This application claims priority to Indian patent application No 2982/CHE/2011 filed on Aug 30, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Tenofovir, and further conversion to Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:

Tenofovir Disoproxil is chemically known as 9-[-2-(R)-[[bis [[(isopropoxycarbonyl) oxy]methoxy] phosphinoyl]methoxy]propyl]-adenine, having the following structural formula-I.

Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil fumaric acid salt under the brand name VIREAD® in the form of 300mg of oral tablets and in combination with other antiviral agents.

Tenofovir Disoproxil hemifumarate is a highly potent antiviral agent, particularly for the therapy or prophylaxis of retroviral infections and belongs to a class of drugs called
Nucleotide Reverse Transcriptase Inhibitors (NRTI) which blocks reverse transcriptase an enzyme crucial to viral production in HIV-infected people.

Tenofovir Disoproxil and its pharmaceutically acceptable salts were first disclosed in US 5,922,695 and this patent discloses the synthetic route for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine by condensation of (R)-9-[2-(hydroxyl) propyl] adenine with Diethyl p-toluenesulfonyloxymethyl phosphonate in presence of Lithium tert-butoxide in Tetrahydrofuran followed dealkylation with Bromotrimethylsilane in Acetonitrile.

US 5,733,788 discloses the process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine which involves condensation of (R)-9-[2-(hydroxyl) propyl] adenine and Diethyl p-toluenesulfonyloxy methylphosphonate in presence of Lithium hydride in Dimethylformamide followed by dealkylation with Bromotrimethylsilane in Acetonitrile.

US 2004/0018150 discloses a process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine where Diethyl p-toluenesulfonyloxymethyl phosphonate is condensed with (R)-9-[2-(hydroxyl)propyl]adenine in presence of Magnesium isopropoxide or Magnesium tert-butoxide in Dimethylformamide medium followed by dealkylation with Bromotrimethylsilane in Acetonitrile with an overall yield 48%.

The above prior art publications discloses use of highly expensive metal alkoxides such as Magnesium isopropoxide or Magnesium tert-butoxide. The usage of metal alkoxides will increase manufacturing cost.

Thus the present invention provides an improved and cost effective process for the preparation of Tenofovir, and further conversion into Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide an improved process for the preparation of Tenofovir.

Another object of the present invention is to provide further conversion of Tenofovir into Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof.

One aspect of the present invention provides, an improved process for the preparation of
Tenofovir comprising the steps of:

a) reacting adenine of formula-II, wherein P is H or amino protecting group with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate in presence of metal hydrides and a metal catalyst in a suitable solvent to obtain (R)-9-[2-(Di-alkyl-phosphonomethoxy)propyl]adenine of Formula-Ill, wherein "Alk" represents C1-4 alkyl;

b) converting compound of Formula-Ill to Tenofovir.

Another aspect of the present invention provides, an improved process for the preparation
of Tenofovir comprising the steps of:

a) reacting adenine of formula-II, wherein P is H or amino protecting group with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate in presence of Dialkyl magnesium in a polar aprotic solvent to obtain (R)-9-[2-(Di-alkyl-phosphonomethoxy)propyl]adenine of Formula-Ill, wherein "Alk" represents C1-4 alkyl;

b) converting compound of Formula-Ill to Tenofovir.

Another aspect of the present invention provides, further conversion of Tenofovir obtained from the above process into Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof by the conventional methods.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Tenofovir, and further conversion to Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof.

In one aspect, the present invention provides an improved process for the preparation of
Tenofovir comprising the steps of:

a) reacting adenine of formula-II, wherein P is H or amino protecting group with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate in presence of metal hydrides and a metal catalyst in a suitable solvent to obtain (R)-9-[2-(Di-alkyl-phosphonomethoxy)propyl]adenine of Formula-Ill, wherein "Alk" represents C1-4 alkyl;

b) optionally deprotecting the amino group; and

c) dealkylating with a suitable dealkylating agent to obtain Tenofovir.

In one embodiment, condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is carried out in presence of metal hydrides. The metal hydrides used in this invention are selected from sodium hydride or lithium hydride, preferable Sodium hydride.

In one more embodiment, metal catalyst used in the condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is selected from metal halides such as magnesium chloride, calcium chloride or zinc bromide, preferably Magnesium chloride.

In one more embodiment, condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is carried out using metal hydride and metal catalyst optionally in presence of dehydrating agent, The dehydrating agent is selected from Thionyl chloride or Trimethylchlorosilane.

