Chlorotrimethylsilane → 2,2-Difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acid ethyl ester

HRID 920582Notes

Reaction equation

HRID 920582 reaction equation
Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[O:35][CH2:34][CH2:33][N:32]([CH2:36]N3C4C=CC=CC=4N=N3)[CH2:31]2)=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1COCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:36][N:32]1[CH2:33][CH2:34][O:35][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=2)[CH2:31]1)[CH3:12]

Participants

6

Reactant 3

HCID 6397ChlorotrimethylsilaneHCID 69585Ethyl bromodifluoroacetateHCID 681938081-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole

Product 1

HCID 670323722,2-Difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of zinc dust (0.34 g; 5.2 mmol) in dry THF (10 mL) was added chlorotrimethylsilane (0.33 mL; 2.6 mmol) and ethyl bromodifluoroacetate (0.50 ml; 3.9 mmol), this mixture was heated under reflux for 10 min. and then cooled to RT. To the resulting mixture was added drop-wise a solution of 1-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole in THF (5 mL). After the addition is complete the resulting mixture is heated under efflux for 2 hours. After cooling to RT the reaction mixture was filtered over Kieselguhr and the filter-cake was washed with ethanol. The solvents were removed in vacuo and the residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 2,2-difluoro-3-(2-(4-octyloxy-phenyl)-morpholin-4-yl)-propionic acid ethyl ester (0.58 g).

Workup

  1. temperaturethis mixture was heated
  2. temperatureunder reflux for 10 min.
  3. additionAfter the addition
  4. temperatureis heated under efflux for 2 hours
  5. temperatureAfter cooling to RT the reaction mixture
  6. filtrationwas filtered over Kieselguhr
  7. washthe filter-cake was washed with ethanol
  8. customThe solvents were removed in vacuo
  9. customthe residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1)

Sources & evidence

ORD record
ord-fce632c0f1fe43acb59629c1b95b43fc
Source dataset
uspto-grants-2016_03
Patent number
US09273017B2

Reaction notes

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