Methyl iodide → 10-[4-((R)-2,2,2-Trifluoro-1-methoxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one

HRID 1023644Notes

Reaction equation

HRID 1023644 reaction equation
[H-].[Na+].[F:3][C:4]([F:29])([F:28])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:26][CH2:25][C:15]3([CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[C:14]2=[O:27])=[CH:9][CH:8]=1)[OH:6].I[CH3:31]>CN(C=O)C>[F:29][C:4]([F:3])([F:28])[C@@H:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:26][CH2:25][C:15]3([CH2:16][CH2:17][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:23][CH2:24]3)[C:14]2=[O:27])=[CH:11][CH:12]=1)[O:6][CH3:31]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 5823010310-[(R)-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one

Product 1

HCID 6822762810-[4-((R)-2,2,2-Trifluoro-1-methoxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-oneYield 91.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% dispersion in mineral oil, 311 mg) was combined with DMF (10 mL) under argon. The suspension was cooled down to 0° C. and a solution of 10-[(R)-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (1.50 g) in DMF (15 mL) was added dropwise over a period of 10 minutes. The mixture was stirred for 45 minutes at 0° C., then, iodomethane (663 mg) was added dropwise over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then warmed up to RT for 1.5 hours. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was once again evaporated with toluene (200 mL). The crude material was purified by flash chromatography (gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (1.42 g). MS (ESI): 400.2 (MH+).

Workup

  1. stirringThe mixture was stirred at 0° C. for 15 minutes
  2. temperaturewarmed up to RT for 1.5 hours
  3. extractionwas extracted two times with ethyl acetate
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customthe solvent was evaporated
  8. customThe residue was once again evaporated with toluene (200 mL)
  9. customThe crude material was purified by flash chromatography (gradient of ethyl acetate in heptane)

Sources & evidence

ORD record
ord-5ed384c5322c4e96ade7fb280b75bbcb
Source dataset
uspto-grants-2014_05
Patent number
US08722721B2

Reaction notes

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