In another embodiment, suitable solvent used in the condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is polar aprotic solvent and hydrocarbon solvent or mixtures thereof. The polar aprotic solvents are selected from N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, Sulphalane, N,N-Dimethyl formamide and N,N-Dimethyl acetamide, preferably N-methyl-2-pyrrolidone. Hydrocarbon solvent is selected from Toulene, Xylene, preferably Toluene.

In another embodiment, deprotection of amino group of formula-Ill is carried out as per the process known in the art.

In another embodiment, dealkylation is carried out in presence of a suitable dealkylating agents are selected from mineral acids like Aq. HBr, Aq. HC1, HBr in acetic acid or HC1 gas in Isopropyl alcohol (IPA) with mole ratio ranging from 3 to 15 preferably 7.5 moles and typically at a temperature of about 25 to 110°C, usually at 90 to 95°C.

In one more embodiment, Dealkylation is carried out by using the prior art procedures as described in US 5,922,695, US 5,733,788, US 2004/0018150 and WO 2008/007392.

In one more embodiment, Di-alkyl-p-toluenesulfonyloxymethyl phosphonate used in the present invention is Diethyl p-toluenesulfonyloxymethyl phosphonate and the obtained compound of Formula-Ill is (R)-9-[2-(Diethyl phosphonomethoxy) propyl] adenine.
In one more embodiment, the Tenofovir obtained by present invention is further converted into Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof by the conventional methods such as described in US 5,922,695, US 2004/0018150, and WO 2010/026603.

In another aspect, the present invention provides an improved process for the preparation
of Tenofovir comprising the steps of:

a) reacting adenine of formula-II, wherein P is H or amino protecting group with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate in presence of Dialkyl magnesium in a polar aprotic solvent to obtain (R)-9-[2-(Di-alkyl-phosphonomethoxy)propyl]adenine of Formula-Ill, wherein "Alk" represents CM alkyl;

b) optionally deprotecting the amino group; and

c) dealkylating with a suitable dealkylating agent to obtain Tenofovir.

In one embodiment, Dialkyl magnesium used in condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is selected from Butyl methyl magnesium, dimethyl magnesium, dibutyl magnesium.

In another embodiment, polar aprotic solvent used in the condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is selected from N-methyl-2-pyrrolidone or N-Ethyl-2-pyrrolidone.

In another embodiment, Dealkylation is carried out in presence of a suitable dealkylating reagents selected from mineral acids like Aq. HBr, Aq. HC1, HBr in acetic acid or HC1 gas in IPA with mole ratio ranging from 3 to 15 preferably 7.5 moles and typically at a temperature of about 25 to 110 °C, usually at 90 to 95 °C.

In one more embodiment, Dealkylation is carried out by using the prior art procedures as described in US 5,922,695, US 5,733,788, US 2004/0018150 and WO 2008/007392.

In one more embodiment, Di-alkyl-p-toluenesulfonyloxymethyl phosphonate used in the present invention is Diethyl p-toluenesulfonyloxymethyl phosphonate and the obtained compound of Formula-Ill is (R)-9-[2-(Diethyl phosphonomethoxy) propyl] adenine.

In another aspect, the present invention provides an improved process for the preparation
of Tenofovir comprising the steps of:

a) reacting adenine of formula-II, wherein P is H or amino protecting group with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate in presence of organometallic compound in a polar aprotic solvent to obtain (R)-9-[2-(Di-alkyl-phosphonomethoxy)propyl]adenine of Formula-Ill, wherein "Alk" represents CM alkyl;

b) optionally deprotecting the amino group; and

c) dealkylating with a suitable dealkylating agent to obtain Tenofovir.

In one embodiment, organometallic compound used in condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is selected from Grignard reagent such as Methyl Magnesium chloride.

In another embodiment, polar aprotic solvent used in the condensation of adenine of formula-II with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate is selected from N-methyl-2-pyrrolidone or N-Ethyl-2-pyrrolidone.

In another embodiment, Dealkylation is carried out in presence of a suitable dealkylating reagents selected from mineral acids like Aq. HBr, Aq. HC1, HBr in acetic acid or HC1 gas in IPA with mole ratio ranging from 3 to 15 preferably 7.5 moles and typically at a temperature of about 25 to 110 °C, usually at 90 to 95 °C.

In one more aspect, the Tenofovir obtained by present invention is further converted into Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof by the conventional methods such as described in US 5,922,695, US 2004/0018150, and WO 2010/026603.

Process for the preparation of Tenofovir disoproxil fumarate from Tenofovir is schematically represented in scheme-1.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way
and several variants of these examples would be evident to person ordinarily skilled in the art.

