aisoproxn iumarate {i).

BACKGROUND OF THE INVENTION

Tenofovir disoproxil fumarate (I) is chemically known as 9-[(i?)-2-[[bis[[(isopro poxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate. Tenofovir disoproxil is a prodrug of Tenofovir. Tenofovir disoproxil belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (NRTIs), which block reverse transcriptase, an enzyme crucial to viral production in HIV-infected people. Tenofovir disoproxil fumarate is marketed under the brand name of Viread®. It has been approved in combination with other antiretroviral agents for the treatment of HIV-1 infection. Tenofovir disoproxil is disclosed in US 5,922,695. This patent discloses a process for the preparation of Tenofovir disoproxil and its further isolation as the fumarate salt. The process as disclosed in US '695 comprises esterification of (i?)-9-[2-(phosphono-methoxy)propyl]adenine (Tenofovir) (II) with chloromethyl isopropyl carbonate (III) in presence of triethylamine and l-methyl-2-pyrroIidinone to produce Tenofovir disoproxil (IV) which is subsequently treated with fumaric acid in presence of isopropanol to produce Tenofovir disoproxil fumarate.

The process is as shown in scheme-I below:

Tenofovir disoproxil fumarate (I)

Scheme-I

WO 2011/111074 A2 discloses esterification of (i?)-9-[2-(phosphonomethoxy)propyl] adenine (II) with chloromethyl isopropyl carbonate (III) in presence of a base, phase transfer catalyst and optionally dehydrating agent, in a suitable solvent. It has been observed that in the above prior-art processes, the esterification reaction is carried out by addition of TEA to the mixture of NMP and Tenofovir, wherein Tenofovir-TEA salt precipitated out from the reaction mass, which is further esterified with chloromethyl isopropyl carbonate (III) and found that Tenofovir disoproxil is formed up to 67% during the reaction. Further, the esterification reaction takes longer time and reaction mass product starts degrading resulting in undesired impurities along with Tenofovir disoproxil. These impurities are difficult to separate and required repeated purification processes for Tenofovir disoproxil which results in lower yield of Tenofovir disoproxil fumarate to about 48%, thereby increasing the product cost.

Hence, there is a need to develop a process, which requires less reaction time and controls the formation of undesired degradation by-product hydroxymethyl Tenofovir disoproxil (V). In the instant invention, it has been found that addition of a base to the mixture of (R)-9-[2 (phosphonomethoxy)propyl]adenine (Tenofovir) (II) and chloromethyl isopropyl carbonate (III), which avoids the precipitation of triethylamine salt of Tenofovir, thereby improving the rate of esterification reaction as well as improving the formation of Tenofovir disoproxil fumarate up to 85% during reaction.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple, cost effective and an improved process for the preparation of Tenofovir disoproxil fumarate (I) on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of Tenofovir disoproxil fumarate (I); which comprises:

(i) adding a base to the mixture of (R)-9-[2-(phosphonomethoxy)propyl] adenine (II) and chloromethyl isopropyl carbonate (III) in a solvent and optionally a phase transfer catalyst to produce Tenofovir disoproxil (IV);

(ii) treating Tenofovir disoproxil (IV) with fumaric acid in a solvent to produce Tenofovir disoproxil fumarate (I).

The process comprises, adding a base to the mixture of (i?)-9-[2-(phosphonomethoxy)propyl] adenine (II) and chloromethyl isopropyl carbonate (III) in a solvent and optionally a phase transfer catalyst (PTC) to produce Tenofovir disoproxil (IV). The base used in the above esterification reaction is selected from organic base such as diethylamine, triethylamine, tert-butylamine, diisopropylamine or mixture thereof; or an inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate or mixture thereof. The solvent used is selected from N-methyl-2-pyrrolidine, N,N-dimethylacetamide, N,N dimethylformamide, N,N-dimethylsulfoxide, acetone, toluene, ethyl acetate or mixtures thereof. The reaction is carried out at a temperature of about 30-100°C for a period of about 30 min to 3 hours. The phase transfer catalyst used in the above reaction is selected from quaternary ammonium salts such as methyl triethyl ammonium bromide, tetra-butyl ammonium bromide and tetra-methyl ammonium bromide; tetraethylammonium bromide, cetyl trimethylammonium bromide (CTAB), tetramethylammonium chloride, tetramethylammonium hydroxide, tetramethylammonium pentafluoroxenate, preferably tetra butyl ammonium bromide. Preferably the reaction is carried out under anhydrous conditions.

