Field of the invention

The present invention relates to an improved process for the preparation of Tenofovir. More particularly the present invention relates to the preparation of Tenofovir disoproxil fumarate.

Background of the invention

Tenofovir (Viread) is an antiviral drug that is approved for the treatment of HIV infection. It is able to reduce the amount of HIV in the blood, help prevent or reverse damage to the immune system and reduce the risk of AIDS-related illnesses. Tenofovir belongs to the nucleotide reverse transcriptase inhibitor (NtRTI) class of drugs. Tenofovir disoproxil fumarate is a prodrug form of tenofovir. Considering the importance of Tenofovir several patents discloses process for the preparation of same.

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-toluenesulfonyloxymethylphosphonate in presence of Lithium hydride in dimethylformamide followed by dealkylation with bromotrimethylsilane in acetonitrile.

IN 2076/DEL/1997 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-toluenesulfonyloxymethylphosphonate in presence of lithium tert-butoxide in tetrahydrofuran or DMF followed by dealkylation with bromotrimethylsilane in acetonitrile.

IN 568/MUMNP/2011 discloses a process for preparation of tenofovir, which comprises reacting 9-(2-hydroxyethyl) adenine with diethyl p-toluenesulfonyloxymethylphosphonate in the presence of magnesium isopropoxide or magnesium t-butoxide in a non-polar solvent such as N,N-dimethylformamide followed by dealkylation with bromotrimethylsilane.

IN 1352/CHE/2006 discloses a process for preparation of tenofovir by reaction of 9-[2-(R)-hydroxypropyl) adenine with diethyl-p-
toluenesulfonyloxymethylphosphonate 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.

IN 3791/CHE/2010 discloses a process for preparation of tenofovir, which comprises reacting 9-(2-hydroxyethyl) adenine with diethyl p-toluenesulfonyloxymethylphosphonate in the presence of amide base and a metal catalyst in an organic solvent followed by dealkylation.

IN 3930/CHE/2011 Alprovides a process for preparation of tenofovir by dealkylation of its phosphonate ester using Ionic complexes selected from the group comprising a complex of amide and an acid, a complex of aluminium salt and an amide-acid reagent and a complex of aluminium salt and an amine.

The inventors have published the present invention in Organic chemistry-An Indian Journal OCAIJ, 8(11), 2012 pages 432-436 in November 2012.

Above discussed prior art has associated with one or more of the following drawbacks:

1) Utilizes highly corrosive and expensive reagents like bromotrimethylsilane and chlorotrimethylsilane hence requires special handling procedures due to its highly corrosive in nature.

2) Use of strong base like NaH, LiH, which is difficult to handle in industrial point of view.

Considering the importance of Tenofovir, there is need for a simple, economical and industrially viable process for the synthesis of Tenofovir. With a view to find a simple process the present applicant diligently worked and identified a robust and economical process for the preparation of Tenofovir.

Objectives of the invention

The main objective of the present invention is to provide an improved process for the preparation of Tenofovir that avoids the use of hazardous reagents.

Another objective of the present invention is to provide a robust process for the preparation of Tenofovir with high purity and yield.

Summary of the invention

Accordingly, there is provided an improved process for the preparation of

the said process comprising the steps of: i) reacting 9-[2-(R)-(hydroxy)propyl] adenine of formula (II) with compound of formula (III),

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent in the absence or presence of an alcohol to obtain compound of formula (IV); and

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base.

Detailed description of the invention

In an embodiment of the present invention, the leaving group in compound of formula (III) is selected from halogen, tosyl, mesyl and the like; and Ak in compound of formula (III) denotes lower alkyl group selected from methyl, ethyl, propyl, butyl, isopropyl, and the like.

In another embodiment of the present invention, the polar solvent used in step (i) is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMPO) and the like. Preferably N-methylpyrrolidinone. The alcohol used in step (i) is selected from methanol, ethanol, propanol, isopropanol, butanol, amyl alcohol and the like.

In yet another embodiment of the present invention, the alkyl group in dialkylmagnesium is selected from methyl, ethyl, propyl, n- butyl, t-butyl, pentyl, hexyl etc. Preferably dialkylmagnesium is selected from dimethylmagnesium, diethylmagnesium, dibutylmagnesium is used. The use of dibutylmagnesium has several advantages like i) it avoids the use of highly expensive bases like lithium tert-butoxide, magnesium isopropoxide and magnesium tert-butoxide; ii) avoids the use of strong bases such as sodium hydride and lithium hydride which require special care in manufacturing point of view (possible of exothermic reaction) iii) avoids the additional use of base like sodium amide, lithium amide which reacts violently with water. Hence the use of dibutylmagnesium constitutes one of the novelty of the present invention.

In another embodiment of the present invention, the de-alkylation of compound of formula (IV) is carried out by conventional methods. One such method involves the use of acid like acetic acid, oxalic acid, citric acid, propionic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like and mixtures thereof. The compound of formula (IV) is taken to next stage with or without isolation.

