FIELD OF INVENTION:
The present invention relates to Tenofovir disoproxil hemifumarate salt and the process for preparation thereof.

BACKGROUND OF THE INVENTION:

Tenofovir disoproxil is chemically known as 9-[-2-(R)-[[bis[[(isopropoxycarbonyl) oxy]methoxy]phosphinoyl]methoxy] propyl] adenine represented by the following structure:

The above compound is a highly potent antiviral agent, particularly for the therapy or prophylaxis of retroviral infections and belongs to a class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTI) which blocks reverse transcriptase an enzyme crucial to viral production in HIV-infected people. These are related to Nucleoside Reverse Transcriptase Inhibitors (NRTI).

SUMMARY OF THE INVENTION:
The main object of the present invention is to provide hemifumarate salt of Tenofovir disoproxil.

Another object of the present invention is to provide a process for the preparation of Tenofovir disoproxil hemifumarate.

BRIEF DESCRIPTION OF THE DRAWINGS:

The invention will now be described in further detail with reference to the drawings, wherein:

Fig. 1 consists of two IR spectra, wherein FIG.l A is the IR spectrum of Tenofovir disoproxil fumarate, and FIG. IB is the IR spectrum of Tenofovir disoproxil hemifumarate;

Fig-2: consists of two X-ray difractograms, wherein FIG.2A is the X-ray difractogram of Tenofovir disoproxil fumarate, and FIG.2B is the X-ray difractogram of Tenofovir disoproxil hemifumarate;

Fig-3: consists of two thermograms, wherein FIG.3A is the thermogram of Tenofovir disoproxil fumarate, and FIG.3B is the thermogram of Tenofovir disoproxil hemifumarate;

Fig-4: consists of two 'H-NMR spectra, wherein FIG.4A is the 'H-NMR spectra of Tenofovir disoproxil fumarate, and FIG.4B is the ' H-NMR spectra of Tenofovir disoproxil hemifumarate;

DETAILED DESCRIPTION OF THE INVENTION:
The inventors have found a new salt of Tenofovir disoproxil, the hemifumarate salt. The new salt is characterized by its infrared spectrum and X-ray powder diffraction pattern as shown in Figures 1 and 2, respectively.

The PXRD spectrum of hemi-fumarate is characterized by the following peaks with 20 angle positions at about 2 9 7.8, 8.0, 9.8, 10.5, 10.9, 11.9, 13.6, 14.2, 14.6, 16.0, 16.7, 17.2, 17.9, 18.4, 19.1,20.3, 21.1, 21.6, 22.5, 23.3, 24.2, 25.2, 26.3, 26.7, 27.0, 28.5, 29.7, 30.3, 31.1, 31.9, 32.8, 34.7 ± 0.2

The Fumaric acid content in the hemifumarate salt was analysed by chemical analysis and found to be 10.2.

In one aspect, Tenofovir disoproxil hemifumarate can be prepared by dissolving Tenofovir disoproxil fumarate in a suitable solvent followed by cooling the solution and isolating the product by the conventional methods.

In another aspect Tenofovir disoproxil hemifumarate is prepared by converting Tenofovir disoproxil fumarate to Tenofovir disoproxil and treating Tenofovir disoproxil with stoichiometric equivalent quantity of fumaric acid in a suitable solvent and isolating the
product by the conventional methods.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:

The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.

EXAMPLE-1

Tenofovir disoproxil fumarate (100 Gms, 0.1574 moles) is suspended in Isopropyl alcohol (800 ml) at 25-35°C. The suspension is heated to about 60°C for clear solution. The obtained clear solution is maintained for 1 hr at 60-65°C. Slowly cooled the mass to 30°C in 1 hr and again cooled to 8°C and maintained for lhr at 8 - 10°C. The precipitated product is filtered and washed with chilled Isopropanol. The wet material is dried at 50-55°C under vacuum to give Tenofovir disoproxil hemifumarate.

Yield: 85.0 Gms
Fumaric acid content: 10.2%

EXAMPLE-2
Tenofovir disoproxil fumarate (100 Gms, 0.1574 moles) is suspended in DM water (500 ml) and ethyl acetate (500 ml) at 25-35°C and adjusted pH to neutral with saturated Sodium bicarbonate solution. Reaction mixture is settled and the separated ethyl acetate layer is evaporated under vacuum below 45°C to get Tenofovir disoproxil as residue.
In another flask Fumaric acid (9.12 gm, 0.0786 moles) is suspended in Isopropyl alcohol (800 ml) at 25-35°C and raised the temperature to 50°C. To the obtained solution above Tenofovir disoproxil residue is added and maintained for 1 hr at 50-55°C. The reaction mass is cooled to 25-3 5°C and maintained for 2 hrs. The reaction mass is cooled to 10°C and maintained for 4 hrs. The crystallized product is filtered and washed with chilled Isopropyl alcohol. The wet material is dried at 50-55°C under vacuum to give Tenofovir disoproxil hemifumarate.

Yield: 82.0 Gms
Fumaric acid content: 10.2%

WE CLAIM :

1. Tenofovir disoproxil hemifumarate.

2. Tenofovir disoproxil hemifumarate according to claim 1, characterized by PXRD peaks at 2 011.9, 14.2, 14.6, 16.7, 21.1, 24.2 ± 0.2

3. Tenofovir disoproxil hemifumarate according to claim 1, characterized by IR spectrum as depicted in Fig IB.

4. Tenofovir disoproxil hemifumarate according to claim 1, characterized by DSC as depicted in Fig 3B

5. A process for the preparation of Tenofovir disoproxil hemifumarate which comprises:

i) dealkylating (R)-9-[2-(Diethylphosphonomethoxy)propyl]adenine to give
tenofovir.

ii) condensing Tenofovir with chloromethyl isopropyl carbonate to get tenofovir disoproxil,

iii) optionally crystallizing to get crystalline Tenofovir disoproxil, iv) treating Tenofovir disoproxil with fumaric acid in an organic solvent and v) Isolating the Tenofovir disoproxil hemi-fumarate.

6. The process according to claim 5, wherein the organic solvent employed is
alcohol i.e. isopropyl alcohol.

7. A process for the preparation of Tenofovir disoproxil hemifumarate which
comprises:

a. treating Tenofovir disoproxil with fumaric acid in an organic solvent and
b. Isolating the Tenofovir disoproxil hemi-fumarate.

8. The process according to claim 7, wherein the organic solvent employed is
alcohol i.e. isopropyl alcohol.