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

HRID 527053Notes

Reaction equation

HRID 527053 reaction equation
Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]2)[C:17]([F:28])=[CH:16][N:15]=1>C1COCC1.[Zn]>[Cl:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C@:23]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([OH:27])[CH2:22]2)[C:17]([F:28])=[CH:16][N:15]=1

Participants

6

Reactant 3

HCID 6397ChlorotrimethylsilaneHCID 7748Ethyl bromoacetateHCID 86667417(S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanone2×

Product 1

HCID 86667446ethyl 2-((1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate

Reagents, catalysts & solvents 2

HCID 23994ZincCatalyst2×HCID 8028TetrahydrofuranSolvent4×

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).

Workup

  1. temperaturethen heated
  2. temperatureto reflux
  3. temperaturecooled
  4. temperatureThe mixture was refluxed for 2 hours
  5. concentrationthen concentrated in vacuo
  6. additionEtOAc and aqueous saturated NaHCO3 solution were added
  7. extractionthe product was extracted with additional EtOAc (3×)
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated in vacuo
  10. customPurification by silica gel chromatography (Hexanes:EtOAc)
  11. customseparated 2 products
  12. additionFractions containing the second (minor) peak
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-efe042e4a1804ab0847255c713a08247
Source dataset
uspto-grants-2016_05
Patent number
US09345708B2

Reaction notes

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