FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION [See section 10, rule 13]
An Improved and Commercially Viable Process For the Preparation of Famciclovir
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention provides an improved and commercially viable process for preparation of famciclovir of compound of formula (I), in high purity and good yield

BACKGROUND OF INVENTION
Famciclovir is an antiviral drug marketed by SmithKline Beecham and is available as Famvir. Famvir is indicated for the treatment of acute herpes zoster (shingles). It is also indicated for treatment or suppression of recurrent genital herps in immunocompetent patients and for treatment of recurrent mucocutaneous herpes simplex infections in HIV infected patients. The chemical name for famciclovir is [2-(acetyloxymethyl)-4-(2-aminopurin-9-yl) butyl] acetate.
Processes for the preparation of purine derivatives such as famciclovir were disclosed in various patents such as EP182024, US5684153, US5138057, US5917041, US6761767, WO 2004/110343, EP302644, GB2426247 and US6846927.
According to EP182024 famciclovir is prepared as described in below Scheme 1, 2-amino-6-chloro-9-[2-(2, 2-dimethyl-l, 3-dioxan-5-yl)ethyl] purine was treated with 10% Pd/C gave 2-amino-9-(4-hydroxy-3-hydroxymethylbut-l-yl) purine, which on acetylation gave famciclovir.
2

The yields obtained in this process are very low. Moreover, preparation of compound of formula A starting from diethyl malonate is also a very lengthy process, which makes this process tedious and incompatible on the large scale.
As described below in Scheme 2, US5684153 patent describes preparation of Famciclovir, which comprises the reaction of 2-amino-6-chloropurine (herein after referred to as ACP) with 2-acetoxymethyl-4~(leaving group)-but-l-yI acetate of compound of formula B giving 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine, followed by dechlorination leads to famciclovir.


This process suffers in two aspects,
1) Column purification is required to isolate N-9 alkylated product obtained in step 1
2) Intermediate of formula B is not commercially available and also the synthesis of it has multisteps.
One method, set out below in Scheme 3, is known from EP 302644.

The starting material, ACP is commercially available and is inexpensive. However, a common problem associated with this process is lack of regioselectivity. Undesired N-7 isomer at alkylation stage gets generated along with N-9 isomer. In the said process undesired N-7 isomer is removed by crystallization and column chromatography which makes the process complicated and commercially not viable. The overall yield of famciclovir from using this process is only 7-10%.

US5138057 discloses the preparation of famciclovir starting from 2-amino-6,8-dichloropurine. However, this process also suffers with the common problem of column chromatographic separation of desired isomer.
US5971041 describes the preparation of Famciclovir as depicted in Scheme 4 below

The above method tried to remove the formation of undesired isomer through careful control of the reaction condition. However, the starting materials of formula C and D are not commercially available and have to be prepared separately through
multi steps.
Another method set out in Scheme 5 is known from WO2004/110343


The method includes several steps and also suffers in overall yield of Famciclovir. One more method, set out as Scheme 6, is described in US6846927


Scheme 6
According to US6846927, ACP treated with triethyl-3-bromopropane-l,l,l-tricarboxylate, in the presence of inorganic base, such as potassium carbonate in a suitable solvent, such as N,N-dimethylforrnamide, at a temperature 60°C to 63°C for 22 hour gave crude triethyl-3-(2-amino-6-chloro-9H-purin-9-yl)propane-l,l,l-tricarboxylate (herein after referred to as triester), which was then converted to dimethy1-2-(2-(2-arnino-6-chloro-9H-purin-9-yl)ethyl)malonate (herein after referred to as diester) by treatment with sodium methoxide in methanol. Resulting diester on reduction with sodium borohydride gave crude 2-(2-(2-amino-6-chlro-9H-purin-9yl)-ethyl)propane)propane-l,3-diol (herein after referred to as diol). Diol on acetylating with acetic anhydride gave 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine, which is finally, dechlorinated by hydrogenolysis reaction to yield famciclovir.