In still another embodiment of the present invention, Tenofovir is isolated from the reaction mass using conventional methods.

In a preferred embodiment, the present invention provides an improved process for the preparation of Tenofovir of formula (I),

the said process comprising the steps of: i) reacting 9-[2-(R)-(hydroxy)propyl]adenine of formula (II) with compound of formula (III),

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMPO) a to obtain compound of formula (IV);

and

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base.

In another preferred embodiment, the present invention provides an improved process for the preparation of Tenofovir of formula (I), CH3

the said process comprising the steps of: i) reacting 9-[2-(R)-(hydroxy)propyl] adenine of formula (II)

NH,

with compound of formula (III),

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent in the presence of alcohol selected from methanol, ethanol, propanol, isopropanol, butanol, amyl alcohol to obtain compound of formula (IV);

and

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base.

In another embodiment, the present invention provides a process for the preparation of Tenofovir disoproxil and its pharmaceutically acceptable salts, which comprises the steps of: i) reacting 9-[2-(R)-(hydroxy)propyl]adenine of formula (II) with compound of formula (III),

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent in the absence or presence of alcohol to obtain compound of formula (IV);

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base and iii) esterifying the Tenofovir obtained in step (ii) with chloro methyl isopropyl carbonate in presence of base to produce Tenofovir disoproxil ester of formula (v)

and

(iv) converting the Tenofovir disoproxil ester into pharmaceutically acceptable salts.

The pharmaceutically acceptable according to the present invention is selected from fumarate, succinate, citrate, oxalate, besylate, maleate, tosylate, phosphate, lactate and the like.

The staring material is prepared by utilizing the processes disclosed in the prior art.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments.The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.

Example 1

Preparation of (R)-9-[2-(phosphonomethoxy)propyl] adenine To the suspension of (R)-9-[2-(hydroxyl)propyl]adenine (100 gm, 0.518 mol) in NMPO (200ml) was added slowly (drop-wise) dibutylmagnesium (400ml, 1M soln in toluene,0.4338 mol) at 25-35°C and stirred. To the reaction mass p-toluenesulfonyloxymethylphosphonate (300 gm, 0.9324 mol) was added and heated to 76-80°C and stirred till completion of reaction (HPLC monitoring). After completion of reaction, the reaction mixture was cooled to 25-30°C and acetic acid (63gm, 1.05mol) was added followed by (48 %) aqueous HBr (721 gm) and heated to 95°C and maintained till completion of hydrolysis (HPLC monitoring). The reaction mixture was cooled to 0-5°C and the precipitated salts were filtered. The filtrate was diluted with water and washed using methylene dichloride. The aqueous layer was cooled to about 10-15°C, and the pH was adjusted to between 2.8 and 3.2 with 40% sodium hydroxide solution at 3-6°C. The precipitated product was stirred at 5-8°C and the product isolated by filtration. The solids were washed with chilled water and dried under vaccum below 65°C to yield 65 g of (PMPA.H20, 41.1%); HPLC purity >99%; moisture content of 6 % w/w.

Example 2

Preparation of (R)-9-[2-(phosphonomethoxy)propyl] adenine To the suspension of (R)-9-[2-(hydroxyl)propyl]adenine (100 gm, 0.518 mol) in NMPO (30ml) and tert-butanol (70gm,0.944 mol) was added p-toluenesulfonyloxymethylphosphonate (300 gm, 0.9324 mol) and stirred. To reaction

mass was added slowly (drop wise) dibutylmagnesium (400ml, 1M soln in toluene, 0.4338 mol) at 25-35°C and heated to 76-80°C and stirred till completion of reaction (HPLC monitoring). After completion of reaction, the reaction mixture was cooled to 25-30°C and to mass acetic acid (63gm, 1.05mol) was added followed by (48%) aqueous HBr (721 gm) and heated to 95°C and maintained till completion of hydrolysis (HPLC monitoring). The reaction mixture was cooled to 0-5°C and the precipitated salts were filtered. The filtrate was diluted with water and washed using methylene dichloride. The aqueous layer was cooled to about 10-15°C, and the pH was adjusted to between 2.8 and 3.2 with 40% sodium hydroxide solution at 3-6°C. The precipitated product was stirred at 5-8°C and the product isolated by filtration. The solids were washed with chilled water and dried under vacuum below 65°C to yield 90 g of (PMPA.H20, 57%); HPLC purity >99%; moisture content of 6 % w/w.

