Phosphoric Acid → (5S)-3-Oxo-5-hydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-6-heptenoic acid ethyl ester

Participants

Reaction Conditions

Reaction Steps

Under nitrogen a dry 1,000 mL flask is charged with 1.44 g of (S)-BINOL, 14.8 g of molecular sieves 4A powder (previously stored for at least 24 hours in an ordinary convection oven at 110° C.), and 210 mL of anhydrous tetrahydrofuran. The mixture is stirred at 20±2° C. for about 15 minutes, then 1.49 mL of titanium (IV) isopropoxide is added dropwise and the dark red mixture is warmed to 50±1° C. and stirred for 30 minutes, then cooled back to 20±2° C. 32.0 g of (2E)-3-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}-2-propenal is added as a solid and the mixture stirred for 10 minutes. Five portions of 64.6 g (about 71 mL) of the compound of Example 2, 1-ethoxy-1,3-bis-trimethylsilanyloxy-buta-1,3-diene are then added, adding each portion over about 5 minutes (mildly exothermic) and waiting 30 minutes before adding the next portion. The internal temperature is maintained at 20±2° C. Disappearance of aldehyde is monitored by TLC (2:1 (v/v) hexane/EtOAc, Rf aldehyde=0.65). When the reaction is complete, the mixture is cooled with an ice bath and 40 mL of 20% (v/v) aqueous trifluoroacetic acid is added. The mixture is warmed to room temperature. After 30 minutes, the desilylation is judged complete by TLC (disappearance of silyloxy aldol adduct Rf=0.75, appearance of de-silylated product Rf=0.22). The mixture is cooled with an ice bath and 80 g of 25% (v/v) aqueous phosphoric acid is added (exothermic) while maintaining the internal temperature below 25° C. The mixture is stirred for 3 hours, then the layers are separated. The aqueous layer is extracted with 210 mL of t-butyl methyl ether and the organic layers are combined and washed with 4×150 mL of 10% aqueous sodium chloride. Solvents are removed by rotoevaporation and the resulting oil is dissolved in 150 mL of n-butanol and evaporated under reduced pressure. This process is repeated with an additional 150 mL of n-butanol to form (E)-(5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoic acid ethyl ester in 99.3% optical purity (HPLC: Chiralpak AD; eluent, hexane/I-PrOH—94/6; flow rate 1 mL/min.; UV @ 254 nM). The product may be used in the next step without further purification.

Provenance & Evidence