It was observed that the process from ACP is generally described in US6846927 is an improved process over the process specifically described in other prior art.
We have repeated the famciclovir synthetic procedure described in the US6846927 and found that crude triester obtained by alkylation process have approximately 80:20 ratio of N-9:N-7 positional isomers. Mixture of N-9:N-7 isomers was further subjected for sodium methoxide treatment. Diester which was precipitated out was filtered to get pure N-9 in 64% yield. Subsequently diester was treated with sodium borohydride to get crude Diol. Crude Diol gave 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine with 62% yield through acetylation followed by dechlorination to get famciclovir with 90% yield. This process gives overall yield of 35.7% from chloroguanine in five steps.
Thus, the process still requires modifications with respect to yield, quality and scalability.
A more recent method, set out as scheme 7, is known from GB2426247

The method depicted in Scheme 7 tried to address common problem of formation of undesired isomer and tried to maximize the percentage of desired 9-substituted compound by reacting 1,2-dibromoethane with ACP in N,N-dimethylformamide at

60°C temperature in presence of potassium carbonate gave compound of formula E with 91% yield.
However, in our observation it was found that the dimerized product as well as the unwanted isomer has been formed as by products in the very first step.
Based on the above mentioned drawbacks, it is noted that there is a need to improve process of preparing pure famciclovir and make it commercially viable which solves the problems associated with processes described in the prior art.
OBJECT OF INVENTION
An object of the present invention is to provide an improved process for preparation of famciclovir of compound of formula (I)
Another object of the present invention is to provide a simple and efficient process for the isolation of desired isomer of triester at first step.
Another object of the present invention is to provide a process for direct reduction of triester to diol by avoiding the decarboxylation step.
Yet another object of the present invention is to provide a commercially feasible process for preparation of famciclovir with improved yield and quality.
SUMMARY OF INVENTION
The present invention describes an improved and efficient process for preparation of famciclovir of compound of formula (I) with high purity and good yield. The process is viable for large scale production with improved yield.


The present invention also describes a simple and efficient process for isolation of desired isomer of triester, obtained by alkylation reaction, which avoids column chromatographic separation of isomers and also provides improved yield of the product.
The present invention further describes the process for the direct reduction of triester to diol. The process of present invention avoids the decarboxylation step and thus avoids formation of diester compound.
DESCRIPTION OF INVENTION
The present invention provides an improved and commercially viable process for preparation of famciclovir of compound of formula (I), in high purity and good yield

The process of present invention comprises the steps of 1) formation of triester compound by alkylation reaction 2) direct reduction of triester compound to diol

compound followed by acetylation of diol in the same step 3) hydrogenolysis of acetylated compound to famciclovir. Thus, present invention involves 3 steps process for preparation of famciclovir which avoids decarboxylation step as described in US6846927.
The present invention also provides simple and efficient process for isolation of triester compound to obtain desired N-9 isomer by avoiding column chromatographic separation.
According to the present invention, there is provided an improved process for
preparation of famciclovir of compound of formula (I) as shown above, which
comprises,
(i) Isolation of desired N-9 isomer of triester of compound of formula (II), in good
yield

by precipitating it with a suitable solvent at room temperature from the reaction mixture, obtained by reacting compound of formula (III)

with compound of formula (IV)


in presence of potassium bicarbonate or potassium carbonate as a base in suitable organic solvent such as N-methylpyrrolidone or N, N-dimethylformamide ii) converting first triester of compound of formula (II) to diol of compound of formula (V)

by reduction of triester compound using reducing agent in presence of inert solvent alone or in combination with alcohol followed by acetylation of diol of formula (V) using acetic anhydride in an inert solvent like dichloromethane, dichloroethane, chloroform in presence of triethylamine as a base and catalytic quantity of 4-dimethyl amino pyridine to give compound of formula (VI)

iii) Converting compound of formula (VI) to famciclovir of formula (I) by dehalogenation process as known in the art
The process of the present invention is as depicted in the Scheme 8 below


