Process for the preparation of Tenofovir

1. A process for the preparation of tenofovir of formula I, comprising the steps of:

a) reacting 9-[2-(R)-(hydroxy)propyl]adenine (HPA) of formula III

with di-Alk-p-toluene sulfonyloxy methyl phosphonate in presence of a base and a metal salt in an organic solvent to obtain (R)-9-[2-(di-Alk-phosphono methoxy)propyl]adenine of formula II;

wherein “Alk” represents C 1-4 alkyl, and wherein the metal salt is represented by the formula MX 2 , wherein M represents a divalent metal cation, and X represents halide, acetate, or trifluoromethane sulfonate; and

b) dealkylating the compound of formula II with a suitable dealkylating agent to obtain tenofovir.

2. The process of claim 1 , further comprising the step of converting the tenofovir into a tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

3. The process of claim 1 , wherein the C 1-4 alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, and isobutyl.

4. The process of claim 1 , wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal hydrides, amide bases, alkali metal alkoxides, and alkyl lithium compounds.

5. The process of claim 1 , wherein the divalent metal cation selected from the group consisting of zinc, beryllium, magnesium, calcium, strontium, and barium.

6. The process of claim 1 , wherein the halide is selected from the group consisting of fluoro, bromo, chloro, and iodo.

7. The process of claim 1 , wherein in the organic solvent is selected from the group consisting of amides, ethers, aromatic hydrocarbons, and nitriles.

8. The process of claim 1 , wherein the organic solvent is selected from dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidinone, toluene, tetrahydrofuran, acetonitrile, and mixtures thereof.

9. The process of claim 1 , wherein the suitable dealkylating agent is selected from the group consisting of trialkyl silyl halides, hydrobromic acid, and methane sulfonic acid.

10. The process of claim 9 , wherein the trialkyl silyl halides is selected from the group consisting of chloro trimethyl silane, bromotrimethyl silane, and iodo trimethyl silane.

11. A process for the preparation of tenofovir disoproxil fumarate, comprising the steps of:

a) reacting 9-[2-(R)-(hydroxy)propyl]adenine (HPA) with diethyl p-toluene sulfonyloxy methyl phosphonate in presence of a base selected from the group consisting of sodium amide and sodium hydride, and a metal salt selected from the group consisting of magnesium chloride and magnesium acetate, in an organic solvent, to obtain (R)-9-[2-(diethylphosphono methoxy)propyl]adenine;

b) dealkylating the (R)-9-[2-(diethylphosphono methoxy)propyl]adenine with aqueous hydrobromic acid to obtain tenofovir:

c) reacting the tenofovir with chloromethyl isopropyl carbonate to obtain tenofovir disoproxil; and

d) reacting of the tenofovir disoproxil with fumaric acid to obtain tenofovir disoproxil fumarate.

12. A process for the preparation of tenofovir of formula I, comprising the steps of:

a) reacting 9-[2-(R)-(hydroxy)propyl]adenine (HPA) of formula III

with di-Alk-p-toluene sulfonyloxy methyl phosphonate in presence of a base and a metal salt in an organic solvent to obtain (R)-9-[2-(di-Alk-phosphono methoxy)propyl]adenine of formula II;

wherein “Alk” represents C 1-4 alkyl, and wherein the base is selected from the group consisting of sodium hydride, lithium hydride, sodium amide, potassium amide, sodium dimethyl amide, sodium methoxide, and butyl lithium; and

b) dealkylating the compound of formula II a suitable dealkylating agent to obtain tenofovir.

13. The process of claim 12 , further comprising the step of converting the tenofovir into a tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

14. The process of claim 12 , wherein the C 1-4 alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, and isobutyl.

15. The process of claim 12 , wherein the organic solvent is selected from the group consisting of amides, ethers, aromatic hydrocarbons, and nitriles.

16. The process of claim 12 , wherein the organic solvent is selected from dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidinone, toluene, tetrahydrofuran, acetonitrile, and mixtures thereof.

17. The process of claim 12 , wherein the suitable dealkylating agent is selected from the group consisting of trialkyl silyl halides, hydrobromic acid, and methane sulfonic acid.

18. The process of claim 12 , wherein the trialkyl silyl halides is selected from the group consisting of chloro trimethyl silane, bromotrimethyl silane, and iodo trimethyl silane.