Examples

Example-1

Process for the preparation of Tenofovir

A mixture of N-Methyl-2-pyyrolidone (300 gm) and Sodium hydride (26 gm) was taken in a flask and cooled to 0-5° C. To this (R)-9-[2-(hydroxyl)propyl]adenine (100 gm) was added in portions and temperature was maintained at 0-5° C for 60min. Another Mixture of toluene (150 ml), Magnesium chloride (52 ml), and thionyl chloride (16 gm) was taken in another flask and refluxed. Toluene was distilled off from the reaction mass. To this reaction mixture Toulene (150 ml) was added and cooled to 30° C. This reaction mixture was added to the above mixture of N-Methyl-2-pyyrolidone and Sodium hydride and maintained at a temperature of 75° C for 2 hr. The reaction mass was cooled to 60° C. To this Diethyl p-toluenesulfonyloxymethyl phosphonate (300 gm) was added at the same temperature and heated to 75° C. To this acetic acid (60 gm) was added and maintained at 35° C for 1 hr. Mixture of toluene and N-Methyl-2-pyyrolidone was distilled off from the reaction mixture under vacuum below 75° C. To this aqueous HBr (650 gm) was added and maintained at the temperature at 95° C for 2 hrs. After completion of the reaction the reaction mass was cooled to -5 - 0°C and stirred for 2 hrs. The salts were filtered and methylene dichloride was added the filtrate. The layers were separated and methylene dichloride was added to the aqueous layer and settled for 30 min. The layers were separated and pH of the aqueous layer was adjusted to 2.5-3 with CS lye below 10 °C. To this purified water was added, washed with acetone and dried to yield Tenofovir (110 gm).

Example-2

Process for the preparation of Tenofovir

A mixture of N-Methyl-2-pyyrolidone (300 gm) and Sodium hydride (26 gm) was taken
in a flask and cooled to 0-5° C. To this (R)-9-[2-(hydroxyl)propyl]adenine (100 gm) was
added in portions and temperature was maintained at 0-5° C for 60min. Another Mixture
of toluene (150 ml), Magnesium chloride (52 ml), and Trimethylchlorosilane (29.2 gm) was taken in another flask and refluxed. Toluene was distilled off from the reaction mass.

To this reaction mixture Toulene (150 ml) was added and cooled to 30° C. This reaction mixture was added to the above mixture of N-Methyl-2-pyyrolidone and Sodium hydride and maintained at a temperature of 75° C for 2 hr. The reaction mass was cooled to 60° C. To this Diethyl p-toluenesulfonyloxymethyl phosphonate (300 gm) was added at the same temperature and heated to 75° C. To this acetic acid (60 gm) was added and maintained at 35° C for 1 hr. Mixture of toluene and N-Methyl-2-pyyrolidone was distilled off from the reaction mixture under vacuum below 75° C. To this aqueous HBr (650 gm) was added and maintained at the temperature at 95° C for 2 hrs. After completion of the reaction the reaction mass was cooled to -5 - 0°C and stirred for 2 hrs. The salts were filtered and methylene dichloride was added the filtrate. The layers were separated and methylene dichloride was added to the aqueous layer and settled for 30 min. The layers were separated and pH of the aqueous layer was adjusted to 2.5-3 with CS lye below 10 °C. To this purified water was added, washed with acetone and dried to yield Tenofovir (110 gm).

Example-3

Process for the preparation of Tenofovir

A mixture of N-Methyl-2-pyyrolidone (500 gm) and (R)-9-[2-(hydroxyl)propyl]adenine (100 gm) was taken in a flask and cooled to 0-5° C. To this Methyl magnesium chloride (280 ml-2.6M) was added and temperature was maintained at 0-5° C for 60min. The temperature was raised to 80°C and maintain for 2 hrs. The reaction mass was cooled to 60° C. To this Diethyl p-toluenesulfonyloxymethyl phosphonate (300 gm) was added at the same temperature and heated to 75° C and maintain for 360min. To this acetic acid (60 gm) was added and maintained at 35° C for 1 hr. To this aqueous HBr (650 gm) was added and maintained at the temperature at 95° C for 2 hrs. After completion of the reaction the reaction mass was cooled to -5 - 0°C and stirred for 2 hrs. The salts were filtered and methylene dichloride was added the filtrate. The layers were separated and methylene dichloride was added to the aqueous layer and settled for 30 min. The layers were separated and pH of the aqueous layer was adjusted to 2.5-3 with CS lye below 10°C. To this purified water was added, washed with acetone and dried to yield Tenofovir (80gm).