Scheme S
The reaction of step (I) may be carried out between 25°C to 140°C temperature, preferably carried out between 60°C to 90°C, more preferably at 60°C temperature.
The reaction is carried out for 12 to 48 hrs., preferably for 22hrs.
According to an aspect of present invention, after completion of the reaction desired N-9-positional isomer of triester is isolated by precipitating it with addition of suitable solvent such as water, which is then separated by simple Alteration where N-7-isomer goes to solution. Thus, it has been found that employment of above step process result in isolation of pure N-9-substituted compound of formula (II),
The amount of water used for the precipitation is preferably 0.5 to 1.5-fold in a volume ratio to the organic solvent, more preferably 1 to 1.5-fold.
It has also been discovered that use of potassium bicarbonate as a base, with combination of N-methyl pyrrolidone solvent gives exclusive desired isomer with 70-75% yield on isolation of product by precipitating it with water and N7 isomer goes to the filtrate.

While, in case of potassium carbonate base and N, N Dimethylformamide solvent combination, it has been observed that N9 and N7 both the isomers are precipitated simultaneously in (84:16) ratio respectively with 85-90% of total yield.
In another aspect of the present invention there is provided a process for direct reduction of triester of compound of formula (II) to diol of compound of formula (V).

The step (ii) process involves the direct reduction reaction of triester to diol followed by acetylation reaction of diol.
It has surprisingly been discovered that during triester reduction, decarboxylation also take place simultaneously without any side reactions. We also observed that conversion of triester to diol was a clean reaction. (Clean reaction referred to as complete conversion of triester to pure diol only). The process of present invention evades conversion of formula (II) to formula (VII). Thus, eliminates trans-esterification step which is the key difference of the present invention and the process described in US6846927.


It has also been discovered that reduction of triester with mixture of N9.N7 isomer (obtained from step(I) reaction as mentioned in Example 2) also gives desired N9 isomer of acetylated product, while respective N7 isomer of acetylated product goes to the filtrate during purification of acetylated product in methanol and water (as described in Example 4).
Reduction may be carried out using reducing agents like, sodium borohydride, potassium borohydride, sodium or potassium cyanoborohydride and lithium aluminum hydride, preferably sodium borohydride
Reduction may be carried out in an inert solvent alone or in combination with alcohol. Inert solvent is selected from dichloromethane, dichloroethane, tetrahydrofuran and chloroform, more preferably dichloromethane and alcohol is selected from methanol, ethanol or, isopropanol, preferably methanol is used.
The reaction temperature is conveniently in the range of 0-60°C. At lower temperatures, longer duration of reaction time is required for example as long as 20 hours or more may be required for reduction at 0°-5°C. At higher temperature (50-60°C) reaction becomes uncontrolled which gives number of by products.
The reaction is carried out at temperature 15-20°C, with total reaction hours of 1 to 8, more preferably from 4-5 hours.
The acetylation reaction of step (ii) is carried out using acetic anhydride in an inert solvent like dichloromethane, dichloroethane or chloroform, using triethylamine as a base with catalytic quantity of 4-dimethyl amino pyridine.
Dehalogenation was done in step (iii) in presence of suitable catalyst, such as Pt, Pd, Raney Ni by known prior art process. Preferably dehalogenation is carried out with 5% Pd on carbon using triethylamine in ethyl acetate as a solvent under hydrogen pressure to give famciclovir of formula (I).