After completion of the reaction, a solvent selected from chlorinated hydrocarbon solvent such as methylene chloride, ethylene chloride, trichloroethylene; aromatic hydrocarbon such as toluene, xylenes; ester solvent such as ethyl acetate, methyl acetate, or mixtures thereof, is added and cooled the reaction mass to 0 to 30°C, followed by stirring for 30 min to 2 hrs. Optionally treating the Tenofovir disoproxil (IV) with carbon, followed by filtration and concentrated to a residue containing Tenofovir disoproxil (IV). Tenofovir disoproxil (IV) obtained by the above process is treated with fumaric acid in a solvent to produce Tenofovir Disoproxil fumarate (I). The solvent used is selected from alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol or mixtures therof; preferably isopropyl alcohol. The salt formation step is carried out at a temperature about 50-55°C. The solution containing Tenofovir disoproxil fumarate is optionally seeded and cooled to 0 to 15°C. The crystallized Tenofovir disoproxil fumarate is isolated by conventional methods such as filtration, followed by drying the product.

It has been observed that the addition of a base to the mixture of (i?)-9-[2-(phosphonomethoxy)propyl] adenine (II) and chloromethyl isopropyl carbonate (III) resulted the esterification reaction in 2 hours time with 85% conversion of Tenofovir disoproxil (IV). Further, resulted Tenofovir disoproxil fumarate with increased yield by 37%. (R)-9-[2-(phosphonomethoxy)propyl]adenine (II) used in the present invention is prepared by reacting adenine (VI) with (R)-propylene carbonate in presence of a base to produce (R)-9-HPA (VII) which is further condensed with tosylate (VIII) in presence of a base in a solvent to produce diethyl (R)-PMPA (IX). Hydrolysis of diethyl (i?)-PMPA (IX) to produce (i?)-9-[2-(phosphonomethoxy)propyl] adenine (Tenofovir) (II).

The process is as shown in scheme-II below:

Example-1

Preparation of Tenofovir disoproxil fumarate: (R)-9-[2-(Phosphonomethoxy)propyl]adenine (II) (50gm; 0.174 mole; 0.7% of MC) and tetra-butyl ammonium bromide (19.63 g; 0.0609 moles) were suspended in N-methyl-2-pyrrolidinone (150 ml) at 20-30°C and heated to 55-60°C under nitrogen atmosphere. Chloromethyl isopropyl carbonate (III) (111.5 gm; 0.731 moles) was added to the reaction mass at 55-60°C. Triethyl amine (44 gm; 0.435 moles) was added to the reaction mass at 55-75°C and stirred for 2 h. The resulting reaction mass was cooled to 20-25°C and methylene chloride (750 ml) followed by DM water (100 ml) were added to the reaction mass. The organic layer was separated, washed with DM water (5 x 250 ml), treated with activated carbon, filtered, concentrated and dissolved in isopropyl alcohol (55 ml).

Fumaric acid (24.24 gm; 0.209 moles) was dissolved in isopropyl alcohol (447 ml) at 65-75°C and added to the above reaction mass at 50-55°C. The solution was seeded with Tenofovir disoproxil fumarate (0.10 gm), cooled to 10-15°C and stirred for 8 h at 10-15°C. The slurry was further cooled to -5 to -3°C, stirred for 5 h, filtered, and washed with a mixture of isopropyl acetate di-n-butyl ether (1:6; 210 ml) ). The wet product was suspended in a mixture of isopropyl acetate (120 ml) and di-n-butyl ether (473 ml), stirred for 2 h at 20-25°C, filtered, washed with a mixture of isopropyl acetate and di-n-butyl ether (1:6; 210 ml) and dried at 35-40°C under reduced pressure. Yield: 72.5 gm (65.61 % on theory) Chromatography purity: 99.7%

