FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
SUBSTITUTED-2-AMINO-1H-PURIN-6-ONES AND SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides substituted-2-amino-1H-purin-6-ones and salts
thereof.
The following specification particularly describes the invention and the manner in
which it is to be performed.

4. DESCRIPTION
The invention provides substituted-2-amino-1H-purin-6-ones and salts thereof and process of preparation of the same. The invention further provides a pharmaceutical composition comprising substituted-2-amino-1H-purin-6-ones and salts thereof.
Valacyclovir is chemically, L-valyl ester of acyclovir designated as 2-[(2-amino-1,6-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.


H,N

FORMULA I
U.S. Patent No 4,957,924 provides process for preparation of valacyclovir or salt thereof.
Several other processes are known in the art for preparation of valacyclovir such as U.S. Patent No 6,849,737; U.S. patent application No. 2005130993; U.S. patent application No 20050192296; U.S. patent application No 20050059684, U.S. patent application No 2005070711, U.S. patent application No 2007021444, PCT application Nos. WO 2006011874, WO 2006035452 and WO 2007013645.
There are several polymorphic forms of valacyclovir or its salt known in the art through U.S. Patent No 6,107,302 and U.S. Patent No 6,849,736; U.S. patent

application No 2005043329, U.S. patent application No 20040197396, U.S. patent application No 20050085491 and U.S. patent application No 2005187229; and PCT Patent application WO 2004106338.
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The inventors while developing a process for the preparation of valacyclovir have found that compound of formula II or salts thereof is produced. Further, Inventors provides a process of preparation of compound of formula II as depicted in scheme-l by reacting compound of formula-Ill with compound of formula-IV in presence of polar solvent, o
HN 'T \ j_ /CX /CI
A X /+ R
Scheme-l
(HI) (IV)
wherein R is C1-C6 alkyl.
In one aspect of the invention there is provided a compound of formula II or salts thereof,
o

wherein R is C1-C6 alkyl.
The specific compounds of invention include;
1) 2-amino-9-(methoxymethyl)-1 H-purin-6(9H)-one.
2) 2-amino-9-(ethoxymethyl)-1 H-purin-6(9H)-one.
3) 2-amino-9-(n-propyloxymethyl)-1 H-purin-6(9H)-one.
4) 2-amino-9-(iso-propyloxymethyl)-1 H-purin-6(9H)-one.
5) 2-amino-7-(methoxymethyl)-1 H-purin-6(7H)-one.
6) 2-amino-7-(ethoxymethyl)-1 H-purin-6(7H)-one.

7) 2-amino-7-(n-propyloxymethyl)-1 H-purin-6(7H)-one.
8) 2-amino-7-(iso-propyloxymethyl)-1 H-purin-6(7H)-one.
In this disclosure, CrC6 alkyl refers to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. The examples of C1-C6 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, and n-hexyl.
In this disclosure, the term "salts" refers to pharmaceutically acceptable acid addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, (3-hydroxybutyric, galactaric and galacturonic acid.
In another aspect of the invention there is provided a process for the preparation of compound of formula II, which includes the steps of:
o

HN
H7N N

(U, ^

a) treating compound of formula-Ill with compound of formula-IV in presence of polar solvent,
-N
o HN'

H,N N
2IN IN j_j
(III) (IV)
b) isolating compound of formula II from the reaction mixture thereof.
The compound of formula II was prepared by treating compound of formula III reaction solution with compound of formula IV at a reflux temperature. The compound of formula III reaction solution is prepared by adding compound of formula III in hexamethyldisilazane and ammonium sulphate in catalytic amount. The hexamethyldisilazane was distilled under vacuum and the resulting mass was dissolved in polar solvent followed by compound of formula IV. Compound of formula II was isolated from the reaction mixture thereof.
The polar solvent includes from the group of dimethyl sulphoxide, dimethyl formamide, hexamethyldisilazane, dioxane, tetrahydrofuran, dimethylacetamide, N-methylpyrrolidone, acetonitrile, propionitrile, benzonitrile, glutaronitrile, malononitrile, butyronitrile, adiponitrile, caprinitrile, acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like or mixture thereof.
In yet another aspect of the invention there is provided a pharmaceutical composition containing compound of formula II in association with a pharmaceutically acceptable excipient and/or carrier wherein the composition may comprise a formulations such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.

