Reaction #162196

Reaction equation

(3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone

29b

(S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanone

ethyl 2-bromoacetate

chloro(trimethyl)silane

→

63a

ethyl 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate

Solvents

THF

THF

THF

THF

Conditions

Workup

1. 1
   Temperaturethen heated
2. 2
   Temperatureto reflux
3. 3
   Temperaturecooled
4. 4
   TemperatureThe mixture was refluxed for 2 hours
5. 5
   Concentrationthen concentrated in vacuo
6. 6
   workup.ADDITIONEtOAc and aqueous saturated NaHCO3 solution were added
7. 7
   Extractionthe product was extracted with additional EtOAc (3×)
8. 8
   Dryingdried (Na2SO4)
9. 9
   Concentrationconcentrated in vacuo
10. 10
    OtherPurification by silica gel chromatography (Hexanes:EtOAc)
11. 11
    Otherseparated 2 products
12. 12
    workup.ADDITIONFractions containing the second (minor) peak
13. 13
    Concentrationconcentrated

Procedure

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N2. THF (8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at room temperature then heated to reflux and cooled. A solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture, then a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCO3 solution were added and the product was extracted with additional EtOAc (3×), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. Fractions containing the second (minor) peak were combined and concentrated to give 470 mg of 63a. LCMS+: 332.13 at 3.2 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

Source