Example 3

Preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine To the suspension of (R)-9-[2-(hydroxyl)propyl]adenine (100 gm, 0.518 mol) in NMPO (30ml) and ethanol (55gm,0.944 mol) was added p-toluenesulfonyloxymethylphosphonate (300 gm, 0.9324 mol) and stirred. To reaction mass was added slowly (drop wise) dibutylmagnesium (400ml, 1M soln in toluene, 0.4338 mol) at 25-35°C and heated to 76-80°C and stirred till completion of reaction (HPLC monitoring). After completion of reaction, the reaction mixture was cooled to 25-30°C and to mass acetic acid (63gm, 1.05mol) was added followed by (48%) aqueous HBr (721 gm) and heated to 95°C and maintained till completion of hydrolysis (HPLC monitoring). The reaction mixture was cooled to 0-5°C and the precipitated salts were filtered. The filtrate was diluted with water and washed using methylene dichloride. The aqueous layer was cooled to about 10-15°C, and the pH was adjusted to between 2.8 and 3.2 with 40% sodium hydroxide solution at 3-6°C. The precipitated product was stirred at 5-8°C and the product isolated by filtration. The solids were washed with chilled water and dried under vacuum below 65°C to yield 71 g of (PMPA.H20, 45%); HPLC purity >99%; moisture content of 6 % w/w.

Example 4

Preparation of (R)-9-[2-(phosphonomethoxy)propyl] adenine To the suspension of (R)-9-[2-(hydroxyl)propyl]adenine (100 gm, 0.518 mol) in NMPO (30ml) and isopropyl alcohol (57gm, 0.944 mol) was added p-toluenesulfonyloxymethylphosphonate (300 gm, 0.9324 mol) and stirred. To reaction mass was added slowly (drop wise) dibutylmagnesium (400ml, 1M soln in toluene, 0.4338 mol) at 25-35°C and heated to 76-80°C and stirred till completion of reaction (HPLC monitoring). After completion of reaction, the reaction mixture was cooled to 25-30°C and to mass acetic acid (63gm, 1.05mol) was added followed by (48%) aqueous HBr (721 gm) and heated to 95°C and maintained till completion of hydrolysis (HPLC monitoring). The reaction mixture was cooled to 0-5°C and the precipitated salts were filtered. The filtrate was diluted with water and washed using methylene dichloride. The aqueous layer was cooled to about 10-15°C, and the pH was adjusted to between 2.8 and 3.2 with 40% sodium hydroxide solution at 3-6°C. The precipitated product was stirred at 5-8°C and the product isolated by filtration. The solids were washed with chilled water and dried under vacuum below 65°C to yield 79 g of (PMPA.H20, 50%); HPLC purity >99%; moisture content of 6 % w/w.

We claim:

1. An improved process for the preparation of Tenofovir of formula (I), ui-13 the said process comprising the steps of:

i) reacting 9- [2-(R)-(hydroxy)propyl] adenine of formula (II) with compound of formula (III),
l-VJ

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent in the absence or presence of an alcohol to obtain compound of formula (IV);

and

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base.

2. The process as claimed in claim 1, wherein the leaving group is selected from halogen, tosyl, mesyl.

3. The process as claimed in claim 1, wherein the polar solvent used in step (i) is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMPO).

4. The process as claimed in claim 1, wherein the alcohol used in step (i) is selected from methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol.

5. The process as claimed in claim 1, wherein the dialkylmagnesium is selected from dimethylmagnesium, dimethylmagnesium or dibutylmagnesium.

6. An improved process for the preparation of Tenofovir of formula (I), the said process comprising the steps of: i) reacting 9-[2-(R)-(hydroxy)propyl]adenine of formula (II) with compound of formula (III),

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMPO) a to obtain compound of formula (IV);

and

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base.

7. An improved process for the preparation of Tenofovir of formula (I),
the said process comprising the steps of: i) reacting 9-[2-(R)-(hydroxy)propyl] adenine of formula (II) with compound of formula (III),

LG

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent in the presence of an alcohol selected from methanol, ethanol, propanol, isopropanol, butanol, amyl alcohol to obtain compound of formula (IV);

and

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base.

8. A process for the preparation of Tenofovir disoproxil and its pharmaceutically acceptable salts, which comprises the steps of:

i) reacting 9-[2-(R)-(hydroxy)propyl] adenine of formula (II) with compound of formula (III),

wherein LG represents a leaving group and Ak denotes alkyl, in the presence of a dialkylmagnesium in a polar organic solvent in the absence or presence of alcohol to obtain compound of formula (IV);
CH3

ii) dealkylating the compound of formula (IV) to yield Tenofovir; characterized that the step (i) reaction is carried out in the absence of base and iii) esterifying the Tenofovir obtained in step (ii) with chloro methyl isopropyl carbonate in presence of base to produce Tenofovir disoproxil ester of formula (v)

and

(iv) converting the Tenofovir disoproxil ester into pharmaceutical^ acceptable salts.

9. The process as claimed in claim 8, wherein the pharmaceutical^ acceptable is selected from fumarate, succinate, citrate, oxalate, besylate, maleate, tosylate, phosphate, lactate.

10. An improved process for the preparation of Tenofovir, prepared according to the examples as described herein.