The examples of solid composition include compressed tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules. The examples of liquid composition include emulsions, solutions, suspensions, syrups and elixirs. The examples of injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example
2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one
Guanine (5.0 g, formula III) was added slowly in hexamethyldisilazane (300.0 ml) followed by ammonium sulphate (300.0 mg). The reaction mixture was refluxed for 20-28 hours. Hexamethyldisilazane was distilled under vacuum and this mass was dissolved in dimethylformamide (25.0 ml). To this mixture methoxy methyl chloride (2.6 g) was added. The reaction mixture was stirred at room temperature till the formation of the product. The reaction mixture was quenched with water and the organic layer was concentrated. The 2-amino-9-(methoxymethyl)-1H-purin-6(9H)-one was then isolated from reaction mixture thereof.
Yield : 0.95 g
1H NMR (400 MHz, DMSO): 5 3.21 (3H,s), 5.24 (2H, s), 6.50 (2H, bs), 7.78 (1H,
s), 10.62 (1H,bs).
1H NMR (400 MHz, DMSO/D20): 6 3.19 (3H,s), 5.23 (2H, s), 7.78 (1H, s).
Mass(m/e): 196.0 (M+1).
13C NMR (100 MHz, DMSO): 157.5, 154.5, 152.1, 138.4, 117.1,73.8,56.5

We claim:

1. A compound of formula II or salts thereof,
0 o
m\T \ OR HN' ,.
R H2r'
(ID "°
wherein R is C1-C6 alkyl.
2. The compound of claim 1, wherein specific compounds include;
a) 2-amino-9-(methoxymethyl)-1 H-purin-6(9H)-one.
b) 2-amino-9-(ethoxymethyl)-1 H-purin-6(9H)-one.
c) 2-amino-9-(n-propyloxymethyl)-1 H-purin-6(9H)-one.
d) 2-amino-9-(iso-propyloxymethyl)-1 H-purin-6(9H)-one.
e) 2-amino-7-(methoxymethyl)-1 H-purin-6(7H)-one.
f) 2-amino-7-(ethoxymethyl)-1 H-purin-6(7H)-one.
g) 2-amino-7-(n-propyloxymethyl)-1 H-purin-6(7H)-one. h) 2-amino-7-(iso-propyloxymethyl)-1 H-purin-6(7H)-one.
3. A process for the preparation of compound of formula II, which comprises of:
o


a) treating compound of formula-Ill with compound of formula-IV in presence of polar solvent,
-N
O HN'
N
FT
HoN N
I2IM IN H
(III) (IV)

wherein R is C1-C6 alkyl.
b) isolating compound of formula II from the reaction mixture thereof.
4. The process of claim 3, wherein polar solvent includes one or more from the group of dimethyl sulfoxide, dimethylformamide, hexamethyldisilazane, dioxane, tetrahydrofuran, dimethylacetamide, N-methylpyrrolidone, acetonitrile, propionitrile, benzonitrile, glutaronitrile, malononitrile, butyronitrile, adiponitrile, caprinitrile, acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like or mixture thereof.
5. The process of claim 3, wherein reaction of formula III and formula IV is carried out at a reflux temperature.
6. A pharmaceutical composition containing compound of formula II an II' in association with a pharmaceutically acceptable excipient and/or carrier.
7. The pharmaceutical composition of claim 6, wherein the composition comprise a formulations which includes solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.

Abstract
The invention provides substituted-2-amino-1H-purin-6-ones and salts thereof and process of preparation of the same. The invention further provides a pharmaceutical composition comprising substituted-2-amino-1H-purin-6-ones and salts thereof.
In yet another aspect of the invention there is provided pharmaceutical composition of valacyclovir.
In this disclosure, pharmaceutical composition of valacyclovir refers to a pharmaceutical composition of valacyclovir and salts thereof with a content of compound of formula II content of 1% or less.