PREPARATION OF ESTERS OF PURINE DERIVATIVES
FieJd of the Invention
The present invention relates to the preparation of valganciclovir or a pharmaceutically acceptable salt thereof stable to degradation.
Background of the Invention
Valganciclovir of Formula I is chemically, L-valine 2-(2-amino-l, 6-dihydro-6-oxo-purin-9-yl)methoxy-3-hydroxypropyl ester. Valganciclovir is commercially available in the form of its hydrochloride salt.
(Formula Removed)
Valganciclovir is the mono L-valyl ester of Ganciclovir of formula II,
(Formula Removed)
European Patent No 0 375 329 (herein after the '329 patent) discloses amino acid ester prodrugs of ganciclovir and physiologically acceptable salts thereof. The esters disclosed include, for example, the bis-L-valyl ester of ganciclovir of Formula III,
(Formula Removed)
The '329 patent discloses a process for the preparation of amino acid esters (e.g., bis-L-valyl ester of ganciclovir of Formula III), which involves refluxing ganciclovir of Formula II (as above) or amino-protected derivative thereof and protected L-valine of Formula IV,
wherein Z is an amino protecting group, in N,N-dimethylformamide and deprotecting the resulting compound using 10% palladium on carbon and acetic acid.
US Patent Nos. 5,700,936; 5,756,736; 5,840,890; 5,840,891; 5,856,481; 6,040,446; 6,103,901; 6,215,017 and 6,218,568; US Patent application No. 2002/0042424 and European Patent No. EP 0 694 547 provide a process for preparation of valganciclovir of Formula I,
(Formula Removed)
or pharmaceutically acceptable salt thereof, which involves reaction of protected ganciclovir of Formula V,
(Formula Removed)
wherein P, is an amino protecting group and P2 is a hydroxy protecting group, with protected L-valine of Formula IV
(Formula Removed)
wherein Z is an amino protecting group, to get protected mono L-valyl ester of ganciclovir of Formula VI,
(Formula Removed)
which is then deprotected to get valganciclovir of Formula I or pharmaceutically acceptable salt thereof.
PCT Publication No. WO 2005/092891 (herein after WO '891) discloses a process wherein Ganciclovir is reacted with N- benzyloxycarbonyl L-valine in dimethylsulphoxide to get N-benzyloxycarbonyl valganciclovir which is deprotected to get Valganciclovir. WO '891 further discloses methods for the recovery and recycling of
ganciclovir and bis-L-valyl ganciclovir from valganciclovir. The recovery process for ganciclovir involves treating a suspension comprising ganciclovir and valganciclovir in aqueous methanol with trifluoroacetic acid (105 mL) and adding dichloromethane whereby valganciclovir is extracted into dichloromethane and ganciclovir remains in aqueous solution and is recovered therefrom.
Summary of the Invention
The present inventors observed that during the separation of a mixture of ganciclovir and valganciclovir by extraction with an organic solvent from an aqueous medium containing trifluoroacetic acid, traces of trifluoroacetic acid carried over to the organic solvent layer lead to degradation of valganciclovir. When the excess of trifluoroacetic acid is removed by washing with water, an inseparable, thick emulsion forms. In an effort to solve this problem, the present inventors found that product degradation can be minimized by reducing the quantity of trifluoroacetic acid. The present inventors also found that if the organic solvent layer is diluted with water and then the organic solvent is recovered, product degradation is minimized.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of valganciclovir of Formula I, or a pharmaceutically acceptable salt thereof,
(Formula Removed)
wherein the process comprises,
a) suspending a mixture comprising ganciclovir of Formula II, protected mono L-valyl ester of ganciclovir of Formula VI wherein P1| is an amino protecting group and P2 is a hydroxy protecting group
(Formula Removed) 3
in an aqueous first organic solvent,
b) treating the mixture of step a) with less than about 75 mL of trifluoroacetic acid
c) extracting the mixture of step b) with a second organic solvent
d) separating the second organic solvent from the mixture of step c) and diluting with water
e) recovering the second organic solvent from the mixture of step d) to obtain protected mono L-valyl ester of ganciclovir of Formula VI
f) deprotecting the protected mono L-valyl ester of ganciclovir of Formula VI obtained in step e).
g) isolating valganciclovir of Formula I from the reaction mass thereof.
h) if required, converting valganciclovir of Formula I to a pharmaceutically acceptable salt thereof.
