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

Temperature

20 °C

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.

1. waitpreviously stored for at least 24 hours in an ordinary convection oven at 110° C.
2. temperaturethe dark red mixture is warmed to 50±1° C.
3. stirringstirred for 30 minutes
4. temperaturecooled back to 20±2° C
5. stirringthe mixture stirred for 10 minutes
6. additionadding each portion over about 5 minutes (mildly exothermic) and
7. waitwaiting 30 minutes
8. additionbefore adding the next portion
9. temperatureThe internal temperature is maintained at 20±2° C
10. temperaturethe mixture is cooled with an ice bath
11. temperatureThe mixture is warmed to room temperature
12. waitAfter 30 minutes
13. temperatureThe mixture is cooled with an ice bath
14. temperaturewhile maintaining the internal temperature below 25° C
15. stirringThe mixture is stirred for 3 hours
16. customthe layers are separated
17. extractionThe aqueous layer is extracted with 210 mL of t-butyl methyl ether
18. washwashed with 4×150 mL of 10% aqueous sodium chloride
19. customSolvents are removed by rotoevaporation
20. dissolutionthe resulting oil is dissolved in 150 mL of n-butanol
21. customevaporated under reduced pressure

ORD record

ord-315a8190fbfe4ea18395c03b6824a6d7

Source dataset

uspto-grants-2004_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06835838B2