Sodium hydride → Methyl 2-chloro-5-cyclopentyl-7-[4-(difluoromethyl)-3-fluorophenyl]-5-hydroxy-3-oxoheptanoate

Temperature

-40 °C

To a slurry of NaH (450 mg, 18.65 mmol) in dry THF (6 mL) at −40° C. under nitrogen was added a cold solution of methyl 2-chloroacetoacetate (2.67 g, 17.76 mmol) in 20 mL dry THF (20 mL) at such a rate that the temperature was maintained within 5° C. of −40° C. When the addition was complete, the mixture was stirred at this temperature for an additional 30 min, then cooled to −70° C. with a dry ice/acetone bath. Cold n-BuLi (9 mL, 2.08 M, 18.65 mmol) was slowly added via syringe, maintaining the temperature at −70° C. The mixture was stirred for an additional 45 min at this temperature. A solution of 1-cyclopentyl-3-[4-(difluoromethyl)-3-fluorophenyl]propan-1-one (4 g, 14.8 mmol) in dry THF (20 mL) was added slowly via an addition funnel. The reaction was allowed to stir at −70° C. for 45 min, then warmed to room temperature. After stirring for 2 h, the mixture was quenched with 4M aqueous NH4Cl (9.35 mL, 37.3 mmol), stirred for 5 min, then concentrated in vacuo. The oily residue was treated with water and extracted with CH2Cl2 (3×50 mL). The extract was dried over Na2SO4, filtered and concentrated to a orange resin. Purification by column chromatography on silica gel and a gradient of 10% ethyl acetate/hexanes to 100% ethyl acetate afforded 3.5 g (8.32 mmol, 56%) of methyl 2-chloro-5-cyclopentyl-7-[4-(difluoromethyl)-3-fluorophenyl]-5-hydroxy-3-oxoheptanoate. This hydroxyester intermediate was dissolved in toluene (20 mL), treated with bis(dibutylchlorotin)oxide (2.07 g, 3.75 mmol, 0.45 equiv), and the mixture refluxed for 1 h. The solution was cooled to room temperature, the solvent removed in vacuo, and the resin filtered through a plug of silica gel, eluting with 5% MeOH/ethyl acetate. The fractions containing the product were evaporated and recrystallized from ethyl ether, affording 437 mg (13.5% yield) of the title product.

1. additionWhen the addition
2. temperaturecooled to −70° C. with a dry ice/acetone bath
3. temperaturemaintaining the temperature at −70° C
4. stirringThe mixture was stirred for an additional 45 min at this temperature
5. stirringto stir at −70° C. for 45 min
6. temperaturewarmed to room temperature
7. stirringAfter stirring for 2 h
8. stirringstirred for 5 min
9. concentrationconcentrated in vacuo
10. additionThe oily residue was treated with water
11. extractionextracted with CH2Cl2 (3×50 mL)
12. dry with materialThe extract was dried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated to a orange resin
15. customPurification by column chromatography on silica gel

ORD record

ord-662121b6aac0424b847806ce6efc588b

Source dataset

uspto-grants-2006_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07148226B2