FIELD OF INVENTION
The present invention relates to an improved process for the preparation of an acid addition salt of Abacavir (I).
Formula I
wherein, A refers to an acid.
BACKGROUND OF THE INVENTION
Abacavir (la) is chemically known as (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-l-methanol.
Abacavir sulfate (II) is an antiretroviral used to treat HIV/AIDS.

Abacavir sulfate (II) is a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1 and is used in combination with other antiretroviral agents, it has been approved for the treatment of Human Immunodeficiency Virus (HIV-1) infection. Abacavir sulfate (II) is marketed in the US under the trade name Ziagen .
U.S. Patent No. 5,034,394 discloses Abacavir or a pharmaceutical^ acceptable ester or a pharmaceutical^ acceptable salt thereof and its process.
US '394 discloses a process for the preparation of Abacavir (la) by condensation of (1 S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1 -methanol (III) with cyclopropylamine in methanol to produce Abacavir (la).
The process is as shown in scheme-I below:
U.S. Patent No. 6,294,540 discloses hemisulfate salt of Abacavir or a solvate thereof and its process.
US '540 also discloses a process for the preparation of hemisufate salt of Abacavir (II) by reacting (lS,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate salt (IV) with sulfuric acid to produce Abacavir sulfate (II). The process is as shown in scheme-II below:

Scheme-II
EP 0777669 discloses succinate salt of Abacavir (IV) and its process for the preparation by treating Abacavir (I) with succinic acid in ethanol and water to give Abacavir succinate (IV). The process is as shown in scheme-Ill below:
The major disadvantage with the above process is the use of organic solvent which leads to tedious work-up^ procedure to isolate the required product. Removal of solvent by distillation leads to exposure of product to high temperature and leads to the formation of undesired impurities. This process is not eco friendly and low yielding with less purity;
Hence, there is a need to develop a cost effective and commercially viable process for the preparation of an acid addition salt of Abacavir (I).
The present invention is directed to a one pot process for the preparation of Abacavir (I) acid addition salt, wherein (lS,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-

cyclopentene-1-methanol hydrochloride (III) is condensed with cyclopropylamine to produce Abacavir (la) which is in-situ treated with an acid in the absence of an organic solvent.This process leads to the recovery of regent, which can be re used.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple, cost effective process for the preparation of an acid addition salt of Abacavir (I) with high purity and good yield on commercial scale.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of an acid addition salt of Abacavir (I),
wherein, A refers an acid, which comprises:
a) reacting (15,4/?)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1 -
methanol hydrochloride (III) with cyclopropylamine to produce Abacavir of formula (la),

b) treating Abacavir (la) in-situ with an acid in absence of an organic solvent to
produce an acid addition salt of Abacavir (I),
c) optionally, recovering cyclopropylamine,
d) optionally, converting an acid addition salt of Abacavir (I), obtained in step(b) to Abacavir sulfate (II).
In another embodiment of the present invention, the acid is an organic acid comprises succinic acid, fumaric acid, maleic acid, melonic acid and oxalic acid, glutarate, hemisuberate (i.e. salt formed from 2:1, base: suberic acid), adipate, fumarate, hemisebacate (i.e. salt formed from 2:1, base: sebacic acid), and pimelate salts; or an inorganic acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of an acid addition salt of Abacavir (I).
The process comprises, reacting (15,47?)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol hydrochloride (III) with cyclopropyl amine to produce Abacavir (la).
In still another embodiment of the present invention, the above process may be carried in the absence of organic solvent.
In still another embodiment of the present invention, the reaction is carried out at suitable temperature may be less than about 150°C, less than about 100°C, less than

about 80°C, less than about 60°C, less than about 40°C, less than about 30°CS less than about 20°C, less than about 10°C, or any other suitable temperature.
In another embodiment, after completion of the reaction, the reaction mass is basified with an aqueous base. The reaction mass is cooled to a temperature ranging from 65° C to 80°C. The reaction mass is neutralized with an acid.
In another embodiment, the base used in the above reaction comprises sodium hydroxide, sodium carbonate, trisodium phosphate, potassium hydroxide, potassium carbonate, calcium hydroxide and ammonia or mixtures thereof.
In another embodiment, the acid used in the above reaction comprises hydrochloric acid and sulfuric acid.
Yet another embodiment of the present invention, Abacavir (la) obtained by the above invention is used as such without isolation, to prepare acid addition salt of Abacavir (I).
In another embodiment, the process to prepare acid addition salt of Abacavir (I) comprises an acid is added to Abacavir (la).
In another embodiment, the reaction is carried out in presence of water at a temperature ranging from 20°C to 35°C.
In another embodiment, the acid used in the above reaction is an organic acid. comprises succinic acid, fumaric acid, maleic acid, melonic acid and oxalic acid, glutarate, hemisuberate (i.e. salt formed from 2:1, base: suberic acid), adipate, fumarate, hemisebacate (i.e. salt formed from 2:1, base: sebacic acid), and pimelate salts; or an inorganic acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid.
In another embodiment of the present invention, an acid addition salt of Abacavir (I) obtained by the above invention is isolated by conventional methods.
Yet another embodiment of the present invention, an acid addition salt of Abacavir (I) may be isolated by methods including removal of water, cooling, concentrating

