FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "A process for preparation of pure Famciclovir"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.


A PROCESS FOR PREPARATION OF PURE FAMCICLOVIR
FIELD OF THE INVENTION
A process for preparing pure Famciclovir compound of formula I comprising reducing acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b] pyridin-3-yl)-butyl ester compound of formula IV in ether solvent by catalytic hydrogenation.
BACKGROUND OF THE INVENTION
Famciclovir is chemically 2-[2-(2-amino-9H-purin-9-yl)ethyl]-l,3-propanediol diacetate and is represented by formula I.

umciclovir is indicated for the treatment of acute herpes zoster (shingles). It is so indicated for the treatment or suppression of recurrent genital herpes in cmunocompetent patients and for the treatment of recurrent mucocutaneous crpes simplex infections in HIV infected patients.
Famciclovir and a process for its preparation is disclosed in U.S. Patent. No. 5,246,937. The process disclosed therein involves reduction of 9-(4-acetoxy-3-

acetoxymethylbut-l-yl)-2-amino-6-chloropurine by 10% palladium-on-charcoal in methanol containing ammonium formate.
U.S. Patent. No. 5,138,057 describes a process for preparing Famciclovir by reduction of 9-(4-acetoxy-3-acetoxymethylbut1-yl)-2-amino-6, 8-dichloropurine in ethanol in the presence of trietyl amine base by catalytic hydrogenation using 5% palladium on charcoal as catalyst
U.S. Patent. No. 5,066,805 describes a process for preparing Famciclovir by condensing 2-aminopurine and 2-acetoxymethyl-4-iodo-butyl-l-acetate in the presence of anhydrous potassium carbonate in dry dimethylformamide solvent wherein 2-aminopurine is being prepared by reduction of 2-amino-6-chloropurine in an aqueous solution in the presence of a base essentially devoid of an organic solvent by catalytic hydrogenation using palladium on charcoal as catalyst.
U.S. Patent. No. 6,846,927 describes a process for preparing Famciclovir by reduction of 9-(4-acetoxy-3-acetoxymethy!but!-yl)-2-amino-6,8-dichloropurine in ethyl acetate in the presence of trietylamine base by catalytic hydrogenation using 5% palladium on charcoal as catalyst.
U.S. Patent. Publication No. 2004/0266795 describes a process for preparing Famciclovir by reacting acetic acid 2-acetoxymethy]-4-(5-amino-7-chloro-imidazo [4,5-b]pyridin-3-ylbutyl) ester in the presence of a Catalyst in a C1-C6 alkyl acetate or in a mixture of C1-C6 alkyl acetate, C1-C4 alcohol and ammonium formate
U.S. Patent. Publication No. 2005/0143400 describes a process for preparing Famciclovir by reacting acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo [4,5-b]pyridin-3-yl)-butyl ester in the presence of a palladium catalyst and water, followed by the addition of ammonium formate.

U.S. Patent. Publication No. 2005/0215787 describes a process for preparing Famciclovir by desulfurising 9-[4-Acetoxy-3-(acetoxymethyl) butyl]-2-amino-6-[(4-methylphenyl)sulphenyI]-9H-purine with Raney-Nickel in ethanoi-water.
U.S. Patent. Publication No. 2008/0154038 describes a process for preparing Famciclovir by reducing 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine in methanol by catalytic hydrogenation using palladium on charcoal (50% wet) as catalyst.
The prior-art processes hitherto reported for preparing Famciclovir leads to the formation of following impurities:
1. Monohydroxy Famciclovir compound of formula II

2. Dihydroxy Famciclovir compound of formula III


It is very difficult to remove above mentioned impurities by conventional crystallization methods and often requires column chromatographic purification step. Therefore, it results in overall lower yield and low process efficiency.
Accordingly there is a need to develop an alternate process for preparing Famciclovir, which would avoid the aforediscussed shortcomings associated with the prior art methods.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a cost effective and industrially advantageous process for the preparation of Famciclovir.
A second aspect of the present invention is to provide a pure Famciclovir compound of formula I substantially free from monohydroxy Famciclovir compound of formula II and dihydroxy Famciclovir compound of formula III.
A third aspect of the present invention is to provide a process for preparing pure Famciclovir compound of formula I comprising reducing acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyndin-3-yl)-butylester compound of formula IV in ether solvent by catalytic hydrogenation.


DETAILED DESCRIPTION OF THE INVENTION:
Acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butyl ester compound of formula IV may be prepared by any of the methods known in the art including those described in U.S. Patent Nos 5,246,937 and 5,684,153 which are incorporated herein by reference only.
The reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo [4,5-6] pyridin-3-yl)-butyl ester compound of formula IV may be carried out in the presence of ether solvents.
Examples of ether solvents may include tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixture(s) thereof.
The reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-irnidazo [4,5-A] pyridin-3-yl)-butyl ester compound of formula IV may be carried out in the presence of ammonium formate.
The catalyst used for the reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butyl ester compound of formula IV may include palladium on carbon.
The reduction of acetic acid 2-acetoxymethyM-(5-amino-7-chIoro-imidazo[4,5-b] pyridin-3-yl)-butyl ester compound of formula IV may be carried out at a temperature in the range of 25°C to 60°C.
The reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b] pyridin-3-yl)-butyl ester compound of formula IV may be carried out for 30 minutes to 12 hours.

