Field of invention:
Present invention is directed towards the cost effective industrially applicable process for the Dealkylation of Phosphonate esters by using mineral acids as dealkylating agents with improved yields.
Background of the invention:
The present invention discloses a process for the dealkylation of an intermediate in the preparation of antiretroviral compound which is chemically known as (R)-9-[2-(phosphono 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).
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 5,922,695 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 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%.
US 6,465,649 discloses a process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine by dealkylation of (R)-9-[2-(Diethyl phosphonomethoxy) propyl] adenine with Chlorotrimethylsilane in Chloroform under pressure.
The entire above prior art processes describe the processes involves the usage of highly corrosive and expensive reagents like Bromotrimethylsilane and Chlorotrimethylsilane which require special handling procedures. Such differences provide a compelling basis to develop simple dealkylation procedure for Phosphonate ester with improved yields without using expensive reagents like Trialkylsilylhalides.
Summary of the invention:
The main object of the present invention is to provide a process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine.
Another object of the present invention is to provide a process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine without using Trialkylsilylhalides.
Another object of the present invention is to provide a process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine by using mineral acids.
Another object of the present invention is to provide a process for the preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine with improved yield.

Present invention is directed toward the dealkylation step in the preparation of anti retroviral compound by the use of mineral acids in aq. media and alcohols in place of Trialkylsilylhalides used in the prior art. The process in present invention is cost effective, industrially applicable, uses less cumbersome steps and advantageous over the prior art processes where Trialkylsilylhalides are employed for dealkylation.


Detailed description of the invention:
The present invention provides an improved process for the preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine comprising the steps of:
• Reacting (R)-9-[2-(hydroxyl)propyl]adenine with Diethyl p-toluenesulfonyloxy methylphosphonate in presence of Magnesium tert-butoxide to get (R)-9-[2- (Diethylphosphonomethoxy)propyl]adenine
• Dealkylation of (R)-9-[2-(Diethyl phosphonomethoxy)propyl]adenine with mineral acid(s)
• Isolation and drying the product to get (R)-9-[2-(phosphonomethoxy) propyl] adenine
According to the present invention (R)-9-[2-(hydroxyl)propyl] adenine is condensed with Diethyl p-toluene sulfonyloxy methylphosphonate in presence of Magnesium tert-butoxide in a polar solvent preferably Dimethylformamide at a temperature of 70° to 80°C. After the reaction completion the reaction mass is neutralized by adding an acid preferably acetic acid and the solvent is distilled off completely. The obtained crude is dissolved in a chlorinated hydrocarbon selected from Methylenedichloride, Chloroform, and Ethylene dichloride and water is added. The reaction mixture is filtered to remove the salts and Methylenedichloride layer is separated. Methylenedichloride is distilled off completely to get (R)-9-[2-(phosphonomethoxy) propyl] adenine.
Dealkylation of (R)-9-[2-(Diethyl phosphonomethoxy) propyl] adenine 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. (R)-9-[2-(Diethyl phosphonomethoxy) propyl] adenine and one of the acid described above are maintained at 90 to 95°C for about 3 to 15 hrs, after completion of reaction, the reaction mass is washed with Methylenedichloride and pH is adjusted to about 1.5 to 3.5 preferably at 2.5 to 3.0 with Caustic lye solution. Reaction mass is cooled to about 25 to 35°C and finally to about 0 to 5°C over 4 to 10 hrs. The precipitated product is filtered and the wet material is

recrystallized in water to get pure (R)-9-[2-(phosphonomethoxy) propyl] adenine with improved yield.
The required (R)-9-[2-(hydroxyl) propyl] adenine is prepared by the prior art methods. The present invention is best described with the following examples.
Example 1: Preparation of (R)-9-[2-(phosphonomethoxy)propy 1] adenine
(R)-9-[2-(hydroxyl)propyl]adenine (100 gm, 0.518 mol) was suspended in Dimethylformamide (200 ml) at 25-35°C and added Magnesium tert-butoxide (71 gm, 0.415 mol), heated to 60°C, maintained for 1 hr, raised the temperature to 74°C, added Diethyl p-toluenesulfonyloxymethyl phosphonate (200 gm, 0.6216 mol) in 2 hrs 74-78°C, maintained for 5 hrs at that temperature, cooled to 25-35°C, Acetic acid (60 gm, 1.0 mol) was added. Distilled off the solvent completely under vacuum at below 80°C, cooled to 25-35°C, charged Methylenedichloride (600 ml), water (100 ml), filtered the salts and separated the layers. Distilled off Methylenedichloride, added aq. HBr (655 gm, 3.88 mol), heated to 90°C, maintained for 5 hrs, cooled to RT, charged Water (300 ml) and Methylenedichloride (300 ml), maintained for 1 hr, adjusted the aq. layer pH to 2.5 to 3.0 with Caustic lye, cooled to 5°C, maintained for 4 hrs, filtered the mass. Wet cake heated to reflux with water for dissolution, cooled to RT, finally to 5°C, filtered the material, washed with water and dried the material.
The dry weight of (R)-9-[2-(phosphonomethoxy)propyl]adenine is 110 gms (Yield 70%).
Example 2: Preparation of (R)-9-[2-(phosphonomethoxy) propyl] adenine
(R)-9-[2-(hydroxyl)propyl]adenine (100 gm, 0.518 mol) was suspended in Dimethylformamide (200 ml) at 25-35°C and added Magnesium tert-butoxide (71 gm, 0.415 mol)) and heated to 60°C, maintained for 1 hr, raised the temperature to 74°C, added Diethyl p-toluenesulfonyloxymethylphosphonate (200 gm, 0.6216 mol) in 2 hrs 74-78°C9 maintained for 5 hrs at that temperature, cooled to 25-35°C, added Acetic acid (60 gm, 1.0 mol). Distilled off the solvent completely under vacuum at below 80°C, cooled to 25-35°C, charged Methylenedichloride (600 ml), water (100 ml), filtered the salts and separated the layers.

Distilled off Methylenedichloride. Added HBr/Acetic acid (24%) (610 gms, 3.5 mol), heated to 55°C, maintained for 10 hrs, cooled to 25 to 30°C, charged DM water (300 ml) and Methylenedichloride (300 ml), maintained for 1 hr, adjusted the aq. layer pH to 2.5 to 3.0 with Caustic lye, cooled to 5°C, maintained for 4 hrs and filtered the mass. The wet cake heated to reflux with water for dissolution, cooled to RT, finally to 5°C and filtered the material, washed with water and dried the material.
The dry weight of (R)-9-[2-(phosphonomethoxy)propyl]adenine is 90 gms (Yield 60 %).