PREPARATION OF ABACAVIR AND ITS SALTS

INTRODUCTION Aspects of the present application relates to an improved process for the preparation of abacavir and its salts thereof.

Abacavir sulfate is chemically described as (1S,cis)-4-[(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)]-2-cyclopentene-1-methanol sulfate. It has the structure of Formula (I).

Abacavir sulfate is a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1 and is used in combination with other antiretroviral agents, are - indicatedforthe treatment of-human HmmunodeJflcienGy-virus (HIV-1 Hnfection. -U.S. Patent No. 5,034,394 discloses abacavir or a pharmaceutfcally acceptable; ester or a pharmaceutically acceptable salt thereof and its process. U.S. Patent No. 6,294,540 discloses hemisulfate salt of abacavir or a solvate thereof and its process.

U.S. Patent No. 6,646,125 discloses in-situ process for the preparation of abacavir by reacting (1R, 4S)-cis-[4-(hydroxymethyl)-2-cyclopentene-1-yl] carbamic acid with N-(2-amino-4, 6-dichloro-5-pyrimidinyl) formamide to give (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol, followed by in situ ring closure of the resultant intermediate with trialkyl orthoformate in the presence of a mineral acid to give (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol, further it converted to abacavir.

There remains a need to provide improved process for the preparation of abacavir or a pharmaceutically acceptable salt thereof that are cost-effective and environment friendly.

SUMMARY In an aspect, the present application provides an improved process for the preparation of abacavir or a pharmaceutically acceptable salt thereof of formula (II),
which includes one or more of the following steps, individually or in the sequence recited:

a) reacting N-(2-amino-4,6-dichloro-5-pyrimidinyl) formamide of formula (III) with (1S,4R)-(4-aminocyclopent-2-enyl)methanol or a pharmaceutically acceptable salt thereof of formula (IV) in the presence of base to give (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol of formula (V);

b) cyclizing the (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)
amino]-2-cyclopentene-1 -methanol of formula (V) with a cyclizing reagent to provide
(1 S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1 -methanol or
pharmaceutically acceptable salt thereof of formula (VI);

c) reacting (1 S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol or a pharmaceutically acceptable salt thereof of formula (VI) with cyclopropylamine to provide abacavir of formula II; and

d) optionally, converting abacavir in to a pharmaceutically acceptable salt thereof.

In an aspect, the present application provides a process for preparing an amorphous form of abacavir, which includes one or more of the following steps:
a) providing a solution of abacavir in a solvent or mixture of solvents; and
b) isolating an amorphous form of abacavir.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of a crystalline form of abacavir, prepared according to Example 6.

Fig. 2 is an illustration of a differential scanning calorimetry (DSC) thermogram of a crystalline form of abacavir, prepared according to Example 6.

Fig. 3 is an illustration of a thermogravimetric analysis (TGA) curve of a crystalline form of abacavir, prepared according to Example 6.

Fig. 4 is an illustration of powder X-ray diffraction (PXRD) pattern of an amorphous form of abacavir, prepared according to Example 7.

Fig. 5 is an illustration bfa differential scanning calorimetry (DSC) thermogram of an amorphous form of abacavir, prepared according to Example 7.

Fig. 6 is an illustration of a thermogravimetric analysis (TGA) curve of an amorphous form of abacavir, prepared according to Example 7.

DETAILED DESCRIPTION All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25° C and normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.

As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements that are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. As used herein, "consisting essentially of means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed

invention. All ranges recited herein include the endpoints, including those that recite a range "between" two values. The terms "about," "generally," "substantially,", or the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

Where this document refers to a material, such as for example, in this instance, abacavir, and the unique solid and/or crystalline forms, salts, solvates, and/or optical isomers thereof by reference to patterns, spectra, or other graphical data, it may do so by qualifying that they are "substantially" shown or depicted in a figure, or by one or more data points. It will be appreciated that patterns, spectra, and other graphical data may be shifted in their positions, relative intensities, or other values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X ray diffraction arts, shifts in peak positions, or the relative intensities of one or more peaks of a pattern can occur because of, without limitation: the equipment used, the sample

preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, or the like. However, those of ordinary skill in the art will be able to compare the figures herein with a pattern generated of an unknown form of, in this case, abacavir, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques which may be reported herein, as well as for distinguishing between amorphous forms.

