A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost

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.

Figure 1

Chemical structures of PGF_2α analogs used in the therapy of glaucoma and ocular hypertension.

Scheme 1

Corey strategy for synthesis of tafluprost (5).

Scheme 2

Novel strategy for convergent synthesis of tafluprost (5) from prostaglandin phenylsulfone 16 and aldehyde ω-chain synthon 17, based on the reverse order of side chain attachment to the derivative of Corey lactone (12).

Scheme 3

Synthesis of the racemic aldehyde ω-chain synthon 17. Conditions: (1) TsCl, Py, 0 °C for 10 min, then r.t. overnight, 99% yield; (2) Method A: phenol, NaOH, EtOH-H₂O, reflux for 30 h, 90% yield. Method B: phenol, PPh₃, DIAD, toluene, 99–100 °C for 18 h, 96% yield; (3) 1.0 M HCl, acetone, 70 °C for 1 h, 98% yield; (4) PivCl, Py-CH₂Cl₂, 0 °C for 1 h, then 1.5 h at r.t., 93% yield; (5) TBDMSCl, ImH, DMF, 0 °C for 15 min, then 18 h at r.t., 94% yield; (6) DIBAL-H, CH₂Cl₂, −78 °C for 20 min, then 2 h at r.t., 95% yield; (7) DMP, NaHCO₃, CH₂Cl₂, 0 °C for 15 min, then 1 h at r.t., 94% yield.

Scheme 4

Synthesis of tafluprost (5), tafluprost methyl ester (32) and tafluprost ethylamide (33) from phenylsulfone 16 and aldehyde 17. Reagents and conditions: (1) LDA, THF, −78 °C, 1 h; (2) Na/Hg, Na₂HPO₄, MeOH, 0 °C for 60 min, then 16 h at r.t.; (3) PPTS, CH₂Cl₂, MeOH, 3 h at r.t., 79% yield from 16; (4) TEA, DMAP, Ac₂O, CH₂Cl₂, 97% yield; (5) CAS, MeOH, CH₂Cl₂, 7 h at r.t., 82% yield; (6) DMP, NaHCO₃, CH₂Cl₂, 99% yield; (7) Deoxo-Fluor, CH₂Cl₂; 0 °C for 15 min, then reflux for 24 h, 78% yield; (8) K₂CO₃, MeOH, 24 h at r.t., 76% yield; (9) LiOH H₂O, MeOH, overnight, 98% yield; (10) i-PrI, DBU, acetone, 21 h at r.t., 83% yield; (11) EtNH₂, H₂O, 60 h at r.t.; 85% yield.