FIELD OF INVENTION

The present invention relates to an improved process for the preparation of Valganciclovir (I) and
pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

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

Valganciclovir (I) is a mono-L-valyl ester (prodrug) of the antiviral compound Ganciclovir (II) and 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 (la) 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-)]).

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

US 6,083,953 discloses crystalline Valganciclovir hydrochloride (la). US '953 also discloses a process for the preparation of Valganciclovir hydrochloride (la), by reacting benzyloxymethyloxirane (III) with paraformaldehyde in dichloromethane to produce chloromethyl ether intermediate (IV) followed by reacting with potassium acetate in acetone to produce (l-chloro-2-acetoxymethoxy-3-benzyloxy)propane (V). Compound (V) is further reacted with persilylated guanine to produce chloro benzyl Ganciclovir (VI) along with its N-7 isomer, which is further reacted with potassium acetate and DMF to produce monoacetyl monobenzyl Ganciclovir (VII), which is treated with ammonia in methanol to produce monobenzyl Ganciclovir (VIII). Compound (VIII) is then reacted with N-(benzyloxycarbonyl)-L-valine to produce compound (IX), which is further converted to Valganciclovir hydrochloride (la) by hydrogenation using Pd/C in methanol in the presence of hydrochloric acid, and finally crystallized from isopropanol. The process is shown in scheme-I.

The major disadvantage with the above process is that monobenzyl Ganciclovir is converted to diprotected Valganciclovir (IX), which is subsequently converted to Valganciclovir hydrochloride. This process requires deprotection of two protecting groups viz., benzyl and benzyloxycarbonyl groups. The deprotection is carried out by hydrogenation in the presence of palladium on carbon catalyst, which is highly expensive. Additionally, it requires extra care while handling palladium catalyst on a large scale, due to its pyrophoric nature.

US 5,756,736 discloses a process for the preparation of Valganciclovir, by reacting Ganciclovir (II) with a trityl halide to produce a compound (X) 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 N,0-bistrityl-monovaline ester of Ganciclovir (XI), followed by the removal of the protecting groups to produce Valganciclovir hydrochloride (la). The process is shown in scheme II.
wherein, X is bromo or chloro, P3 is an amino-protecting group and A is a carboxy-activating group.

SCHEME-II
The major disadvantage with the above process is that Ganciclovir is converted to ditrityl t-Boc Valganciclovir (XI), which is subsequently converted to Valganciclovir hydrochloride. In the final step, deprotection of trityl groups and t-Boc groups are required to be removed. The removal these protecting groups requires excess amount of trifluoroacetic acid, which is industrially difficult to operate. Further, the Valganciclovir hydrochloride (la) produced by this process is contaminated with traces of trifluoroacetic acid and tritanol. Removal of these impurities is difficult and requires repeated crystallizations, which results in the low yield of Valganciclovir.

US 2007/0225305 Al discloses a process for the preparation of Valganciclovir hydrochloride (la), which comprises selective hydrolysis of triacetyl Ganciclovir (XII) to produce monoacetyl Ganciclovir (XIII), which is reacted with N-carbobenzyloxy L-valine (CBz L-Valine) and a coupling agent to produce monoacetyl mono benzyloxycarbonyl protected Valganciclovir (XIV). Compound (XIV) is hydrolyzed under basic conditions to produce N-benzyloxy carbonyl Valganciclovir (XV), followed by hydrogenolysis in the presence of hydrogenation catalyst in hydrochloric acid to produce Valganciclovir hydrochloride (la). The process is shown in scheme HI.

The major disadvantage with the above process is deprotection of benzyloxycarbonyl group, which is carried out by hydrogenation in the presence of palladium on carbon catalyst, which is highly expensive. Additionally, it requires extra care while handling palladium catalyst on a large scale, due to its pyrophoric nature.

Hence, there is a need to develop a process, which provides the use of readily accessible and cheaper reagents under relatively mild reaction conditions, which avoids the additional expensive de-protection operations in the preparation of Valganciclovir (I). The process of present invention requires less reaction time and controls the formation of undesired degradation by-products during the production of Valganciclovir hydrochloride (la).