In addition, where a reference is made to a figure, it is permissible to select any number of data points illustrated in the figure that uniquely define that crystalline form, salt, solvate, and/or optical isomer, within any associated and recited margin of error, for purposes of identification. Again, by way of example, it is permissible to select any number of PXRD peaks represented in Figure 1 to uniquely identify a crystalline form of abacavir.

Unless specified otherwise, the word "pure" as used herein means that the material is at least about 99% pure. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting

materials. In the case of stereoisomers, "pure" as used herein also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure" as used herein means at least about 98% pure and, likewise, "essentially pure" as used herein means at least about 95% pure.

The phrase "substantially free of one or more of its corresponding impurities" as used herein, unless otherwise defined, means comprising less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.1%, less than about 0.05%, or less than about 0.01% by weight, of one or more of the corresponding impurities as measured by HPLC.

In an aspect, the present application provides an improved process for the preparation of abacavir or a pharmaceutically acceptable salt thereof of formula (II),
which includes one or more of the following steps, individually or in the sequence recited:

a) reacting N-(2-amino-4,6-dichloro-5-pyrimidinyl) formamide of formula (III) with (1S,4R)-(4-aminocyclopent-2-enyl)methanol or a pharmaceutically acceptable salt thereof of formula (IV) in the presence of base to provide (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol of formula (V);

b) cyclizing the (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl) amino]-2-cyclopentene-1-methanol of formula (V) with a cyclizing reagent to provide (1S,4R)-4-

(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol or a pharmaceutically acceptable salt thereof of formula (VI);

c) reacting (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-
methanol or a pharmaceutical^ acceptable salt thereof of formula (VI) with
cyclopropylamine to provide abacavir of formula II; and

d) optionally, converting abacavir in to a pharmaceutically acceptable salt
thereof.

Step (a) involves reacting N-(2-amino-4,6-dichloro-5-pyrimidinyl) formamide of
formula (III) with (1S,4R)-(4-aminocyclopent-2-enyl)methanol or a pharmaceutically
acceptable salt thereof of formula (IV) in the presence of base to provide (1S,4R)-4-[(2-
amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1 -methanol of
formula (V).

Suitable bases that may be used in step (a) include, but are not limited to organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino) pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, or the like; inorganic bases, such as for example, alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides, such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; and ion exchange resins including

resins bound to ions, such as for example, sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium ions, or the like; or any other suitable bases.
Step (a) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.

Suitable temperature that may be used in step (a) 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°C, less than about 20°C, less than about 10°C, or any other suitable temperature.

(1 S,4R)-4-[(2-Amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-:1-methanol of formula (V) may be isolated by methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, 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.

Suitable techniques that may be used for the removal of solvent include, but are not limited to, rotational distillation using a device, such as for example, a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), or the like, optionally under reduced pressure.

Suitable solvents that may be used for isolation of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol of formula (V) include, but are not limited to water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like;

esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, o-xylene, chlorobenzene, tetralin, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; and any mixtures thereof
The isolated (1 S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol of formula (V) may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids.

The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like.
The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures of less than about 120°C, less than about 100°C, less than about 80°e, less than about 60°C, or any other suitable temperature.

Step (b) involves cyclizing the (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1 -methanol of formula (V) with a cyclizing reagent to provide (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol or a pharma-ceutically acceptable salt thereof of formula (VI).
Suitable cyclizing reagents that may be used in step (b) include, but are not limited to: trialkyl orthoformates, for example tributyl orthoformate, tripropyl orthoformate, triisopropyl orthoformate, triethyl orthoformate, trimethyl orthoformate, or the like.

Step (b) may be carried out in the presence of an acid. Suitable acids that may be used in

step (b) include, but are not limited to hydrochloric acid, hydrobromic acid, sulfuric, methane sulfonic acid, methanolic HCI, ethanolic HCI, isopropanolic HCI, or the like.

Step (b) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; and any mixtures thereof.

Suitable temperature that may be used in Step (b) may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°G, less than about 10°C, or any other suitable temperature.

