FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF VALACYCLOVIR OR SALT THEREOF
2, APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of valacyclovir or salt thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention relates to an efficient process for the preparation of valacyclovir or salt thereof.
Valacyclovir is chemically, L-valyl ester of acyclovir designated as 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valyl ester. It is commercially available in form of its hydrochloride salt (Formula I) as Valtrex® Tablets. Valacyclovir hydrochloride is indicated for the treatment of Herpes Zoster, Genital Herpes and Herpes labialis.

FORMULA I
US Patent No 4,957,924 provide process for preparation of valacyclovir or salt thereof wherein the process involves condensation of acyclovir with N-benzyloxycarbonyl-L-valine in presence of N,N-dimethylformamide as solvent. Under these conditions it is observed that N-benzyloxycarbonyl-valacyclovir obtained has about 2-5% of the unwanted isomer. The reaction also takes about 40 hours for completion. The so obtained protected valacyclovir is hydrogenated to remove the protecting group in presence of methanol, tetrahydrofuran and 0.5N hydrochloric acid. The reaction takes about 24 hours and the volume of solvents is very high.
Several other processes are known in the art for preparation of valacyclovir such as US Patent No 6,849,737; US Application No 2005130993; US Application No 20050192296; US Application No 20050059684, US Application No 2005070711.
There are several polymorphic forms of valacyclovir known in the art through US Patent No 6,107,302 and US Patent No 6,849,736; US Application No 2005043329, US Application No 20040197396, US Application No 20050085491 and US Application No 2005187229; and PCT Patent Application WO 2004106338.
Present inventors while working on process for preparation of valacyclovir or salt thereof have surprisingly found that when acyclovir is condensed with protected L-valine in presence of dimethylsulphoxide as solvent, the reaction takes about 5 hours for completion and the product obtained has less than 1% of the unwanted
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isomer. The protected valacyclovir so obtained when hydrogenated in presence of only methanol and 1N hydrochloric acid, the reaction takes less than 5 hours for completion.
One of the aspects of the present invention provides a process for preparation of valacyclovir or salt thereof wherein the said process comprises of a) condensing acyclovir of Formula II,

H.

FORMULA II
with protected L-valine of Formula III,

FORMULA III
wherein Pi or P2 are independently hydrogen or suitable mono-valent or combine together to form divalent amino protecting group with a proviso that both Pi and P2 are not hydrogen; in presence of dimethylsulphoxide and a catalyst, b) isolating compound of Formula IV,

FORMULA IV
wherein Pi or P2 are as defined above from the reaction mass thereof,
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c) removing the protecting group from the compound of Formula IV to get valacyclovir or salt thereof.
Valacyclovir or salt thereof can be prepared by condensing acyclovir of Formula II with an amine protected L-valine of Formula III wherein Pi or p2 are independently hydrogen or suitable mono-valent or combine together to form divalent amino protecting group with a proviso that both Pi and P2 are not hydrogen; in presence of dimethylsulphoxide (DMSO) as solvent, and a catalyst which comprises a mixture of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. DMSO as a solvent offers better temperature control during the addition of esterifying L-valyl residue to acyclovir and additionally, the formation of unwanted isomer is found to be less than 1% .The reaction is carried out at room temperature and stirring continued for about 4 to 10 hrs. The reaction mixture is filtered and the clear filtrate is quenched with water and the precipitate of crude protected valacyclovir of Formula IV is isolated. The so obtained product can be further stirred in aqueous methanol for removing unwanted side products. The so obtained product has less than 1% of the unwanted isomer.
Another aspect of the present invention provides a process for preparation of valacyclovir or salt thereof wherein the said process comprises of a) hydrogenating the compound of Formula IV