A mixture comprising Ganciclovir of Formula II and protected mono L-valyl ester of ganciclovir of Formula VI can be obtained by the method disclosed in WO '891. Alternatively, a mixture of the above compounds obtained as a product from reactions known in the associated art can be employed. A mixture comprising Ganciclovir of Formula II and protected mono L-valyl ester of ganciclovir of Formula VI was suspended in an aqueous first organic solvent and the resultant mixture was acidified with less than about 75 mL of trifluoroacetic acid. To the acidified mixture a second organic solvent was added. The layer comprising the second organic solvent was separated and diluted with water. From the resultant mixture, the second organic solvent was recovered under reduced pressure to obtain protected mono L-valyl ester of ganciclovir of Formula VI,
which was deprotected to obtain valganciclovir of Formula 1. Valganciclovir of Formula 1 thus obtained can be converted to a pharmaceutically acceptable salt thereof such as the hydrochloride salt by the method disclosed in EP 0 694 547.
Suitable first organic solvents include water-miscible organic solvents such as alkanols, ketones, nitriles, polar aprotic solvents or mixtures thereof. Suitable alkanols include methanol, ethanol, n-propanol and isopropanol or mixtures thereof.
Suitable polar aprotic solvents include tetrahydrofuran, 1,4-dioxane, dimethylsulphoxide, N,N-dimethylformamide, N,N-dimethylacetamide and sulpholane or mixtures thereof. Example of a suitable ketone is acetone. Example of a suitable nitrile is acetonitrile.
Suitable second organic solvent include non-polar water-immiscible or partially immiscible solvents characterized by the fact that said solvent dissolves valganciclovir of Formula 1 and has poor solubility for ganciclovir of Formula II (e.g., dichloromethane, ethyl acetate or mixtures thereof).
The process of the present invention may involve one or more of the following embodiments. In one embodiment, the volume of trifluoroacetic acid ranges from 50-60 mL. In another embodiment, the volume of trifluoroacetic acid is 52 mL. In another embodiment, the first organic solvent is water-miscible selected from alkanols (e.g., methanol, ethanol, n-propanol, isopropanol or a mixture thereof), ketones, nitriles, polar aprotic solvents or a mixture thereof. In yet another embodiment, the second organic solvent is non-polar water-immiscible or partially immiscible organic solvent selected from dichloromethane, ethyl acetate or a mixture thereof. In yet another embodiment, the first organic solvent is methanol and the second organic solvent is dichloromethane.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Reference Example
Step a): reaction of benzyloxycarbonyl protected L-valine with Ranciclovir
To a solution of benzyloxycarbonyl protected L-valine (88.4 g) in dimethylsulphoxide (350 mL) at 18-20°C was added dicyclohexylcarbodiimide (105 g) followed by 4-dimethylamino pyridine (2.8 g). The resultant mixture was stirred for 10 minutes and was added to a solution of anhydrous ganciclovir (100 g) in dimethylsulphoxide (650 mL) in one lot at 20-25°C. The reaction mixture was stirred at 20-25°C for 60 minutes and then quenched by adding water (400 mL) slowly at 20-30 C. The reaction mixture was stirred again at 20-25°C for 30 minutes and the solid that separated was filtered and washed with a solution of dimethylsulphoxide (60 mL) in water (40 mL).
Analysis of the filtrate showed:
CBZ-protected mono-L-valyl ester of ganciclovir : 50%
Ganciclovir: 35%
CBZ-protected Bis L-valyl ester of ganciclovir: 15%.
Step b): removal of benzyloxycarbonyl protected bis-L-valyl ester ganciclovir
To the filtrate obtained in step a) was added ethyl acetate (1.0 L) and the mixture was stirred at 20-30°C for 10 minutes. To this mixture, water (300 mL) was added at 36-38°C. The resultant mixture was stirred for 10 minutes and allowed to settle. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 1 L) at 36-38°C. The aqueous layer was treated with water (1.2 L) and cooled to 0°C and further stirred at 0-5°C for 3 hours. The separated product was filtered to obtain a wet solid (200 g)-
Analysis of the solid obtained showed: CBZ-protected mono-L-valyl ester of ganciclovir : 70% Ganciclovir: 30%; CBZ-protected Bis L-valyl ester of ganciclovir: < 1%.