(1S,4R)-4^[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol or a pharmaceutical^ acceptable salt thereof of formula (VI) may be isolated by methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, 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.

Suitable techniques that may be used for the removal of solvent include, but are not limited to, rotational distillation using a device, such as for example, a Buchi Rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), or the like, optionally under reduced pressure.

Suitable solvents that may be sued for isolation of (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1 -methanol or a pharmaceutically acceptable salt thereof of formula (VI) include, but are not limited to: water; alcohols, such as for example,

methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, o-xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; and any mixtures thereof.

The isolated (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1-methanol or a pharmaceutically acceptable salt thereof of formula (VI) may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids.

The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like.

The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures of less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperature.

Step (c) involves the reacting (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-- cyclopentene-1-methanol hydrochloride of formula (VI) with cyclopropylamine to abacavirof formula II.

Step (c) may be carried out in one or more suitable solvents. Suitable solvents that may be used in step (d) include, but are not limited to, water; alcohols, such as for example, methanol, ethanol, propanol, isopropanol, 2-butanol, pentanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; and any mixtures thereof.

Suitable temperature that may be used in Step (c) 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°C, less than about 20°C, less than about 10°C, or any other suitable temperature.

Abacavir of Formula (II) isolated by methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, 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.

Suitable techniques that may be used for the removal of solvent include, but are not limited to, rotational distillation using a device, such as for example, a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), or the like, optionally under reduced pressure.

Suitable temperatures for the isolation of abacavir of formula (II) may be 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. Suitable ' times for the isolation may be less than about 5 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or longer times may be used. The exact temperature and time required for complete isolation may be readily determined by a person skilled in the art and will also depend on parameters, such as for example, concentration and temperature of the solution or slurry.

The isolated compound of Formula (II) may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids. The abacavir of Formula (II) thus isolated may carry some amount of occluded mother liquor and have higher than desired levels of impurities. The solid may be washed with a suitable solvent or a mixture of solvents.

The isolated compound of Formula (II) may be further purified by recrystallizing one or more times from a suitable solvent or a mixture of solvents, such as for example: water; alcohols, including, for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl

formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.

The recovered solid may be optionally further dried. Drying may be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures as long as the abacavir of Formula (II) is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 to about 8 hours, or longer.

Step (d) involves optionally, converting abacavir of formula (II) in to a pharmaceutically acceptable salt thereof.

Abacavir of formula (il) may be converted in to a pharmaceutically acceptable
salt thereof by any process including the processes described in the art. For example

Abacavir of formula (II) may be converted in to a pharmaceutically acceptable salt thereof by the processes described in US 5,034,394, US 6,294,540 and EP 0777669 B1.

In another embodiment, the present application provides a process for the preparation of an amorphous form of abacavir, which include one or more of the following steps:

a) providing a solution of abacavir in a solvent or mixture of solvents; and

b) isolating the amorphous form of abacavir.

Step (a) involves providing a solution of abacavir in a solvent or mixture of solvents;

Providing a solution in step (a) includes:

i) direct use of a reaction mixture containing abacavir that is obtained in the course of its synthesis; or

ii) dissolving abacavir in a suitable solvent or mixture of solvents.
Any physical form of abacavir, such as crystalline, amorphous or their mixtures may be utilized for providing the solution of abacavir in step a).
Suitable solvents that may be used in step (a) include but are not limited to: water; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, neopentyl alcohol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; or any mixtures thereof.

The dissolution temperature may range from about -20°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of abacavir is obtained without affecting its quality.

The solution-may optionally be treated with carbon, flux-contained diatomaceous earth (Hyflow), or any other suitable material to remove colour and/or to get clarity of the solution.

Optionally, the solution obtained above may be filtered to remove any insoluble particles.

The insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step (b) involves isolation of an amorphous form of abacavir form of the solution of step (a).

In one variant, the isolation may be affected by removing solvent. Suitable techniques which may be used for the removal of solvent include using a rotational

distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), or the like or any other suitable technique.
The solvent may be removed, optionally under reduced pressure at temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

The compound obtained from step (b) may be collected using techniques such as scraping, by shaking the container, or other techniques specific to the equipment used.
The product thus isolated may be optionally further dried to afford an amorphous form of abacavir.
Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or under reduced pressures at less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a tJesired quality, such as from about 15 minutes to several hours.

