Ethanol → HCID 10066254, compound

HRID 1849935Notes

Reaction equation

HRID 1849935 reaction equation
[CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27].CCO>N1C=CC=CC=1.O>[CH2:29]([O:28][C:26]([NH:8][C:7]1[CH:1]=[CH:2][N:3]([C@H:9]2[C:10]([F:17])([F:18])[C@H:11]([OH:16])[C@@H:12]([CH2:14][OH:15])[O:13]2)[C:4](=[O:5])[N:6]=1)=[O:27])[CH:30]=[CH2:31]

Participants

7

Reactant 4

HCID 702EthanolHCID 6397ChlorotrimethylsilaneHCID 18052Allyl chloroformateHCID 60749Gemcitabine Hydrochloride

Product 1

HCID 10066254HCID 10066254, compoundYield 70%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1049PyridineSolvent

Procedure

To a solution of gemcitabine hydrochloride (1.2 g, 4 mmol) in 12 mL pyridine, chlorotrimethylsilane (2.54 mL, 20 mmol) was added at 0° C.; after stirring for 2 h, allyl chloroformate (0.43 mL, 4 mmol) was added at 0° C. The reaction mixture was allowed to warm to RT, and heated at 45° C. overnight, then cooled to 30-35° C. when 12 mL of absolute EtOH was added. The reaction mixture was reheated at 45° C. for 0.5 h, and following the addition of 6 mL of H2O, was heated at 45° C. for 5 h, then cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc and water; The organic layer was separated, and the aqueous layer was again extracted with EtOAc. The organic extracts were combined and washed with saturated aqueous CuSO4 solution, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (5:1→10:1 EtOAc/Hexane) afforded 1 (white solid, 70% yield): 1H NMR (400 MHz, DMSO-d6) δ11.00 (s, 1H), 8.26-8.28 (d, 1H), 7.13-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.18-6.22 (t, 1H), 5.95-6.02 (m, 1H), 5.38-5.43 (d, 1H), 5.34 (t, 1H), 5.27-5.30 (d, 1H), 4.67-4.69 (d, 2H), 4.20-4.25 (m, 1H), 3.90-3.95 (m, 1H), 3.82-3.86 (m, 1H), 3.66-3.72 (m, 1H); MS (HR-ESI): m/z 346.0857 [M−H]−.

Workup

  1. temperatureheated at 45° C. overnight
  2. additionwas added
  3. waitThe reaction mixture was reheated at 45° C. for 0.5 h
  4. temperaturewas heated at 45° C. for 5 h
  5. temperaturecooled to RT
  6. concentrationconcentrated in vacuo
  7. customThe residue was partitioned between EtOAc and water
  8. customThe organic layer was separated
  9. extractionthe aqueous layer was again extracted with EtOAc
  10. washwashed with saturated aqueous CuSO4 solution, saturated aqueous NaHCO3 solution and brine
  11. dry with materialdried over Na2SO4
  12. concentrationconcentrated in vacuo
  13. customPurification by flash column chromatography (5:1→10:1 EtOAc/Hexane)
  14. customafforded 1 (white solid, 70% yield)

Sources & evidence

ORD record
ord-d6a9b14b062b4bd08bfcc98d9aba9c37
Source dataset
uspto-grants-2015_02
Patent number
US08956613B2

Reaction notes

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