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple, cost effective and an improved process for the preparation of Valganciclovir (1) or pharmaceutically acceptable salt thereof on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of Valganciclovir of formula (I) or pharmaceutically acceptable salt thereof, with (2S)-2-[(tert-butyloxy)carbonyl]amino]-3-methylbutanoic acid (t-BOC-L-valine) to produce 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-acetoxy-l-propanyl-N-(tert-butyloxycarbonyl)-L-valinate (acetyl t-BOC Valganciclovir) of formula (XVI),

(ii) hydrolyzing the compound of formula (XVI) obtained in step-(i) to produce 2-[(2 -amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxy-1 -propanyl-n-(tert-butyloxycarbonyl)-l-valinate (t-BOC Val ganciclovir) of formula (XVII),

(iii) treating the compound of formula (XVII) with an acid to produce Valganciclovir of formula (I) or pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Valganciclovir of formula (I) or pharmaceutically acceptable salt thereof.

The process comprises, selective de-acetylation of 2-[(2-acetylamino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]propane-l,3-diyl diacetate (triacetyl Ganciclovir) of formula (XII) using an amine selected from piperidine, piperazine, N-methyl piperazine, ethylenediamine, ethanolamine, N-methylcyclopentylamine, N-ethylphenylamine, diphenylamine, pyridine, triethylamine, diethylamine, dibutylamine,
diisopropylethylamine, morpholine or mixture thereof; in the presence of a solvent selected from alcohols such as methanol, ethanol, isopropanol, isobutanol and the like, esters such as ethyl acetate, isopropyl acetate, n-butyl acetate and the like, nitriles such as acetonitrile, propionitrile and the like, ethers such as tetrahydrofuran (THF), dioxane and the like, polar aprotic solvent such as methylene chloride, acetone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like, and water or mixtures thereof, to produce 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-acetoxy-l-propanol (monoacetyl Ganciclovir) of formula (XIII).

The above selective de-acetylation is carried at a temperature of about 20°C to about 100°C. The sufficient period of time necessary for obtaining compound (XIII) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 5 to about 50 hours.

After completion of reaction as ascertained by the known detection methods reported in the art such as HPLC, solvent selected from cyclohexane, hexane, n-heptane, diisopropylether or mixture thereof is added to the reaction mass and separated the supernatant layer, thereafter the residue is dissolved in a solvent selected from acetone, cyclohexane, hexane, n-heptane, diisopropylether or mixture thereof. The resulting slurry is stirred for 1 to 4 hrs and filtered. The separated solid is filtered and dried under reduced pressure to obtain monoacetyl Ganciclovir (XIII).

Monoacetyl Ganciclovir of formula (XIII) is reacted with (2S)-2-[(tert-butyloxy)carbonyl]amino]-3-methylbutanoic acid (t-BOC-L-valine) optionally using a coupling agent selected from N,N-diisopropylcarbodiimide, N,N-dicyclohexylcarbodiimide, diphenyl carbodiimide, ditolyl carbodiimide and the like; in the presence of a catalyst selected from 4-(dimethylamino)pyridine (4-DMAP), ferrocenyl 4-DMAP and 4-(pyrrolidino)pyridine (4-PPY) and the like, in a solvent selected from chloroform, methylene chloride, toluene, ethyl acetate, dioxane, acetonitrile, pyridine, THF, DMF, DMSO, DMAc or mixture thereof, to produce 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-acetoxy-l-propanyl-N-(tert-butyloxycarbonyl)-L-valinate (acetyl t-BOC Valganciclovir) of formula (XVI).

The above reaction is carried at a temperature of about -10°C to about 50°C. The sufficient period of time necessary for obtaining compound (XVI) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 1 to about 12 hours.

After completion of reaction as ascertained by the known detection methods reported in the art such as HPLC, the reaction mass is filtered and water is added to the filtrate. The resulting mass is stirred for 1 to 5 hrs, thereafter cooled the reaction mass to 0 to 20°C. The resulting reaction mass is filtered, washed with water and dried under reduced pressure to obtain acetyl t-BOC Valganciclovir (XVI).

Hydrolysis of acetyl t-BOC Valganciclovir of formula (XVI) is carried out using a base selected from piperidine, ethylenediamine, N-ethylphenylamine, diphenylamine, pyridine, triethylamine, diethylamine, dibutylamine, diisopropylethylamine, morpholine or mixtures thereof, in the presence of a solvent selected from methanol, ethanol, isopropanol, cyclohexane, methylene chloride, acetonitrile, THF, DMF, DMSO, ethyl acetate, toluene, acetone or mixtures thereof, to produce 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-
yl)methoxy]-3-hydroxy-1 -propanyl-n-(tert-butyloxycarbonyl)-l-valinate (t-BOC Valganciclovir) of formula (XVII).