Abacavir of formula (II) obtained according to the processes of the present application may be substantially free of one or more of its corresponding impurities.
"Substantially free of one or more of its corresponding impurities" as used herein, unless otherwise defined refers to the compound that contains less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.1%, less than about 0.05%, or less than about 0.01%, by weight, of each individual impurity including, without limitation, the compound of formula (VII), the compound of formula (VIII), the compound of formula (IX), the compound of formula (X), the compound of formula (XI), the compound of formula (XII), the compound of formula (XIII), the compound of formula (XIV), the compound of formula (XV), or any other possible residual impurity; and that contains a total amount of impurities of less than about 1%, less than about 0.5%, less than about 0.3%, less than about 0.1%, or less than about 0.05%, by weight as measured by HPLC.

A high performance liquid chromatography method for the analysis of a compound of Formula (II) utilizes C18 or equivalent column. Additional parameters are as shown in Table 1.

The present application provides a crystalline form of abacavir characterized by a powder X-ray diffraction pattern having peak locations substantially as listed in Table 2.

All PXRD data reported herein were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer with copper Ka radiation.
Differential scanning calorimetric analyses reported herein were carried out using a DSC Q1000 model from TA Instruments with a ramp of 10°C/minute up to 200°C. The starting temperature was 50°C and ending temperature was 200°C.

Thermogravimetric analysis analyses reported herein were carried out using a TGA Q500 V6.4 Build 193 from TA Instruments, with a ramp of 10°C/minute up to 200°C.
A pharmaceutical composition comprising abacavir or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients may be formulated as solid oral dosage forms, such as for example, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms, such as for example, syrups, suspensions, dispersions, and emulsions; and injectable preparations, such as for example, solutions, dispersions, and freeze dried compositions. Immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations. Modified release compositions may comprise hydrophilic and/or hydrophobic release rate controlling substances to form matrix and/or reservoir systems. The pharmaceutical compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated.

Pharmaceutical compositions according to the present application comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, diluents, such as for example, starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders, such as for example, acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants, such as for example, starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants, such as for example, stearic acid, magnesium stearate, zinc stearate, or the

like; glidants, such as for example, colloidal silicon dioxide or the like; solubility or wetting enhancers, such as for example, anionic or cationic or neutral surfactants; complex forming agents, such as for example, various grades of cyclodextrins; and release rate controlling agents, such as for example, hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methyl celluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutical^ acceptable excipients which can be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel® is a registered trademark of the Manville Corp.

A "cyclization reagent" is a chemical reagent capable of inducing ring closure between a carbonyl group (OO) and an amino group (NH or NH2) in the same molecule. Without wishing to be bound by theory, cyclization reagents are thought to function by removing water from the molecule undergoing ring closure. "Cyclization reagents" include, but are not limited to, tributyl orthoformate, tripropyl orthoformate, triisopropyl orthoformate, triethyl orthoformate, trimethyl orthoformate, tributyl orthoacetate, tripropyl orthoacetate, triisopropyl orthoacetate triethyl orthoacetate, trimethyl orthoacetate, tetramethyl orthocarbonate, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, tetraethyl orthocarbonate, N.N-dimethylformamide dipropyl acetal, N,N-dimethylformamide di-tert-butyl acetal, tetrabutyl orthosilicate, tetrapropyl orthosilicate, tetraisopropyl orthosilicate tetraethyl

orthosilicate, tetramethyl orthosilicate, or the like.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES

