FIELD OF THE INVENTION
The present invention relates an improved process for the preparation of Tenofovir.
The present invention further relates to an improved process for the preparation of Tenofovir or its salts or its hydrates which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Tenofovir, also known as 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA), is represented by the following structure of Formula I:
Tenofovir is approved for commercial use as in the form of Tenofovir Disoproxil Fumaric acid salt which is highly potent antiviral agent and is available in the market under the brand name V1READ® and in combination with other antiviral agents.
Tenofovir can be used in the preparation of Tenofovir Alafenamide Fumarate, wherein the structure of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate are given below:
Tenfovir disoproxil fumarate Tenofovir Alafenamide Fumarate
Patent publication WO 94/03467 ("the '467 publication") and U.S. Pat. No. 5,733,788 ("the 788 patent") discloses a process for preparation of Tenofovir by reaction of 9-[2-(R)-hydroxypropyl) adenine with di-(2-alkyl)-p-toluenesulfonyloxy methyl phosphonate in

presence of strong bases such as sodium hydride, dimethyl formamide followed by dealkylation with bromotrimethyl silane in acetonitrile. The process disclosed in the 788 patent is schematically represented as follows:
U.S. Pat. No. 5,922,695 ("the '695 patent") discloses a process for preparation of Tenofovir by reaction of 9-[2-(R)-hydroxy propyl)adenine with diethyl-p-toluenesulfonyloxy methyl phosphonate in presence of Lithium tert-butoxide in Tetrahydrofuran followed by dealkylation with bromotrimethylsilane in Acetonitrile.
U.S. Pat. No. 6,465,649 ("the '649 patent") discloses a process for preparation of Tenofovir by dealkylation of 9-[2-(R)-(diethyl phosphonomethoxy)propyl]adenine with chlorotrimethylsilane in chlorobenzene.
The '649 patent further described conventional methods for dealkylating phosphonate esters include reaction with aqueous solutions of concentrated HC1 or HBr are inappropriate as many of the functional groups on the phosphonates are acid labile, which cannot tolerate these harsh acidic conditions for instance amino group as in the case of tenofovir is readily converted into keto compound (Hypoxanthine impurity) under these concentrated acidic conditions.
The '649 patent also mentions that chlorotrimethylsilane is less reactive and can be used only for the deprotection of the more labile phosphonate esters for example dimethyl phosphonate esters. The deprotection of diethyl phosphonate ester requires long reaction times resulting in unsatisfactory yields. In order to overcome this problem, the use of an activating agent like sodium or lithium iodide to the reaction medium results in faster reaction times. However, the use of such salts leads to metal contamination of the final product and thus additional process steps such as solvent crystallization required to remove.
Moreover, the use of halo trimethylsilanes such as bromo and chlorotrimethylsilanes described in the aforementioned literature for dealkylation reaction are moisture sensitive,

expensive and requires special handling procedures due to its highly corrosive in nature, particularly on commercial scale and thus require more care to use; which in turn result to an increase in the manufacturing cost.
U.S. Pat. No. 8,049,009 ("the '009 patent") discloses a process for preparation of Tenofovir by reaction of 9-[2-(R)-hydroxypropyl) adenine with diethyl-p-toluenesulfonyloxy methyl phosphonate in presence of Magnesium tert-butoxide in dimethyl formamide followed by dealkylation with an acid such as aqueous HBr, aqueous HC1, HBr in acetic acid and HC1 gas in isopropyl alcohol. The process enabled in US '009 is more effluent generated process which is not suitable at industrial scale.
It would be desirable to provide a process for the preparation of Tenofovir, which is simple and cost effective; and a process for its use thereof in the preparation of Tenofovir Disoproxil Fumarate in a convenient, cost efficient manner and on a commercial scale.
The present invention provides a process for preparation of Tenofovir using suitable dealkylating agents such as phosphorus halides in the presence of water as a solvent or using phosphorus oxyhalides or thiohalides in the presence of solvent selected from organic, inorganic or water, the use of above dealkylating agents are away from the aforementioned difficulties such as moisture sensitive, corrosive and expensive dealkylating reagents. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.
OBJECT OF THE INVENTION
The main object of the invention is to provide improved process for the preparation of Tenofovir using simple and cost effective dealkylating agents.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Tenofovir of Formula-I
or its salts or its hydrates, which comprises reacting compound of Formula-II