Example
Preparation of Valganciclovir stable to defiradation
A mixture of ganciclovir and CBZ-protected mono-L-valyl ester of ganciclovir (200 g) was suspended in a solution of water (250 mL) and methanol (50 mL) and the suspension was cooled to about 2°C. Trifluoroacetic acid (52.5 mL) was added to the suspension and the resultant mass was stirred for 1 hour to get a clear solution. The solution was diluted with water and extracted with dichloromethane (3 x 500 mL). The combined organic layers were washed with a solution of water (300 mL) and trifluoroacetic acid (17.5 mL). To the organic layer water (350 mL) was added and dichloromethane was recovered under reduced pressure. Solid thus obtained, was filtered, crystallized from ethanol and dried under vacuum to get benzyloxycarbonyl protected mono L-valyl ester of ganciclovir (32 g).
Benzyloxycarbonyl protected mono L-valyl ester of ganciclovir (15 g) was suspended in 20% aqueous ethanol (180 mL) and to this suspension was added concentrated hydrochloric acid (3.9 g, 35% w/w) and palladium on carbon (10%, 50% wet, 1.65 g). The suspension was stirred at 0.5-1.0 Kg hydrogen pressure at 20-40°C. After completion of reaction, catalyst was filtered through celite bed and micron filter and the bed was washed with aqueous ethanol (10%). The filtrate obtained was concentrated completely at 25-38°C under vacuum and the residue was crystallized using water (12 mL) and isopropyl alcohol (97.5 mL). The product so obtained was washed with isopropyl alcohol and dried under vacuum at 55-60°C to get valganciclovir hydrochloride.
Yield: 9-9.75 g. (82.5-89%)
Purity (by HPLC): > 99%;
Bis L-valyl ester of ganciclovir : < 1%;
Ganciclovir: < 1%.
CBZ-protected mono-L-valyl ester of ganciclovir : < 0.15%
CBZ-protected Bis L-valyl ester of ganciclovir : < 0.15%

WE CLAIM:
1. A process for the preparation of valganciclovir of Formula I, or a pharmaceutically acceptable salt thereof,
(Formula Removed)
wherein the process comprises,
a) suspending a mixture comprising ganciclovir of Formula II, protected mono L-
valyl ester of ganciclovir of Formula VI wherein P1 is an amino protecting group
and P2 is a hydroxyl protecting group
(Formula Removed)
in an aqueous first organic solvent;
b) treating the mixture of step a) with less than about 75 mL of trifluoroacetic acid;
c) extracting the mixture of step b) with a second organic solvent;
d) separating the second organic solvent from the mixture of step c) and diluting with water;
e) recovering the second organic solvent from the mixture of step d) to obtain protected mono L-valyl ester of ganciclovir of Formula VI;
f) deprotecting the protected mono L-valyl ester of ganciclovir of Formula VI obtained in step e;
g) isolating valganciclovir of Formula I from the reaction mass thereof;
h) if required, converting valganciclovir of Formula I to a pharmaceutically acceptable salt thereof.
2. The process according to claim 1, wherein the volume of trifluoroacetic acid
ranges from 50-60 mL
3. The process according to claim 2, wherein the volume of trifluoroacetic acid is 52
mL.
4. The process according to claim 1, wherein the first organic solvent is water-
miscible.
5. The process according to claim 4, wherein the organic solvent is selected from the
group comprising of alkanols, ketones, nitriles, polar aprotic solvents or mixtures thereof.
6. The process according to claim 5, wherein the alkanol is selected from the group
comprising of methanol, ethanol, n-propanol and isopropanol or mixtures thereof.
7. The process according to claim 6, wherein the alkanol is methanol.
8. The process according to claim 1, wherein the second organic solvent is non-polar
water-immiscible or partially immiscible organic solvent.
9. The process according to claim 8, wherein the second organic solvent is selected
from dichloromethane, ethyl acetate or mixtures thereof.
10. The process according to claim 9, wherein the second organic solvent is
dichloromethane.