EXAMPLE-1: Preparation of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-

pyrimidinyl)amino]-2-cyclopentene-1-methanol. 2-Amino-4,6-dichloro-5-
formamidopyrimidine (30.0 g), (1S,4R)-(4-amino cyclopent-2-enyl)methanol hydrochloride (22.1 g), isopropyl alcohol (300 ml_), and sodium bicarbonate (36.5 g) are charged in to a round-bottom flask under nitrogen atmosphere and stirred the content at 30°C for 10 minutes. The reaction mixture is heated to 70-75°C and maintained for 30 hours. Filter the reaction mixture through hyflow bed at 70°C, washed with isopropyl alcohol (90 mL) at the same temperature. The organic solvent from the filtrate is evaporated at 55-65°C under reduced pressure up to a level of 60-70%. O-xylene (300 mL) slowly added to the reaction mass at 55°C and stirred for 60 minutes. The solvent from the reaction mass is evaporated at 65°G under reduced pressure up to level of 70%. O-xylene (150 mL) is added to the resultant reaction mass at 65°C and again the solvent from the reaction mass is evaporated at the same temperature under reduced pressure up to a level of 70%. The reaction mass is cooled to 0-5°C and stirred for 1 hour 30 minutes. The obtained solid is collected by filtration, washed with o-xylene (30 mL) and dried at 60-80°C, to afford 36.5 g of the title compound. Purity by HPLC: 95.8%

EXAMPLE-2: Preparation of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol. (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (100 g) is dissolved in isopropyl alcohol (2000 mL). The obtained solution is evaporated completely using a multi-bladed 0.05 m2 agitated thin-film dryer, to afford 82 g of the title compound. Purity by HPLC: 96.77%; ATFD parameters: feed rate: 0.7 Liters/hour, vacuum: 620-650 mm Hg, feed temp; 45-50°C, vapor temp: 34-35°C, hot water inlet temp: 80-82°C, hot water outlet temp: 78-80°C.

EXAMPLE-3: Preparation of (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-
cyclopent-2-enylmethanol hydrochloride. Triethyl orthoformate (100 mL), (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (25 g) are charged in to a round-bottom flask under nitrogen atmosphere at 30°C and stirred for 30 minutes. The reaction mixture is heated to 40-45°C and maintained at same temperature for 3 hours. The reaction mixture is cooled to 0-10°C, pre-chilled (7°C) ethanolic hydrochloride (50 mL) is added to the reaction mixture under nitrogen atmosphere. The reaction mixture is raised to 25-35°C and maintained for 60 minutes. Again ethanolic hydrochloride (25 mL) is slowly added to the reaction mixture at 25-30°C and maintained for 13 hours under nitrogen atmosphere. The reaction mixture is cooled to 0-5°C and stirred for 4 hours under nitrogen atmosphere. The obtained solid is collected by filtration, washed with pre-chilled ethyl acetate (50 mL) and dried under reduced pressure at 50-70°C for 10 hours, to afford 22.9 g of the title compound.
Purity by HPLC: 95.8%

EXAMPLES: Preparation of (1S,4R)-4-[(2-amino-6-(cyclopropylamino) -9H-purin-9-yl)] -2-cyclopentene-1-methanol. Ethyl acetate (400 mL), (1S,4R)-4-[(2-amino-6-chloro-9H-purirr-9-yl)]-2-cyclopent-2-enylmethanol hydrochloride (40 g) and cyclopropylamine (37.6 g) are charged in to a round-bottom flask under nitrogen atmosphere at 25-30°C and stirred for 10 minutes. The reaction mixture is heated to reflux at 77°C and maintained for 4-6 hours. The reaction mixture is cooled to 60-70°C, followed by water (40 mL) is added to the reaction mixture and maintained for 15 minutes to get clear solution. Again the reaction mixture is cooled to 20-25°C, a solution of 20% sodium carbonate (12 g) is added and stirred the mixture for 15 minutes. A solution of 40% sodium hydroxide (8 g) is added to the reaction mass slowly for 30 minutes at 25°C and maintained for 20 minutes. Both layers are separated, the aqueous layer is extracted with ethyl acetate (200 mL) at 25°C. Combine the organic layer and charcoal (2 X 4 g) is added to the organic layer at 30°C and stirred for 30 minutes. The reaction solution filtered through hyflow bed and washed with ethyl acetate (2 X 120 mL). The solvent from the filtrate is evaporated up to 2.5 volumes at 50°C under reduced pressure. The reaction mass is cooled to 40°C and acetone (2 X 240 mL) is added to the reaction mass and stirred for 40 minutes. The solvent from the reaction

mixture is evaporated up to 3.5 volumes at below 45°C under reduced pressure. Again the reaction mass is cooled to 30°C and stirred for 5 hours. Again the reaction mass is cooled to 0-5°C and maintained for 5 hours. The obtained solid is collected by filtration under nitrogen atmosphere, washed with acetone (2 X 40 ml_) and dried under reduced pressure at 35-40°C, to afford 28.5 g of the title compound. Purity by HPLC: 98.6%

