Process for the preparation of Tenofovir

• US 8,049,009 B2
• Filed: 01/12/2009
• Issued: 11/01/2011
• Est. Priority Date: 07/12/2006
• Status: Active Grant

• Current Assignee: Mylan Laboratories Limited (Pfizer Inc.)
• Original Assignee: Matrix Laboratories Limited (Pfizer Inc.)
• Inventors: Vasireddy, Uma Maheswer Rao, Ginjupalli, Sambasiva Rao, Vellanki, Siva Rama Prasad, Balusu, Raja Babu, Pilli, Rama Krishna, Jujjavarapu, Pavan Kumar, Bandi, Naga Durga Rao
• Primary Examiner(s): BERCH, MARK L
• Application Number:
  US12/352,182
• Publication Number:
  US 20090286981A1
• Time in Patent Office: 1,023 Days
• Field of Search: 544/244
• US Class Current: 544/244
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

The present invention relates to novel Tenofovir disoproxil hemifumarate salt, which is prepared by dealkylation of Phosphonate esters by using mineral acids followed by esterification and crystallization to give crystalline Tenofovir disoproxil. The Tenofovir disoproxil is further converted to fumarate salts with improved yield.

Claims

1. Tenofovir disoproxil hemifumarate.

2. Tenofovir disoproxil hemifumarate according to claim 1, characterized by an IR spectrum as depicted in FIG. 1B.

3. Tenofovir disoproxil hemifumarate according to claim 1, characterized by a DSC as depicted in FIG. 3B.

4. A process for the preparation of Tenofovir which comprises:

i) dealkylating (R)-9[2-(diethylphosphonomethoxy)propyl]adenine with a mineral acid and

ii) isolation and drying the product to get Tenofovir.

5. The process as claimed in claim 4, wherein the mineral acid is selected from a group consisting of aq. HBr, aq. HCl, HBr in acetic acid and HCl gas in isopropyl alcohol.

6. The process as claimed in claim 4, wherein the dealkylating agent is used in a molar ratio of 3 to 15.

7. The process as claimed in claim 6, wherein the molar ratio is 7.5 to 8.5.

8. The process as claimed in claim 4, wherein the dealkylation reaction is carried out at a temperature of 25 to 110°

C.

9. The process as claimed in claim 8, wherein the temperature is 90 to 95°

C.

10. The process as claimed in claim 4, wherein the obtained tenofovir is further crystallized in water.

11. The process according to claim 4, further comprising the step of converting the Tenofovir to Tenofovir disoproxil and subsequently to a pharmaceutically acceptable salt thereof.

12. The process according to claim 11, wherein the pharmaceutically acceptable salt is a fumarate salt.

13. The process according to claim 4, wherein the Tenfovir is further converted into Tenofovir disoproxil fumarate.