Example-4

Process for the preparation of Tenofovir

Butyl magnesium chloride (370 ml in THF-2.6 M) was taken in a flask and cooled to 0-5° C. To this n-Butyl lithium (330ml in n-Hexane-1.60M) was added at 0-5°C the temperature and raised to 35°C. The salts were filtered to give dibutyl magnesium. In another flask mixture of (R)-9-[2-(hydroxyl)propyl]adenine (100 gm) and N-Methyl-2-pyrrolidone(500ml) was taken and cooled to 0-5°C. To this dibutyl magnesium solution was added at 0-5°C. The temperatures was raised to 25-30° C and maintain for 1 hr. To this Diethyl p-toluenesulfonyloxymethyl phosphonate (300 gm) was added at 25-30 C. To this acetic acid (60 gm) was added and maintained at 35° C for 1 hr. Mixture of toluene and N-Methyl-2-pyyrolidone was distilled off from the reaction mixture under vacuum below 75° C. To this aqueous HBr (650 gm) was added and maintained at the temperature at 95° C for 2 hrs. After completion of the reaction the reaction mass was cooled to -5 - 0°C and stirred for 2 hrs. The salts were filtered and methylene dichloride was added the filtrate. The layers were separated and methylene dichloride was added to the aqueous layer and settled for 30 min. The layers were separated and pH of the aqueous layer was adjusted to 2.5-3 with CS lye below 10 °C. To this purified water was added, washed with acetone and dried to yield Tenofovir (80 gm).

Example-5

Process for the preparation of Tenofovir

Butyl magnesium chloride (260 ml in THF-2 M) was taken in a flask and cooled to 0-5°C. To this 1,4-Dioxane (22 gm) was added at 0-5°C and temperature was raised to 35°C. The salts were filtered to give dibutyl magnesium. In another flask mixture of (R)-9-[2-(hydroxyl)propyl]adenine (100 gm) and N-Methyl-2-pyrrolidone(500ml) was taken and cooled to 0-5°C. To this dibutyl magnesium solution was added at 0-5°C. The temperature was raised to 25-30° C and maintain for 1 hr. To this Diethyl p-toluenesulfonyloxymethyl phosphonate (300 gm) was added at 25-30° C. To this acetic acid (60 gm) was added and maintained at 35° C for 1 hr. Mixture of toluene and N-Methyl-2-pyyrolidone was distilled off from the reaction mixture under vacuum below 75° C. To this aqueous HBr (650 gm) was added and maintained at the temperature at 95 C for 2 hrs. After completion of the reaction the reaction mass was cooled to -5 - 0 C and stirred for 2 hrs. The salts were filtered and methylene dichloride was added the filtrate. The layers were separated and methylene dichloride was added to the aqueous layer and settled for 30 min. The layers were separated and pH of the aqueous layer was adjusted to 2.5-3 with CS lye below 10 °C. To this purified water was added, washed with acetone and dried to yield Tenofovir (80 gm).

We claim:

1. An improved process for the preparation of Tenofovir comprising the steps of:

a) reacting adenine of formula-II, wherein P is H or amino protecting group with Di-alkyl-p-toluenesulfonyloxymethyl phosphonate in presence of metal hydrides with a metal halide; or Dialkyl magnesium in a suitable solvent to obtain (R)-9-[2-(Di-alkyl-phosphonomethoxy)propyl]adenine of Formula-Ill, wherein "Alk" represents C1-4 alkyl;

b) optionally deprotecting the amino group; and

c) dealkylating with a suitable dealkylating agent to obtain Tenofovir.

2. The process according to claim 1, wherein metal hydride is selected from sodium hydride or lithium hydride.

3. The process according to claim 1, wherein metal halide is selected from magnesium chloride, calcium chloride or zinc bromide.

4. The process according to claim 1, wherein Dialkyl magnesium is selected from Butyl methyl magnesium, dimethyl magnesium or dibutyl magnesium.

5. The process according to claim 1, wherein the suitable solvent is polar aprotic solvent or hydrocarbon solvent or mixtures thereof.

6. The process according to claim 5, wherein polar aprotic solvent is selected from N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, Sulphalane, N,N-Dimethyl formamide or N,N-Dimethyl acetamide.

7. The process according to claim 5, wherein hydrocarbon solvent is selected from toluene or xylene.

8. The process according to claim 1, wherein the dealkylating agents are selected from mineral acids.

9. The process according to claim 8, wherein mineral acid is selected from Aq. HBr, Aq. HC1, HBr in acetic acid or HC1 gas in Isopropyl alcohol.

10. The process according to claim 1, wherein Tenofovir is further converted into Tenofovir Disoproxil or its pharmaceutically acceptable salts thereof.