The invention is now described in more detail with reference to specific embodiment as set out in the following example.
EXAMPLE 1
(Stage 1 Product)
Preparation of 2-Amino-6-chloro-9-(ethyl 2,2-dicarboethoxybutanoate-4-yl)
purine
A mixture of 2-amino-6-chloropurine (10g, 0.0589 moles), triethyl 3-bromopropane-
1,1,1-tricarboxylate (22.00g, 0.0648 moles), potassium bicarbonate (29.48g, 0.2945
moles) and N-methyl pyrrolidinone (170 ml) were stirred together at 60-63oC for 22
hours. After this time, the reaction mixture was cooled to room temperature. Added
water (255 ml) in to the reaction mixture. Precipitated product was filtered and
washed with mixture of NMP: water (4:6, 20 ml) and dried at 60°C for 12 hour
under reduced pressure.
'H NMR (400MHZ, DMSO-d6): 5 1.15-1.19 (t, 9H, -CH2CH3), 2.49-2.60(t, 2H, -
CH2CH<), 4.13-4.18(q, 6H, CH2-CH3), 4.26-4.30(t, 2H, >NCH2), 6.90(brs, H, NH2),
8.03(3, 1H, H-8)
C13 NMR (400MHz, DMSO-d6): 6 13.64, 31.83, 39.44, 62.33, 62.40, 63.65,123.34,
143.15, 149.34, 154.06, 159.75, 165.91.
Yield: 18.0 g (71.34%)
Purity (HPLC).- 99% of desired isomer
EXAMPLE 2
(Stage 1 Product)
Preparation of 2-Amino-6-chloro-9-(ethyl 2,2-dicarboethoxybutanoate-4-yl)
purine
A mixture of 2-Amino-6-chloropurine (lOg, 0.0589 moles), triethyl 3-bromopropane- 1,1,1-tricarboxylate (22.00g, 0.0648 moles), potassium carbonate

(16.25g, 0.1178 moles) and N,N-Dimethy]formamide (170 ml, 17 volumes) were
stirred together at 60-63°C for 22hour. After this time the reaction mixture was
cooled to room temperature. Added water (255 ml) in to the reaction mixture.
Precipitated product was filtered and washed with a mixture of N,N-
Dimethylformamide:water (4:6, 20 ml) and dried at 60°C for 12hour in a vacuum
oven.
Yield: 22.7 g (90%).
Purity (HPLC) :- (84%: 16%) (N-9 position isomer:N-7 position isomer)
The N-9:N-7 position isomer ratio was obtained from the respective integration
value of the H-8 JH NMR signal.
EXAMPLE 3
(Stage 2 Product)
Preparation of 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine
A mixture of Example 1 product (10g, 0.034 moles), sodium borohydride (6.448g, 0.17 moles) and dichloromethane (125 ml) were stirred at 20°C. Methanol (30 ml) was added dropwise over 2.0 hour period while the reaction temperature was maintained at 20-22°C with cooling. The reaction mixture was left to stir for further 1.5 h. Water (30 ml) was added followed by dropwise addition of concentrated hydrochloric acid (7 ml) to pH 6.7 to 7.0 by keeping the reaction temperature at 20-22°C. Solvents were removed under reduced pressure to get a gummy residue. The residue was stirred with methanol (25 ml) and filtered the inorganic salt. The filtrate was evaporated to give the yellow solid. The resulting yellow solid (12-15g) was stirred with triethylamine (5ml), 4-dimethylaminopyridine (0.3g) in dichloromethane (50 ml). Acetic anhydride (13 ml) was added dropwise over 20-30 minutes at such a rate to control the reflux. The reaction mixture was heated under reflux for a further 1.5 hours. The reaction was cooled to 20°C and neutralized with 20% w/w sodium hydroxide solution to pH 6.4-6.5. The dichloromethane layer was separated and the aqueous phase extracted with dichloromethane (100 ml). The combined