EXAMPLE 5: Preparation of (1S,4R)-4-[(2-amino-6-(cyclopropylamino) -9H-purin-9-yl)] -2-cyclopentene-1-methanol. Water (75 ml_), (1S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopent-2-enylmethanol hydrochloride (25 g) and cyclopropylamine (21.2 g) are charged in to a round-bottom flask under nitrogen atmosphere at 30°C and stirred for 10 minutes. The reaction mixture is heated to 50-55°C and maintained for 2 hours. The reaction mixture is cooled to 30-35°C, ethyl acetate (250 mL) is added to the reaction mixture and stirred for 5-10 minutes. A solution of 20% sodium carbonate (37.5 mL), followed by 40% sodium hydroxide (12.5 mL) are added to the mixture and stirred for 45 minutes. Both layers are separated, the aqueous layer is extracted with ethyl acetate (125 mL). Charcoal (2 X 2.5 g) is added to the organic layer at 30°C and stirred for 30 minutes. The obtained solution is filtered through hyflow bed and washed with ethyl acetate (2 X 75 mL). The solvent from the organic layer is evaporated up to 0.5 to 1 volume at 55°C under reduced pressure.- Acetone (2 X 150 mL) is added to the reaction mass and maintained for 60 minutes at 55°C. The reaction mass is cooled to 0-5°C and maintained for 2 hours. The obtained solid is collected by filtration under nitrogen atmosphere, washed with acetone (50 mL) and dried under reduced pressure at 50-55°C, to afford 22.0 g of the title compound. Purity by HPLC: 97.99%

EXAMPLE 6: Purification of (1S,4R)-4-[(2-amino-6-(cyclopropylamino) -9H-purin-9-yl)] -2-cyclopentene-1-methanol. Acetone (112.5 mL), water (12.5 mL) and (1S,4R)-4-[(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)-2-cyclopentene-1-methanol (25 g) are charged in to a round-bottom flask under nitrogen atmosphere at 25°C and stirred for 10 minutes. The reaction mixture is heated to reflux temperature and maintained at 55±3°C for 30 minutes. The reaction mixture is filtered at 55±3°C through a micron filter and washed with a mixture of preheated (50°C) acetone (11.25 mL) and water (1.25 mL). The resultant filtrate is charged in to another round bottom flask, heated to 55±3°C and stirred for 40 minutes. The resultant reaction mixture is cooled to -17.5±2.5°C and

stirred for 60 minutes. The obtained solid is collected by filtration under nitrogen atmosphere, washed with chilled acetone (37.5 mL) and dried under reduced pressure at 45-50°C for 4 hours. Charged the obtained compound and acetone (125 mL) in to a round-bottom flask under nitrogen atmosphere at 25°C and stirred for 10 minutes. The reaction mixture is heated to reflux temperature and maintained at reflux temperature at 56°C for 4 hours. The resultant reaction mixture is slowly cooled to 0-5°C for 2 hours under nitrogen atmosphere and stirred for 2 hours. The obtained solid is collected by filtration under nitrogen atmosphere, washed with acetone (25mL) and dried under reduced pressure at 45-50°C, to afford 20.0 g of the title compound. Purity by HPLC: 99.72%; a compound of formula (XI): 0.005%, a compound of formula (XII): 0.003%, a compound of formula (XIII): 0.02% and a compound of formula (XIV): 0.006%.
Residual solvents by GC-HS: methanol: ND; ethyl acetate: ND; ethanol: ND; acetone: 1314 ppm; isopropyl alcohol: ND; THF: ND; dichloromethane: ND; cyclohexane: ND; toluene: 3 ppm; o-xylene: ND; Cyclopropylamine content by Ion chromatography: ND (ND: Not detected)

EXAMPLE 7: Preparation of amorphous abacavir. Abacavir (10 g) and methanol (100 mL) are charged in to a round-bottom flask at 25-35°C and stirred for 10 minutes. The contents are heated to 45-50°C and stirred for 20-30 minutes to dissolve abacavir completely. The resultant solution is cooled to 30-35°C and is evaporated by subjecting to spray-drying using a Labutima spray dryer (LU-222), to afford 6 g of the title compound. Operating parameters for spray dryer: aspirator: 35-45%, flow rate 0.5 mL/min, inlet temperature 75°C-80°C, outlet temperature 60°C-65°C, vacuum: 80-100 mmWC.