'FORMULA IV
wherein Pi is hydrogen and P2 is benzyloxy-carbonyl protecting group in presence of methanol and 1N hydrochloric acid, b) isolating valacyclovir or salt thereof from the reaction mass thereof.
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The protected valacyclovir of Formula IV is hydrogenated with a mixture of methanol and 1N HCI in presence of hydrogen pressure of 30 to 70 PSI over noble metal catalysts such as palladium over carbon, platinum oxide, palladium acetate, platinum chloride and the like. The reaction can be conveniently carried out at temperatures below 30°C that takes about 5 hours or less for completion. After completion of reaction, the mass is filtered to remove the catalyst and the filtrate is concentrated under vacuum to get a residue, which is reconstituted, in ethanol, stirred and filtered to get valacyclovir hydrochloride, which has less than 1% of unwanted isomer.
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.
EXAMPLE 1
PREPARATION OF N-BENZYLOXYCARBONYL-VALACYCLOVIR
A suspension of Acyclovir (25 gm), N-benzyloxycarbonyl -L-Valine (36.26 gm), dicyclohexylcarbodiimide (34.35 gm) and dimethylaminopyridine (1.35 gm) in dimethylsulfoxide ( 125 ml) was maintained at 20-25°C under stirring for 7-8 hours. The reaction mixture was filtered under suction and washed with dimethylsulfoxide (25 ml). The clear filtrate obtained was poured on water at ambient temperature. After stirring for 15-20 minutes the mass was filtered and washed with water (4 x 50 ml) to get wet title compound.
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The wet cake was crystallized in methanol (400 ml) and filtered at 0-5°. The solid
was washed with methanol (2X50 ml) and dried under vacuum to get title
compound.
Yield = 49 gm
Purity =99.5% (by HPLC)
EXAMPLE 2
PREPARATION OF VALACYCLOVIR HYDROCHLORIDE
In a pressure vessel was charged a mixture of methanol (875 ml) and HCI (125 ml, 1N solution) and cooled to 18-20°C. To this was added N-benzyloxycarbonyl-valacyclovir (50 gm) under stirring and palladium on carbon (50% wet, 5%, 5 gm). Hydrogen gas was passed through the mass to get a pressure of about 50 PSI, which was then maintained for about 6-7 hrs at 20-25°C. The reaction mixture was filtered through celite bed. The clear filtrate was distilled under vacuum to remove solvent completely and to the residue was added water (75 ml). The resultant mass was heated to 60°C and filtered through celite bed. The filtrate was heated to 60-65°C and to it was added ethanol (350 ml). The resultant mixture was heated to reflux and then cooled to ambient temperature and maintained for 1 hour. The mass was further cooled to 0 to -5°C and maintained for 1 hour, filtered and dried under vacuum at 50°C to get title compound. Yield= 26 gm HPLC Purity= 99.84%
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We Claim
1. A process for preparation of valacyclovir or a salt thereof wherein the said process comprises of
2. a) condensing acyclovir of Formula II,

FORMULA II
with protected L-valine of Formula III,

FORMULA III
wherein Pi or P2 are independently hydrogen or suitable mono-valent or combine together to form divalent amino protecting group with a proviso that both Pi and P2 are not hydrogen; in presence of dimethylsulphoxide and a catalyst,
b) isolating compound of Formula IV,

FORMULA IV
wherein Pi or P2 are as defined above from the reaction mass thereof,
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c) removing the protecting group from the compound of Formula IV to get valacyclovir or salt thereof.
2. A process as claimed in claim 1, wherein compound of Formula III is N-benzyloxycarbonyl-L-valine wherein Pi is hydrogen and P2 is benzyloxy-carbonyl group.
3. A process as claimed in claim 1 wherein the catalyst used is a mixture of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine.
4. A process as claimed in claim 1 wherein the removal of protecting group from compound of Formula IV is carried out by hydrogenation.
5. A process for preparation of valacyclovir or salt thereof wherein the said process comprises of
a) hydrogenating the compound of Formula IV

FORMULA IV
wherein Pi is hydrogen and P2 is benzyloxy-carbonyl protecting group in presence of methanol and 1N hydrochloric acid, b) isolating valacyclovir or salt thereof from the reaction mass thereof.
6. A process as claimed in claim 5 wherein hydrogenation is carried out in presence of noble metal catalyst.
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7. A. process as claimed in claim 6 wherein the noble metal catalyst is palladium on carbon.
8. A process as claimed in claims 1 and 5 wherein valacyclovir has less than 1% of unwanted isomer.
9. A process as claimed in claim 5 wherein step a) is carried out at temperature of 30°C or less.
10. A process as claimed in claim 5 wherein compound of Formula IV is N-benzyloxycarbonyl-valacyclovir wherein one of the Pi and P2 is hydrogen and the other is benzyloxycarbonyl.
Dated this 28th. day of March, 2006.
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