Example-2

(i?)-9-[2-(Phosphonomethoxy)propyl]adenine (II) (9.6kg; 2.85% of MC; equivalent to 9.3 kg; 32.380 moles after MC correction) was suspended in toluene (67.7 It) at 20-30°C and heated to 105-110°C and partially distilled out toluene to eliminate water from the slurry. Toluene was completely distilled out under reduced pressure at 70-110°C and N-methyl-2- pyrrolidinone (29 It), followed by tetra-butyl ammonium bromide (3.65 kg; 11.7 moles), were added under nitrogen atmosphere. Chloromethyl isopropyl carbonate (III) (20.75 kg; 136.00moles) was added to the reaction mass at 55-60°C. Triethyl amine (8.2 kg; 81.035 moles) was added to the reaction mass at 55-75°C and stirred for 2 h. The resulting reaction mass was cooled to 20-25°C and methylene chloride (132.5 It) followed by DM water (18.6 It) were added to the reaction mass. The organic layer was separated, washed with DM water (5* 46.5 It), treated with activated carbon, filtered, concentrated and dissolved in isopropyl alcohol (10 It).

Fumaric acid (4.5 kg; 38.77 moles) was dissolved in isopropyl alcohol (83.5 It) at 65-75°C and added to the above reaction mass at 50-55°C. The solution was seeded with Tenofovir disoproxil fumarate (20 gm), cooled to 10-15°C and stirred for 8 h at 10-15°C. The slurry was further cooled to -5 to -3°C, stirred for 5 h, filtered, and washed with a mixture of isopropyl acetate di-n-butyl ether (1:6; 40.4 It). The wet product was suspended in a mixture of isopropyl acetate (22.4 It) and di-n-butyl ether (88 It), stirred for 2 h at 20-25°C, filtered, washed with a mixture of isopropyl acetate and di-n-butyl ether (1:6; 40.4 It) and dried at 35-40°C under reduced pressure.

Yield: 13.5 kg (65.61 % on theory) Chromatography purity: 99.7%

We Claim

1. An improved process for the preparation of Tenofovir disoproxil fumarate (I); which comprises:(i) adding a base to a mixture of (i?)-9-[2-(phosphonomethoxy)propyl] adenine (II), and chloromethyl isopropyl carbonate (III), in a solvent and optionally a phase transfer catalyst to produce Tenofovir disoproxil (IV);(ii) treating Tenofovir disoproxil (IV) with fumaric acid in a solvent to produce Tenofovir disoproxil fumarate (I). triethylamine, tert-butylamine, diisopropylamine or mixture thereof.

2. The process according to claim 1, the base used in step-(i) is selected from organic base or an inorganic base.

3. The process according to claim 2, the organic base is selected from diethylamine, triethylamine, tert-butylamine, diisopropylamine or mixture thereof.

4. The process according to claim 2, the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate or mixture thereof.

5. The process according to claim 1, the solvent used in step-(i) is selected from N-methyl-2-pyrrolidine, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylsulfoxide, acetone, toluene, ethyl acetate or mixtures thereof.

6. The process according to claim 1, the phase transfer catalyst used in step-(i) is selected from quaternary ammonium salts.

7. The process according to claim 6, the quaternary ammonium salt is selected from methyl triethyl ammonium bromide, tetra-butyl ammonium bromide and tetra-methyl ammonium bromide; tetraethylammonium bromide, cetyl trimethylammonium bromide (CTAB), tetramethylammonium chloride, tetramethylammonium hydroxide, tetramethylammonium pentafluoroxenate.

8. The process according to claim 1, the solvent used in step-(ii) is selected from alcohols.

9. The process according to claim 8, the alcohol is selected from methyl alcohol, ethyl alcohol and isopropyl alcohol or mixtures thereof.