dichloromethane phases were evaporated to dryness. The crude solid mass was
purified from 3:1 methanol/water (75 ml), cooling the precipitate to -5°C for
1 hour before filtration. The product was washed with cold methanol/water (3:1) and
dried at 40°C for 16hour under reduced pressure.
1H NMR (400MHz, DMSO-d6): 5 1.86-1.98(m, 3H, -CH2-CH-), 2.00(s, 6H, 2x-
COCHs), 4.02-4.03(d, 4H, 2xCH2OAc), 4.13-4.16(t, 2H, >N-CH2), 6.93(s, 2H, -
NH2), 8.18(s, lH,H-8)
C13 NMR (400MHz, DMSO-d6): 8 20.61, 27.12, 34.43, 40.90, 63.46, 123.39,
143.21, 149.35, 154.08, 159.76, 170.38.
Yield: 5.76g (69.35%)
Purity (HPLC):- 95% to 99.9% of desired isomer
EXAMPLE 4
(Stage 2 Product)
P reparation of 9-(4-acetoxy-3-acetoxymethyIbu t- l-yI)-2-amino-6-chIoro purine
A mixture of Example 2 product (lOg, 0.034 moles), sodium borohydride (6.448g, 0.17 moles) and dichloromethane (125 ml) were stirred at 20°C. Methanol (30 ml) was added dropwise over 2.0hour period while the reaction temperature was maintained at 20-22°C with cooling. The reaction mixture was left to stir for further 1.5 h. Water (30 ml) was added followed by dropwise addition of concentrated hydrochloric acid (7 ml) to pH 6.7 to 7.0 by keeping the reaction temperature at 20-22°C. Solvents were removed under reduced pressure to get a gummy residue. The residue was stirred with methanol (25 ml) and filtered the inorganic salt. The filtrate was evaporated to give the yellow solid. The resulting yellow solid (12-15g) was stirred with triethylamine (5ml), 4-dimethylaminopyridine (0.3g) in dichloromethane (50 ml). Acetic anhydride (13 ml) was added dropwise over 20-30 minutes at such a rate to control the reflux. The reaction mixture was heated under reflux for a further 1.5 hours. The reaction was cooled to 20°C and neutralized with 20% w/w sodium hydroxide solution to pH 6.4-6.5. The dichloromethane layer was separated and the aqueous phase extracted with dichloromethane (100 ml). The combined

dichloromethane phases were evaporated to dryness. The crude solid mass was
purified from 3:1 methanol/water (75 ml), cooling the precipitate to -5°C for
1 hour before filtration. The product was washed with cold methanol/water (3:1) and
dried at 40°C for 16hour under reduced pressure.
1H NMR (DMSO-d6): 5 1.86-1.98(m, 3H, -CH2-CH-), 2.00(s, 6H, 2X-COCH3) 4.02-
4.03(d, 4H, 2xCH20Ac), 4.13-4.16(t, 2H, >N-CH2), 6.93(s, 2H, -NH2), 8.18(s, 1H,
H-8)
C13 NMR (400MHz: DMSO-d6): 5 20.61, 27.12, 34.43, 40.90, 63.46, 123.39,
143.21, 149.35, 154.08, 159.76, 170.38.
Yield: 4.57 g (55%)
Purity (HPLC):- 95% to 99.9% of desired isomer
EXAMPLE 5
(Stage 3 product)
Preparation of 2-Amino-9-(methyl 2-carbomethoxybutanoate-4-yl) purine
A mixture of 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine (15.4 g, 43 mmole), 5% palladium on carbon (6.16 g), triethylamine (6.6 ml, 47 mmole) and ethyl acetate (77 ml) was stirred at 500C under a hydrogen atmosphere at 3 Kg pressure in an autoclave for 3 to 5 hours. After completion of the reaction the mixture was removed from the autoclave which was washed out with ethyl acetate (30 ml). The main reaction mixture was filtered through a celite bed followed by the washings and finally with ethyl acetate (30 ml). Water (46 ml) was added to the combined ethyl acetate filtrate. The ethyl acetate was evaporated to dryness to give crude white solid. This was recrystallised from n-butanol (62 ml) by stirring the cooled solution at 0 to 5°C for 3 h. The product was filtered off. The solid was reslurried in n-heptane (50 ml) stirred for 30 minutes and then filtered. The product was dried at 40°C for 16hours under reduced pressure.
'HNMR (DMSO-d6): 8 1.85-1.94(m, 3H, -CH2CH-), 1.99(s, 6H, 2X-COCH3) 4.01-4.03(d, 4H, 2x-CH20COCH3), 4.12-4.15(t, 2H, >NCH2), 8.09(s, 1H, H-8), 8.56(s, 1H, H-5).