The above reaction is carried at a temperature of about 20°C to about 100°C. The sufficient period of time necessary for obtaining compound (XVII) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 5 to about 50 hours.

After completion of reaction as ascertained by the known detection methods reported in the art such as HPLC, solvent selected from cyclohexane, hexane, n-heptane, diisopropylether or mixture thereof is added and the supernatant layer is removed. The residue is treated with a solvent selected from cyclohexane, hexane, n-heptane, diisopropylether or mixture thereof. The separated solid is filtered and dried under reduced pressure to obtain t-BOC Valganciclovir (XVII).

Treating t-BOC Valganciclovir (XVII) with an acid selected from organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or mixture thereof, in the presence of a solvent selected from ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, a halogenated hydrocarbon, such as methylene chloride, chloroform; ethyl acetate, methyl acetate or mixtures thereof, to produce 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-
yl)methoxy]-3-hydroxy-l -propyl ester hydrochloride (Valganciclovir hydrochloride) of formula (la). _

The above reaction is carried out in presence at a temperature of about 20°C to about 100°C. The sufficient period of time necessary for obtaining compound (la) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 1 to about 10 hours.

After completion of reaction, the reaction mass is concentrated under reduced pressure to remove the solvent and the residue is dissolved in a solvent selected from methanol, ethanol, isopropyl alcohol, water or mixture thereof; and then treated with carbon, and carbon is removed by filtration. The filtrate is diluted with a solvent selected from methanol, ethanol, isopropyl alcohol, water or mixture thereof to crystallize out the product and filtered. The residue containing Valganciclovir hydrochloride (la) is washed with the same solvent and dried under reduced pressure to obtain Valganciclovir hydrochloride (la), which is optionally purified by known methods, for example recrystallization using a solvent selected from methanol, ethanol, isopropanol, water or mixtures thereof.

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.

Example:
Step-1:

Preparation of 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-acetoxy-l- propanol (monoacetylganciclovir) (XIII)

A mixture of 2-[(2-Acetylamino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]- propane-1,3-diyl diacetate (Triacetylganciclovir; 50 g), Piperidine (100 ml) and N,N-dimethylacetamide (100 ml) was stirred at 50-55°C for 48 h. The reaction mass was cooled to 25-30°C and cyclohexane (500 ml) was added. The mass was stirred at 25-30°C for 30 min and supernatant cyclohexare layer was separated. To the residue, acetone (20 ml) was added and diluted with cyclohexane (250 ml). The mass was stirred at 25-30°C for 1 h. The separated solid was filtered, and washed with cyclohexane (50 ml). The product was dried under reduced pressure at 40-45°C to obtain monoacetyl Ganciclovir.

Step-ii:
Preparation of 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)niethoxy]-3-acetoxy-l-propanyl-n-(tert-butyloxycarbonyl)-L-valinate (acetyl t-boc Valganciclovir) (XVI) (2S)-2-[(tert-Butyloxy)carbonyl]amino]-3-methylbutanoic acid (t-BOC-L-valine; 26.30 g) was dissolved in N,N-dimethylformamide (200 ml) under nitrogen atmosphere at 25-30°C and cooled to -5°C to 0°C. N,N-dicyclohexylcarbodiimide (DCC; 18.0 g) was added and continued stirring for 30 min. Thereafter, monoacetyl Ganciclovir; 30 g) and 4-(dimethylamino)pyridine (DMAP; 1.60 g) were added at -5°C to 0°C and stirred at this temperature for 30 min. Thereafter, second lot of N,N-dicyclohexylcarbodiimide (DCC; 18.0 g) was added and continued stirring at -5°C to 0°C for 8 h. The reaction mass was filtered to remove dicyclohexyl urea (DCU) and the filtrate is added to DM water (400 ml) at 25-30°C. The mass was stirred 25-30°C for 1 h. Thereafter, it was cooled to 5-10°C and stirred at this temperature for 2 h. The mass was filtered, washed with DM water (50 ml) and dried at 40-45°C under reduced pressure to obtain acetyl t-BOC Valganciclovir.

