2. Academic Validation
  3. A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost

A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost

  • Molecules. 2017 Jan 31;22(2):217. doi: 10.3390/molecules22020217.
Małgorzata Krupa 1,  Michał Chodyński 2,  Anna Ostaszewska 3,  Piotr Cmoch 4 5,  Iwona Dams 6
Affiliations

Affiliations

  • 1 Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. [email protected].
  • 2 Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. [email protected].
  • 3 Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. [email protected].
  • 4 Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. [email protected].
  • 5 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 42/52, 01-224 Warsaw, Poland. [email protected].
  • 6 Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. [email protected].
PMID: 28146132 DOI: 10.3390/molecules22020217
Abstract

Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde ω-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2-5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

Keywords

Corey lactone; Julia–Lythgoe olefination; fluorination; prostaglandins; tafluprost.

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