the reaction mass, or the like. Suitable temperatures for isolation may be less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperatures. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
Yet another embodiment, the acid addition salt of Abacavir (I) is converted to Abacavir sulfate (II) according to the process disclosed in US 6,294,540.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES: EXAMPLE 1: Preparation of Abacavir Succinate
(1 S,4R)~4-(2- Amino-6-chloro-9H-purin-9-y l)-2-cyclopentene-1 -methanol hydrochloride (III) was suspended in DM water at 25-30°C. The slurry mass was stirred for 10 minutes at 25-30°C. Cyclopropylamine was added to the reaction mass and temperature was raised to 50-55°C and maintained the reaction mass to complete the reaction. After completion of the reaction, the reaction mass was basified with aqueous sodium hydroxide solution. The reaction mass was neutralized with hydrochloric acid. Succinic acid was added to the resulting reaction mass to isolate the Abacavir Succinate. Yield: 66.0 g Chromatographic purity (By HPLC): > 99 %.
EXAMPLE 2:
Preparation of Abacavir Succinate
(liS,4y?)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-l-methanol hydrochloride (III) was suspended in DM water at 25-30°C. The slurry mass was stirred for 10 minutes at 25-30°C. Cyclopropylamine was added to the reaction mass and temperature was raised to 50-55°C and maintained the reaction mass to

complete the reaction. After completion of the reaction, the reaction mass was
basified with aqueous potassium hydroxide solution. The reaction mass was
neutralized with hydrochloric acid. Succinic acid was added to the resulting reaction
mass to isolate the Abacavir Succinate.
Yield: 68.0 g
Chromatographic purity (By HPLC): > 99 %.
EXAMPLE 3:
Preparation of Abacavir Succinate
(1 iS54/?)-4-(2-Amino-6-chloro-9H-purin-9-y l)-2-cyclopentene-1 -methanol hydrochloride (III) was suspended in DM water at 25-30°C. The slurry mass was stirred for 10 minutes at 25-30°C. Cyclopropylamine was added to the reaction mass and temperature was raised to 50-55°C and maintained the reaction mass to complete the reaction. After completion of the reaction, the reaction mass was basified with aqueous ammonia solution. The reaction mass was neutralized with hydrochloric acid. Succinic acid was added to the resulting reaction mass to isolate the Abacavir Succinate. Yield: 64.0 g Chromatographic purity (By HPLC): > 99 %.

We Claim;
1. A process for the preparation of an acid addition salt of Abacavir (I),
wherein, A refers an acid, which comprises: ■
a) reacting (15,47?)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1 -
methanol hydrochloride (III),
with cyclopropylamine to produce Abacavir of formula (la),
b) treating, Abacavir (la) in-situ with an acid in absence of an organic solvent to produce an acid addition salt of Abacavir (I),
c) optionally, recovering cyclopropylamine,
d) optionally, converting an acid addition salt of Abacavir (I), obtained in step(b) to Abacavir sulfate (II).
2. The process as claimed in claim 1, wherein the acid is an organic acid comprises succinic acid, fumaric acid, maleic acid, melonic acid and oxalic acid, glutarate,

hemisuberate (i.e. salt formed from 2:1, base: suberic acid), adipate, fumarate, hemisebacate (i.e. salt formed from 2:1, base: sebacic acid), and pimelate salts; or an inorganic acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid.
3. The process as claimed in claim 1, the condensation in step (a) is carried out in presence of a base.
4. The process as claimed in claim 2, the base comprises sodium hydroxide, sodium carbonate, trisodium phosphate, potassium hydroxide, potassium carbonate, calcium hydroxide and ammonia or mixtures thereof.
5. The process as claimed in claim 1, the condensation in step (a) is carried out in presence of an acid comprises hydrochloric acid and sulfuric acid.
6. The process as claimed in claim 1, the acid in step (b) is carried out in presence of an organic acid or a inorganic acid.
7. The process as claimed in claim 5, the acid is an organic acid comprises succinic acid, fumaric acid, maleic acid, melonic acid and oxalic acid, glutarate, hemisuberate (i.e. salt formed from 2:1, base: suberic acid), adipate, fumarate, hemisebacate (i.e. salt formed from 2:1, base: sebacic acid), and pimelate salts.
8. The process as claimed in claim 5, the inorganic acid comprises an inorganic acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid.
9. The process as claimed in claim 1, which is a single pot synthesis.