C for 15 h. The reaction mass was concentrated to a volume of -1800 ml at 40-55°C under reduced pressure. The concentrated mass was diluted with water (2400 ml) and stirred at 25-30°C for 1 h. The reaction mass was filtered, washed with water (600 ml) and dried at 50-55°C under reduced pressure to obtain crude monobenzyl ganciclovir (439.10 g). Chromatographic Purity (by HPLC): 90.20%.
The crude monobenzyl ganciclovir (420 g) was suspended in methanol (2100 ml) at 25°C, heated to 39°C and hydrochloric acid (35% w/w, 127 g) was added. The resulting clear solution was crystallized by addition of ethyl acetate (4200 ml). The product slurry was cooled to 27°C, and stirred at 27-28°C for 1 h. The product was filtered, washed with ethanol (300 ml) to obtain monobenzyl ganciclovir hydrochloride as a wet solid (chromatographic purity (by HPLC) 95.59%). The obtained wet solid was suspended in a mixture of ethanol (2940 ml) and water (150 ml) and added sodium hydroxide (76 g) at 27°C. The reaction mass was heated to 70-75°C and stirred at this temperature for 1 h. The mass was cooled to 27°C, filtered and washed with ethanol (420 ml) to obtain monobenzyl ganciclovir sodium salt (chromatographic purity (by HPLC): 98.71%), This was suspended in water (1680 ml). Aqueous hydrochloric acid (-18% w/w, 130 ml) was added to adjust pH of the mass to 4.0. The product was filtered, washed with water (2 x 430 ml) and dried at 50-55°C under reduced pressure to obtain 243.50 g of monobenzyl ganciclovir. Chromatographic Purity (by HPLC): 98.79%.

WE CLAIM

1. A process for the a process for the preparation of 2-[(2-amino-l,6-dihydro-6-oxo- 9H-purin-9-yl)methoxy]-3-benzyloxypropan-l-ol (monobenzyl Ganciclovir) of formula (XIII),

which comprises:
(i) condensing 9-acetyl-2-acetylamino-l,9-dihydro-6H-purin-6-one of formula (IVa);

with (2RS)-(l-chloro-2-acetyloxymethoxy-3-benzyloxy)propane of formula (X);

in the presence of an acid catalyst in a solvent to produce a mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa);

(ii) treating the mixture of N-9 and N-7 isomers of N-acetyl chloro benzyl ganciclovir (III and IIIa) with a solvent or/and a solvent mixture or/and treating with acid to produce pure N-acetyl chloro benzyl ganciclovir of formula (III) or its acid addition salt;

(iii) reacting compound of formula (III) or its acid addition salt with an alkali acetate in the presence of an acid in a solvent to produce a mixture of 2- [(2-acetylamino-l ,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-l -acetyloxy- 3-benzyloxypropane (diacetyl monobenzyl ganciclovir) (XXII) and 2-[(2- amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-1 -acetyloxy-3- benzyloxypropane (monoacetyl monobenzyl ganciclovir) (XII);

(iv) treating the mixture of diacetyl monbenzyl ganciclovir (XXII) and monoacetyl monobenzyl ganciclovir (XII) with a base in the presence of a solvent to produce crude monobenzyl Ganciclovir (XIII);

(v) treating the crude monobenzyl Ganciclovir with an acid to obtain an acid addition salt of monobenzyl Ganciclovir;

(vi) treating the acid addition salt of monobenzyl Ganciclovir with a base in the presence of a solvent to produce an alkali salt of monobenzyl Ganciclovir;

(vii) neutrtalization of the alkali salt of monobenzyl Ganciclovir with an acid to produce pure monobenzyl Ganciclovir (XIII).

2. A process according to claim 1, wherein the acid catalyst used in step (i) is selected from p-toluenesulfonic acid monohydrate, methanesulfonic acid, benzenesulfonic acid.

3. A process according to claim 1, wherein the solvent used in step (i) & step (iii) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane or mixtures there of.

4. A process according to claim 1, wherein the solvent used in step (ii) & step (iv) is selected from methanol, ethanol, isopropanol, toluene, 1-butanol, acetone, ethyl acetate or mixtures there of.

5. A process according to claim 1, wherein the acid used in step (ii), step (v) & step (vii) is selected from hydrochloric acid, hydrobromic acid.

6. A process according to claim 1, wherein the alkali acetate used in step (iii) is selected from sodium acetate, potassium acetate.

7. A process according to claim 1, wherein the acid used in step (iii) is selected from acetic acid, formic acid, methane sulfonic acid or mixture there of.

8. A process according to claim 1, wherein the base used in step (iv) & step (v) is selected from aqueous ammonia, sodium hydroxide, potassium hydroxide.

9. A process according to claim 1, wherein use of pure N-acetyl chloro benzyl ganciclovir (III) or its acid addition salt thereof, pure monobenzyl Ganciclovir (XIII) or its acid addition salt thereof to produce Valganciclovir (Ia) or its hydrochloride salt.

10. A process according to claim 1, wherein use of pure N-acetyl chloro benzyl ganciclovir (III) or its acid addition salt thereof, pure monobenzyl Ganciclovir (XIII) or its acid addition salt thereof to produce Ganciclovir (II).