Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
  • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings 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

Definitions

• step b) reacting the step a) mixture with a suitable base to obtain a racemate, c) separating the (R,S,S)-diastereomer of tenofovir alafenamide;
• the present invention provides a process for separation of diastereomers of tenofovir alafenamide, comprising: subjecting the mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide to simulated moving bed chromatography or Preparative HPLC, and separating the (R,S,S)- ' diastereomer of tenofovir alafenamide.
• the present invention provides a process for the racemization of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)- diastereomer of tenofovir alafenamide, said method comprising treating the (R,R,S)- diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer with a suitable base in a suitable organic solvent.
• step b) reacting the step a) mixture with a suitable base to obtain a racemate, c) subjecting the resultant racemate to simulated moving bed chromatography or Preparative HPLC, and
• the starting compound either (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide can be prepared by any known methods, for example starting compound may be obtained by chromatography fractions according to U.S. patent No's 7,390,791.
• Step a) of the foregoing process includes providing a solution or suspension of (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer of tenofovir alafenamide in a suitable organic solvent.
• a solution or suspension may be obtained directly from a reaction mixture in which (R,R,S)-diastereomer or a mixture having (R,S,S) & (R,R,S)-diastereomer is formed and used as such without isolation or it may be obtained after separation of diastereomers by chromatographic separation.
• bases for use in step b) of the foregoing process includes but are not limited to organic amine bases such as primary, secondary, tertiary amines, cyclic amines and the like; or inorganic bases such as alkali metal hydroxide, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alkoxides, alkali metal aryloxides and the like.
• Suitable organic amines include but are not limited to trimethylamine, butylamine, isopropylamine, diethylamine, ethanolamine, dicyclohexylamine and the like.
• the particles of the support material advantageously have an average diameter (based on the particle size) of 5 ⁇ to 500mm, preferably ⁇ to 100 ⁇ , more preferably 20 ⁇ .
• the present invention also provides a process for purification of tenofovir alafenamide, comprising subjecting the racemic mixtures of tenofovir alafenamide diastereomers obtained by the process described as above to a Preparative FIPLC using suitable eluent.
• the process unlike conventional resolution methods, yields, after recycle over several batches, the desired (R,S,S)-diastereomer in high yields with high diastereomeric purity.
• Such racemization is environmentally desirable, and permits direct recycle of the undesired diastereomer, thus ultimately resulting in virtually complete conversion of undesired diastereomer to the desired diastereomer.
• the present invention also provides preparation of pharmaceutically acceptable salts of tenofovir alafenamide, the process comprising reacting tenofovir alafenamide, as starting material or as an intermediate, with pharmaceutically acceptable salts as per saltification procedure known in the art.
• the present invention provides tenofovir alafenamide, obtained by the process described herein, as analyzed using the chiral high performance liquid chromatography ("chiral HPLC”) with the conditions described below:
• Acetone (142 gms) was charged to the residue and concentrated under reduced pressure to obtained an oily residue which was purified by column chromatography over silica gel by eluting with acetone (100%). Pure product fractions were concentrated under reduced pressure to get residue. Acetonitrile was charged to the residue and the mixture was distilled under reduced pressure to get 47 gms of racemic Tenofovir alafenamide diastereomers as foamy solid.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Molecular Biology (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pyrrole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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Cited By (9)

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• 2014
  • 2014-11-27 IN IN5455CH2013 patent/IN2013CH05455A/en unknown
  • 2014-11-27 WO PCT/IN2014/000734 patent/WO2015079455A2/en not_active Ceased

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