Step-iii:
Preparation of 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxy-l-propanyl-n-(tert-butyloxycarbonyl)-L-valinate(t-BOC Valganciclovir)(XVII) A mixture of acetyl t-BOC Valganciclovir (30 g) and piperidine (60 ml) was stirred at 25-30°C for 40 h. Isopropyl alcohol (90 ml) was added to the reaction mass, and stirred at 25-30°C for 30 min. Thereafter, cyclohexane (180 ml) was added to the above mass and stirred at 25-30°C for 30 min. Supernatant cyclohexane layer was removed and cyclohexane (180 ml) was added to the residue and stirred at 25-30°C for 1 h. The separated solid was filtered, washed with cyclohexane (50 ml) and dried at 40-45°C under reduced pressure to obtain t-BOC Valganciclovir.

Step-iv:

Preparation of L-valine 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)-methoxy]-3- hydroxy-1-propyl ester monohydrochloride (Valganciclovir hydrochloride) (la)

A mixture of t-BOC Valganciclovir (25 g) methanol (100 ml) and hydrochloric acid (12.1g) was stirred at 25-30°C for 6 h. The reaction mass was concentrated under reduced pressure to remove methanol. The residue was dissolved in 50% v/v aqueous isopropyl alcohol (40 ml) at 60-65°C and treated with carbon (0.50 g). Carbon was removed by filtration through hyflo and the residue was washed with 50% v/v aqueous isopropyl alcohol (20 ml) at 60-65°C. Isopropyl alcohol (180 ml) was added to the filtrate over a period of 1 h at 60-65°C. The mass was gradually cooled to 25-30°C and stirred at this temperature for 1 h. The product slurry was further cooled to -5°C to 0°C and stirred at this temperature for 1 h. The product was filtered, washed with 2% v/v aqueous isopropyl alcohol (25 ml) and dried at 50-55°C under reduced pressure to obtain L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-methoxy]-3-hydroxy-1 -propylester monohydrochloride (Valganciclovir hydrochloride).

WE CLAIM:

1. A process for the preparation of Valganciclovir of formula (I) or pharmaceutically acceptable salt thereof,
which comprises:

(i) condensing monoacetyl Ganciclovir (XIII),
with (2S)-2-[(tert-butyloxy)carbonyl]amino]-3-methylbutanoic acid (t-BOC-L-valine) to produce 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-acetoxy-1 -propanyl-N-(tert-butyloxycarbonyl)-L-valinate (acetyl t-BOC Valganciclovir) of formula (XVI),

(ii) hydrolyzing the compound of formula (XVI) obtained in step-(i) to produce 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxy-1 -propanyl-n-(tert-butyloxycarbonyl)-l-valinate (t-BOC Valganciclovir) of formula (XVII),

(iii) treating the compound of formula (XVII) with an acid to produce Valganciclovir of formula (I) or pharmaceutically acceptable salt thereof.

2. According to claim 1, wherein the condensation in step-(i) is carried out in presence of a coupling agent in a solvent and a catalyst.

3. According to claim 2, wherein the coupling agent is selected from N,N-diisopropylcarbodiimide, N,N-dicyclohexylcarbodiimide, diphenyl carbodiimide, ditolyl carbodiimide and the like.

4. According to claim 2, wherein the catalyst is selected from 4-(dimethylamino)pyridine (4-DMAP), ferrocenyl 4-DMAP and 4-(pyrrolidino)pyridine (4-PPY) and the like.

5. According to claim 2, wherein the solvent is selected from chloroform, methylene chloride, toluene, ethyl acetate, dioxane, tetrahydrofuran (THF), acetonitrile, pyridine, N,N-dimethylformamide (DMF), N,N-dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide (DMAc) or mixture thereof.

6. According to claim 1, wherein the hydrolysis in step-(ii) is carried out in presence of a base and a solvent.

7. According to claim 6, wherein the base is selected from piperidine, ethylenediamine, N-ethylphenylamine, diphenylamine, pyridine, triethylamine, diethylamine, dibutylamine, diisopropylethylamine, morpholine or mixtures thereof.

8. According to claim 6, wherein the solvent selected from methanol, ethanol, isopropanol, cyclohexane, methylene chloride, THF, DMF, DMSO, ethyl acetate, toluene, acetone or mixtures thereof.

9. According to claim 1, wherein the acid in step-(iii) is selected from organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or mixture thereof.

10. According to claim 1, wherein the step-(iii) is carried out in presence of a solvent selected from ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, a halogenated hydrocarbon, such as methylene chloride, chloroform; ethyl acetate, methyl acetate or mixtures thereof.