Synthetic Route Optimization of PF-00868554, An HCV Polymerase Inhibitor in Clinical Evaluation

Abstract

This paper describes the optimization efforts to establish an enabling synthesis to provide multigram quantity of PF-00868554, an HCV polymerase inhibitor currently in phase II clinical evaluations.

Key words

HCV polymerase inhibitor - Heck reaction - dihydro­pyrone - pyridine synthesis - borane pyridine

References and Notes

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12

Experimental Conditions of Optimized Heck Coupling and Product Characterization
To a solution of benzyl ester 15 (1.30 g, 4.74 mmol) in DMAC (11 mL) in a two-neck round-bottomed flask was added 4-bromo-2,6-diethylpyridine (7, 1.22 g, 5.69 mmol), followed by TBACl (1.30 g, 4.74 mmol), and Pd(OAc)₂. The resulting solution was degassed by house vacuum followed by argon back filling (3×). Dicyclohexylmethylamine (2.0 mL, 9.50 mmol) was added, and the reaction vessel was lowered into a pre-heated oil bath at 90 ˚C. The reaction was stirred at this temperature under argon until all benzyl ester 15 was consumed (about 5 h). The solution was cooled to r.t., diluted with H₂O (60 mL) and then extracted with MTBE
(2 × 50 mL). The combined organic layers were washed with H₂O (2 × 50 mL), sat. NaHCO₃ (50 mL), 5% aq AcOH (50 mL), then brine (sat., 50 mL). The yellow solution was dried (MgSO₄), filtered, and concentrated to provide a crude amber oil (2.1 g). ^¹H NMR (300 MHz, CDCl₃): δ = 1.26-1.32 (m, 6 H), 1.48-1.64 (m, 8 H), 2.71-2.74 (m, 2 H), 2.75-2.84 (m, 5 H), 5.02-5.07 (m, 1 H), 5.10-5.12 (m, 1 H), 6.35-6.42 (m, 1 H), 6.51-6.59 (m, 1 H), 6.89 (s, 2 H), 7.22-7.26 (m, 5 H). MS (APCI): m/z = 408.20 [M + H]⁺.

13

Experimental Conditions for Scheme 3, Step viii
To a solution of pyrone 19 (710 mg, 2.07 mmol) in anhyd MeOH (10 mL) at -25 ˚C was added borane-pyridine complex (ca. 8 M solution, 0.5 mL, 4.13 mmol). To this aldehyde (1.3 equiv, 2.69 mmol, 475 mg) was added, and the reaction was slowly warmed to 0 ˚C. The cloudy mixture was stirred for 3 h during which time it became homogen-eous. H₂O (1 mL) was added to quench the remaining borane. The reaction was stirred for an additional 30 min before it was concentrated to about 1/10 volume and diluted in 10% MeOH-EtOAc. The mixture was extracted with 1 N HCl (2×), and the combined aqueous layers were carefully neutralized to pH 7 with sat. NaHCO₃. The aqueous layer was extracted with 10% MeOH-EtOAc (3×), and the resulting organic extract showed a single peak with mass corresponding to the product. The organic layer was washed with brine and dried (MgSO₄), filtered, and concentrated to a white solid (789 mg, 76%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.23 (t, J = 7.63 Hz, 6 H), 1.48-1.59 (m, 4 H), 1.59-1.75 (m, 4 H), 1.96-2.09 (m, 4 H), 2.38 (d, J = 8.48 Hz, 1 H), 2.63-2.67 (m, 4 H), 2.69-2.80 (m, 9 H), 4.06-4.15 (m, 2 H), 6.76 (s, 2 H), 6.83 (s, 1 H). MS (APCI): m/z = 504.2 [M + H]⁺.