wherein R| alkyl with a dealkylating agent in the presence of water as a solvent, wherein dealkylating agent is selected from phosphorus halides or phosphorus oxyhalides or thiohalides.
In a preferred aspect, the present invention provides an improved process for the preparation of Tenofovir of Formula-I

or its salts or its hydrates, which comprises reacting compound of Formula-II

wherein Ri alkyl with a dealkylating agent selected from phosphorus oxyhalides optionally in

the presence of base or solvent.
In another preferred aspect, the present invention provides an improved process for the preparation of Tenofovir of Formula-I

or its salts or its hydrates, which comprises reacting compound of Formula-II

wherein R| alkyl with Phosphorous oxychloride, wherein the reaction carried out in the presence of water as a solvent.
In yet another preferred aspect, the present invention provides an improved process for the preparation of Tenofovir of Formula-I

or its salts or its hydrates, which comprises a) Reacting compound of Formula IV


with compound of Formula-Ill
wherein R] alkyl or in the presence of base in a solvent to give compound of Formula II

wherein R| is as defined above,
b) Optionally isolating compound of Formula II,
c) Reacting compound of Formula II with Phosphorous oxychloride, wherein the reaction is carried out in the presence of water as a solvent to give Tenofovir of Formula-I or its salts or its hydrates.
In yet another preferred aspect, the present invention provides an improved process for the preparation of hydrate of Tencfovir of Formula-I

which comprises
a) Reacting compound of Formula IV

with compound of Formula-Ill


wherein R| alkyl in the presence of base in a solvent to give compound of Formula JI
wherein Ri is as defined above,
b) Optionally isolating compound of Formula II,
c) Reacting compound of Formula II with Phosphorous oxychloride, wherein the reaction is carried out in the presence of water as a solvent to give hydrate of Tenofovir of Formula-1.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for preparation of Tenofovir using cost effective dealkylating agents such as phosphorus halides, phosphorus oxyhalides or thiohalides. Tenofovir prepared according to the present invention is further converted into Tenofovir Disoproxil or a pharmaceutically acceptable salt or Tenofovir Alafenamide or its salts thereof with high product yield and quality.
In accordance with one embodiment, the present invention provides a process for preparation of Tenofovir, comprising: dealkylating compound of Formula II with a suitable dealkylating agents such as phosphorus halides, phosphorus oxyhalides or thiohalides.
The inventors of the present invention have developed an improved approach for the preparation of Tenofovir which involves the use of simple and cost effective dealkylating agents, and also the process involves the use of water as a solvent which is highly environmental friendly.

By adopting the use of phosphorus halides, phosphorus oxyhalides or thiohalides as a dealkylating agents, the inventors of the present invention have successfully developed the compound of Formula-I with good yield and high purity.
The terra solvent as used in the present invention is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl, ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
The term base used in the present invention is selected from organic base or inorganic base. Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to NaHC03, LiOH, NaOH, KOH, KHCO3, LiHC03. Na2C03, K2C03, Li2C03l CaC03, MgC03, sodium hydride, potassium tert butoxide, sodium tert butoxide, magnesium hydroxide, MgH2, MgCl2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2j Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
The term alkyl represents C|.s alkyl, preferably selected from methyl, ethyl, isopropyl, isobutyl etc.,
The term salts as used in the present invention is selected from Fumarate, Phosphate, succinate; citrate, ferulate and the like.
The term Phosphorus halide used in the present invention is preferably selected from PF5) PF3, PCI5, PCI3, PBr5, PBr3, PBr7, PI5, PI3. Phosphorous oxyhalides are preferably selected from POF3> POCI3, POBr3, POI3, thiohalides selected from PSF3, PSC13, PSBr3,