The pure Famciclovir may be isolated by cooling the reaction mixture, filtration of catalyst, concentrating the reaction mixture under reduced pressure to yield residue and then extraction by chlorinated solvents to get the pure Famciclovir in organic layer,
The organic layer containing pure Famciclovir may be washed with water and dried over anhydrous sodium sulfate.
Examples of chlorinated solvents may include dichloromethane or chloroform.
The pure Famciclovir may be crystallized by concentrating the organic layer under reduced pressure to yield residue followed by the crystallization from organic solvent.
Examples of organic solvent may include «-butanol or toluene.
The pure Famciclovr obtained by the present invention may be dried under reduced pressure at at temperature in the range of40°C to 50°C.
The pure Famciclovir obtained by the present invention is substantially free from monohydroxy Famciclovir compound of formula II and dihydroxy Famciclovir compound of formula IJJ.
The term "substantially free" herein described refers to the amount of less than 0.1%w/w.
The limit of detection (LOD) of monohydroxy Famciclovir compound of formula II and dihydroxy Famciclovir compound of formula HI is 0.1% w/w.
The limit of quantitation (LOQ) of monohydroxy Famciclovir compound of formula II and dihydroxy Famciclovir compound of formula III is 0.25% w/w.

The process of the present invention is described herein below with reference to the following examples, which are illustrative and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES
EXAMPLE 1: PREPARATION OF FAMCICLOVIR
9-(4-Acetoxy-3-acetoxymethylbutyl)-2-amino-6-chIoropurine (100 gm, 0.28 mol)
was suspended in tetrahydrofuran (500 ml), ammonium formate (90 gm, 1.43 mol)
and 20 gm (5% Pd/C, 50% moisture) was added. The reaction mixture was stirred
at 50-55°C for 6 hours. The reaction mixture was cooled to 30-35°C and Pd/C was
removed by filtration. Solvent was distilled under reduced pressure to obtain a
residue, which was taken into methylene chloride (500 mi). The organic layer was
washed with water (2 X 50ml) and dried over with anhydrous sodium sulphate.
Organic layer was concentrated under reduced pressure and resulting residue was
crystallized from n-butanol (300 ml) to produce Famciclovir.
Yield: 81 gm
Purity: 99.9% (By HPLC)
Monohydroxy Famciclovir compound of formula II: 0.04% w/w
Dihydroxy Famciclovir compound of formula III: Not detected
EXAMPLE 2: PREPARATION OF FAMCICLOVIR
9-(4-Acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine (100 gm, 0.28 mol) was suspended in diisopropyl ether (500 ml), ammonium formate (90 gm, 1.43 mol) and 5% Pd/C (20 gm, 50% moisture) was added. The reaction mixture was stirred at 50-55°C till completion of reaction. The reaction mixture was brought to ambient temperature. Catalyst was removed by filtration. Solvent was distilled under vacuum to obtain a residue, which was taken into 500 ml methylene

chloride. The organic layer was washed with water (2X 50ml) and dried over with
anhydrous sodium sulphate. Organic layer was concentrated under reduced
pressure and resulting residue was crystallized from toluene (250 ml) to produce
Famciclovir.
Yield: 80 gm
Purity: 99.9% (By HPLC)
Mono hydroxy Famciclovir compound of formula II: 0.03% w/w
Dihydroxy Famciclovir compound of formula III: Not detected

WE CLAIM:
1. A process for preparing pure Famciclovir compound of formula I comprising
reducing acetic acid 2-acetoxymethyl-4-(5-amino-7-chioro-irnidazo[4,5-b] pyridin-
3-yl)-butyl ester compound of formula IV in ether solvent by catalytic
hydrogenation.

2. The process according to claim 1, wherein reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butylester compound of formula IV is carried out in the presence of ammonium formate.
3. The process according to claim 1, wherein ether solvent is selected from the group comprising of tetrahydrofuran, 1, 4-dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixture(s) thereof.

4. The process according to claim 1, wherein catalyst used for the reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butyl ester compound of formula IV is palladium on carbon.
5. The process according to claim 4, wherein catalyst used for the reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yI)-butyl ester compound of formula IV is 5% palladium on carbon,

6. The process according to claim 1, wherein reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butylester compound of formula IV is carried out at a temperature in the range of 25°C to 60°C.
7. The process according to claim 1, wherein reduction of acetic acid 2-acetoxymethyl-4-(5-amino-7-chloro-imidazo[4,5-b]pyridin-3-yl)-butylester compound of formula IV is carried out for 30 minutes to 12 hours.
8. The process according to claim 1, wherein pure Famciclovir having less than 0.1% w/w of monohydroxy Famciclovir compound of formula II.
9. The process according to claim 1, wherein pure Famciclovir having less than 0.1% w/w of dihydroxy Famciclovir compound of formula III.
10. A process for preparing pure Famciclovir compound of formula I as herein
described in specification and example.

Dated this 10th day of November 2009
Signature: Name: Dr. Rajendra Agarwal