A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost.
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.
Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. m.krupa@ifarm.eu.
Małgorzata
M
Krupa
Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. m.chodynski@ifarm.eu.
Michał
M
Chodyński
Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. a.ostaszewska@ifarm.eu.
Anna
A
Ostaszewska
Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. piotr.cmoch@icho.edu.pl.|Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 42/52, 01-224 Warsaw, Poland. piotr.cmoch@icho.edu.pl.
Piotr
P
Cmoch
Chemistry Department, Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland. dams@ifarm.eu.
Iwona
I
Dams
D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D015237:Dinoprost / Q000737:chemistry / Q000494:pharmacology; D005901:Glaucoma / Q000188:drug therapy; D015394:Molecular Structure; D009798:Ocular Hypertension / Q000188:drug therapy; D011460:Prostaglandins F / Q000138:chemical synthesis* / Q000494:pharmacology
D000959:Antihypertensive Agents; D011460:Prostaglandins F; C485333:tafluprost; D015237:Dinoprost
Corey lactone; Julia–Lythgoe olefination; fluorination; prostaglandins; tafluprost