PSI3.
The present invention provides, an improved process for the preparation of Tenofovir of Formula-I
or its salts or its hydrates, which comprises reacting compound of Formula-IIA

with a dealkylating agent in the presence of water as a solvent, wherein dealkylating agent is selected from phosphorus halides or phosphorus oxyhalides or thiohalides.
In a preferred embodiment, the present invention provides an improved process for the preparation of Tenofovir of Formula-I

or its salts or its hydrates, which comprises reacting compound of Formula-IIA

with a dealkylating agent Phosphorous oxychloride, wherein the dealkylation is carried out in

the presence of water.
In another preferred embodiment, the present invention provides an improved process for the preparation of Tenofovir of Formula-I
NH2
N^VA O OH
^A? y
N * Q-J OH
CH3
Formula-I
NH2
N^VA O OH
^A? y
N " 0_y OH
CH3
Formula-I
or its salts or its hydrates, which comprises . a) Reacting compound of Formula IV
NH2
N Vy°H
CH3
Formula IV
NH2
(IV.
N Vy°H
CH3
Formula IV with compound of Formula-I IIA
r
Formula-IIIA
r
Formula-IIIA
in the presence of base in a solvent to give compound of Formula IIA
NH2
CH3
Formula-IIA
NH2
CH3
Formula-IIA
b) Optionally isolating compound of Formula IIA,
c) Reacting compound of Formula IIA with Phosphorous oxychloride, wherein the reaction is carried out in the presence of water as a solvent to give Tenofovir of Formula-I or its salts or its hydrates.

In yet another preferred embodiment, the present invention provides an improved process for the preparation of hydrate of Tenofovir of Formula-I

which comprises
a) Reacting compound of Formula IV

with compound of Formula-IIIA
r
\^°
Formula-IIIA in the presence of base in a solvent to give compound of Formula IIA

b) Optionally isolating compound of Formula IIA,
c) Reacting compound of Formula IIA with Phosphorous oxychloride, wherein the reaction is carried out in the presence of water as a solvent to give hydrate of Tenofovir of Formula-I.

After completion of the dealkylation reaction, the resultant reaction mass may be cooled to ambient temperature, the filtrate obtained may be washed with toluene, followed by layers separation, the pH of the reaction mass was adjusted with NaOH to pH 2.5-3.0, followed by the isolation of Tenofovir by any method known in the art, for example by solvent crystallization, solvent precipitation and the like. The Tenofovir can be recovered by any conventional technique known in the art, for example filtration.
The resultant product may optionally be further dried. The drying can be carried out at a temperature ranging from about 60° C to about 90° C. A high purity level of the resulting Tenofovir, obtained by the aforementioned process, may have a chemical purity of at least about 97%, as measured by HPLC, preferably at least about 98%, as measured by HPLC and more preferably at least about 99%, as measured by HPLC.
The present invention encompasses methods of preparing Tenofovir and a pharmaceutically acceptable ester, or a salt or a hydrate thereof with high purity. The processes of the invention allow for economical synthesis, shorter reaction times, and yields of high purity.
The present invention provides pharmaceutically acceptable esters, or salts of Tenofovir, obtained by a process comprising providing a Tenofovir as obtained by the process described above, as a starting material or as an intermediate, where the yield and the purity of the pharmaceutically acceptable esters, or a salt thereof, preferably Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide Fumarate salt may have a purity equal to or greater than about 99.5% as determined by HPLC.
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. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

Examples:
Example-1: Preparation of Tenofovir of Formula I

350mL of DMF charged at 25-35°C, reaction mass was cooled to 10-15°C. 80gm of Sodium tert-butoxide was added to the above mass, reaction mass was stirred for 30min at 10-15°C. 39.5gm of Magnesium chloride was added lot wise, reaction mass was stirred at 65°C, lOOgm of compound of Formula-IV was charged to the reaction mass followed by addition of 220gm of compound of Formula-IIIA. Reaction mass was stirred for 120-150min at 70-75°C. The absence of compounds of Formulae IV and IIIA are cionfirmed by HPLC, 30mL of acetic acid was added to the reaction mass followed by distillation. 200mL of water was added followed by the addition of 240gm of Phosphorous oxychloride, reaction mass temperature was raised to 90-95°C, and stirred for 600min. Absence of Formula-IIA is confirmed by HPLC. lOOmL of water was charged followed by the addition of lOOmL of Toluene. Layers separated and pH of the filtrate adjusted to 2.5-3.0 using NaOH solution (150gm of NaOH in 150gm of water). Reaction mass was cooled to 0-5°C, reaction mass was filtered, wet material was unloaded, to the wet material lOOOmL of water was charged. Reaction mass tempeature was raised to 100-105°C. Reaction mass was cooled to 25-35°C which was further cooled to 0-5°C. Wet cake collected and washed with 150mL of precooled acetone. Material was dried at 65-70°C to obtain 85gm of Tenofovir compound of Formula-I.