EXAMPLE-8: Preparation of amorphous abacavir. Abacavir (10 g), water (10 mL) and acetone (90 mL) are charged in to a round-bottom flask at 25-35°C and stirred for 10 minutes. The contents are heated to 50-55°C and maintained for 30 minutes to dissolve abacavir completely. The resultant solution is cooled to 30-35°C and is evaporated by subjecting to spray-drying using a Labutima spray dryer (LU-222), to afford 6.2 g of the title compound. Operating parameters for spray dryer: aspirator: 35-

45%, flow rate 0.5 mL/min, inlet temperature 70°C-75°C, outlet temperature 60°C-65°C, vacuum: 80-100 mmWC.

EXAMPLE 9: Preparation of abacavir hemisulfate. Water (2.0 mL), isopropyl alcohol (70.0 mL) and abacavir (10 g) are charged in to a round-bottom flask at 30°C and stirred for 10 minutes. The reaction mixture is heated to 70-80°C and stirred for 30 minutes. The reaction mixture is cooled to 60-70°C and carbon (0.5 g) is added and stirred for 30 minutes. The reaction mixture is filtered at 67°C, washed with preheated isopropyl alcohol (30 mL). The resultant filtrate charged in to a round-bottom flask and heated to 70°C, followed by a solution of H2S04 (1.746 g) in water (2.0 mL) and isopropyl alcohol (15 mL) is added slowly to the reaction mixture for not less than 2.5 hours and maintained the reaction mixture for 1 hour at 60-70°C. The reaction mixture is slowly cooled to 30°C in 2 hours. Again the reaction mass is cooled to -3°C 2 hours and stirred for 2 hours. The obtained solid is collected by filtration under nitrogen atmosphere, washed with pre-chilled isopropyl alcohol (10 mL), again washed with methanol (10 mL), suck dried for 60 minutes and dried under reduced pressure at 75°C for 10 hours, to afford 11.1 g of the title compound. Methanol (30 mL) and the obtained compound are charged in to- the round-bottom flask at 284>C and stirred for 10 minutes. The reaction mixture is heated to 68°C and stirred for 3 hours. The reaction mixture is slowly cooled to 0°C and stirred for 2 hours. The obtained solid is collected by filtration under nitrogen atmosphere, washed with chilled methanol (10mL) and dried under reduced pressure at 70-75°C, to afford 10.7 g of the title compound. Purity by HPLC: 99.73%

We claim:

1. A process for the preparation of abacavir or a pharmaceutically acceptable salt thereof of formula (II),
which includes one or more of the following steps, individually or in the sequence recited:

a) reacting N-(2-amino-4,6-dichloro-5-pyrimidinyl) formamide of formula (III) with (1S,4R)-(4-aminocyclopent-2-enyl)methanol or a pharmaceutically acceptable salt thereof of formula (IV) in the presence of base to give (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol of formula (V);

b) cyclizing the (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)
amino]-2-cyclopentene-1-methanol of formula (V) with a cyclizing reagent to provide
(1 S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1 -methanol or a
pharmaceutically acceptable salt thereof of formula (VI);

c) reacting (1 S,4R)-4-[(2-amino-6-chloro-9H-purin-9-yl)]-2-cyclopentene-1 -methanol or a pharmaceutically acceptable salt thereof of formula (VI) with cyclopropylamine to provide abacavir of formula II; and

d) optionally, converting abacavir in to a pharmaceutically acceptable salt thereof.

2. A process for preparing an amorphous form of abacavir, which includes one or more of the following steps:

c) providing a solution of abacavir in a solvent or mixture of solvents; and

d) isolating an amorphous form of abacavir.