This application claims priority to Indian patent application No. 1376/CHE/2010 filed on May 17, 2010, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to amorphous form of (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Fosamprenavir calcium is an antiviral compound having HIV aspartyl protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. The chemical name for Fosamprenavir calcium is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

(3S) tetrahydro-3-furanyl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphono oxy)propylcarbamate has increased solubility in the pH range of the gastro-intestinal tract compared to the HIV protease inhibitor [3S-[3R*(1R*,2S*)]]-[3-[[(4-aminophenyl)sulfonyl](2-methyl-propyl)amino]-2 -hydroxy-1 -phenylmethyl)propyl] -tetrahydro-3-furanyl ester (amprenavir, 141W94). Amprenavir, which has poor solubility is available as a solution in gel capsules and has a high pill burden. This new HIV protease inhibitor (Fosamprenavir calcium) with its increased solubility has the potential to reduce the perceived pill burden and may be formulated as a tablet.

The structure of (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl] (isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt, represented as formula I is shown below Formula I US 6436989B1 patent disclosed a range of pharmaceutical acceptable salts of

Fosamprenavir including both organic and inorganic salts such as sodium, potassium,
magnesium, calcium, zinc, ethylene diamine, piperazine and the like. Of these, the
piperazine salt was a crystalline solid, but had the practical disadvantage of likely toxic at the anticipated dose.

US 6514953B1 patent disclosed crystalline form I of (3S)-tetrahydrofuran-3 yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

WO2010134045 Al publication disclosed amorphous Fosamprenavir calcium and process for the preparation thereof by using spray drying and Buchi Rotavapor drying techniques.

Surprisingly, we have found amorphous form of calcium (3S) tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-phosphono-oxy) propyl-carbamate which is presumed to be stable than the prior art forms.

OBJECTIVE AND SUMMARY OF THE INVENTION

The main object of the present invention relates to an amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

Another object of the present invention relates process for the preparation of amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the X-ray powder diffraction pattern of amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

Figure 2 illustrates the Optical Microscope images of amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to amorphous form of (3S)-tetrahydrofuran-3-yl-(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt and process for the preparation thereof.

In one embodiment, the present invention relates to amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt, substantially as shown in Fig. 1.

In another embodiment, the present invention relates to process for the preparation of a amorphous form of (3S)-tetrahydrofuran-3-yl(l S,2R)-3-[[(4-aminophenyl)sulfonyl] (isobutyl)amino-l -benzyl -2-(phosphonooxy) propylcarbamate monocalcium salt comprising the steps of

i) dissolving (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4 aminophenyl)sulfonyl](isobutyl)-amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium in organic solvent, ii) removing the solvent, and

- iii) isolating amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)-sulfonyl](isobutyl)amino]-1 -benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt.

According to the present invention, (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl]-(isobutyl)amino]-1 -benzyl-2-(phosphonooxy) propylcarbamate monocalcium is dissolved in organic solvent and heated to about 80°

C. The resultant solution is filtered and the solvent is removed thus isolating amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy)propylcarbamate monocalcium salt.

According to the present invention the organic solvent is selected from ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof.

According to the present invention, the solvent is removed using techniques such as distillation, distillation under vacuum, freeze drying, spray drying or by agitated thin film evaporator under moisture controlled conditions.

In another embodiment, the present invention relates to a process for preparation of amorphous Fosamprenavir calcium comprising the steps of

a) dissolving Fosamprenavir calcium in an alcoholic solvent,

b) removing the solvent, and

c) isolating amorphous Fosamprenavir calcium.

In another embodiment, the alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol.

In another embodiment, the solvent is removed by thin film drying.

According to the present invention, Amorphous Fosamprenavir calcium obtained by the present process has a polymorphic purity greater than 99.5%.

The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Example:

Preparation of amorphous form of (3S)-tetrahydrofuran-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-l-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt:

Charged Fosamprenavir calcium (5.0Gms) to a RB flask and added methanol. Heated the reaction mass to about 70 °C and maintained for about 30 min. Filtered the reaction mass through a 0.45|u filter paper and washed with methanol (5.0 ml). The resultant filtrate was distilled off completely under vacuum at below 50°C, to afford the title compound.

WE CLAIM:

1) A process for the preparation of amorphous Fosamprenavir calcium comprising the steps of

i) dissolving Fosamprenavir calcium in an organic solvent,

ii) removing the solvent, and

iii) isolating amorphous Fosamprenavir calcium.

2) The process according to claim 1, wherein the organic solvent is selected from ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane

3) The process according to claim 1, wherein the solvent is removed in step ii) by distillation, evaporation, oven drying, tray drying, rotational drying, spray drying, freeze-drying, fluid bed drying, flash drying, spin drying or thin film drying.

4) The process according to claim 3, wherein removing the solvent is under moisture controlled conditions.

5) A process for the preparation amorphous Fosamprenavir calcium comprising the steps of

a) dissolving Fosamprenavir calcium in an alcoholic solvent,

b) removing the solvent, and

c) isolating amorphous Fosamprenavir calcium.

6) The process according to claim 5, wherein alcoholic solvent is methanol or ethanol.

7) The process according to claim 5, wherein the solvent is removed by thin film drying.

8) Amorphous Fosamprenavir calcium having a polymorphic purity greater than 99.5%.

9) Pure amorphous Fosamprenavir calcium according to claim 1 and 5 as substantially represented in Figure 1.

10) Pure amorphous Fosamprenavir calcium according to claim 1 and 5 having optical microscope images as substantially depicted in figure 2.