C13 NMR (400MHz, DMSO-d6): 6 20.61, 27.85, 34.49, 40.23, 63.48,126.93, 142.68, 149.03, 152.98, 160.50, 170.39 Yield: 11-11.3 g (90%) Purity (HPLC)>99.99%
The advantages of process of the present invention are,
a) It provides simple and easy isolation of desired N-9 isomer of triester by precipitation technique, which avoids tedious column separation. Thus, improves yield and purity of the product.
b) Isolation process of the present invention is carried out using water, which is cheapest and environmental friendly solvent,

b) Isolation process of the present invention decreases the overall production cost,
c) It provides direct reduction of triester to diol, which eliminates formation of diester step and hence decreases overall production cost.
d) With streamlining of the less number of process stages and ease isolation of desired isomer step it reduces the production cost, with 40-45% overall yield.

We claim
1. An improved process for preparation of famciclovir of compound of formula (I)

which comprises,
(i) Isolation of desired N-9 isomer of triester of compound of formula (II), in good
yield


with compound of formula (IV)

by precipitating it with a suitable solvent at room temperature from the reaction mixture, obtained by reacting compound of formula (III)

in presence of potassium bicarbonate or potassium carbonate as a base in suitable organic solvent such as N-methylpyrrolidone or N, N-dimethylformamide ii) converting first triester of compound of formula (II) to diol of compound of formula (V)

by reduction of triester compound using reducing agent in presence of inert solvent alone or in combination with alcohol followed by acetylation of diol using acetic anhydride in an inert solvent like dichloromethane, dichloroethane, chloroform as a solvent in presence of triethylamine as a base and catalytic quantity of 4-dimethyl amino pyridine to give compound of formula (VI).

iii) converting compound of formula (VI) to famciclovir of formula (I) by dehalogenation process as known in the art.
2. A simple and efficient process for isolation of desired N-9 isomer of triester of formula (II) exclusively or in the ratio of 84:16 with N-7 isomer, in good yield

by precipitating it with suitable solvent at room temperature from the reactior mixture, obtained by alkylation reaction of compound of formula (III)


and compound of formula (IV)

using potassium bicarbonate or potassium carbonate as a base in presence of suitable organic solvent such as N-methylpyrrolidone or N, N-dimethylformamide
3. The process as claimed in claim I or 2, wherein desired N-9 isomer of triester of formula (II) is isolated exclusively when the alkylation reaction is carried out using potassium bicarbonate as a base and N-methylpyrrolidone as a solvent
4. The process as claimed in claim 1 or 2, wherein desired N-9 isomer of triester of formula (II) is isolated in the ratio of 84:16 with N7 isomer when the alkylation reaction is carried out using potassium carbonate as a base and N, N-dimethylformaide as a solvent
5. The process as claimed in claim \ or 2, wherein suitable solvent used for isolation of desired N-9 isomer of triester of formula (II) is water.
6. The process as claimed in claim 1 or 5, wherein the amount of water used for the precipitation is preferably 0.5 to 1.5-fold in a volume ratio to the organic solvent, more preferably 1 to 1.5 -fold
7. The process of direct reduction of triester of compound of formula (II) to diol of compound of formula (V)


by using reducing agent in presence of inert solvent alone or in combination with alcohol and thus by avoiding decarboxylation step
8. The process as claimed in claim 1 or 7, wherein reducing agent used for direct reduction of triester is selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride or potassium cyanoborohydride and or lithium aluminum hydride, preferably sodium borohydride
9. The process as claimed in claim 1 or 7, wherein inert solvent used for reduction is selected from dichloromethane, dichloroethane, tetrahydrofuran or chloroform, more preferably dichloromethane and alcohol is selected from methanol, ethanol or, isopropanol, preferably methanol
10. The process as claimed in claim 1 or 7, wherein reduction reaction is carried out
at temperature 15-20°C