N,N'-Dimethylethylenediamine → 10-[(R)-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one

HRID 1023643

Reaction equation

HRID 1023643 reaction equation
[O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:16][C:17]([F:28])([F:27])[C@@H:18]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[OH:19].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)C(C1C=CC(I)=CC=1)O>CN(C=O)C>[F:16][C:17]([F:27])([F:28])[C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:22][CH:21]=1)[OH:19]

Participants

7

Reactant 5

HCID 8070N,N'-DimethylethylenediamineHCID 62657Potassium Phosphate, TribasicHCID 582301081,4-Dioxa-10-azadispiro[4.2.4.2]tetradecan-9-oneHCID 594408652,2,2-Trifluoro-1-(4-iodophenyl)ethanolHCID 68227618(R)-2,2,2-trifluoro-1-(4-iodophenyl)ethanol

Product 1

HCID 5823010310-[(R)-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-oneYield 64.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (352 mg, obtained in example 133, step 3) was dissolved in DMF (22 mL) at RT. Then, (R)-2,2,2-trifluoro-1-(4-iodophenyl)ethanol (755 mg, for synthesis see: J. Org. Chem. 2009, 74, 1605-1610), N,N′-dimethylethylenediamine (sym) (294 mg), cuprous iodide (476 mg) and K3PO4 (1.06 g) were added to the reaction mixture. The mixture was heated to 80° C. for 4.5 hours. The reaction mixture was cooled down to 30° C. and more 2,2,2-trifluoro-1-(4-iodophenyl)ethanol (252 mg) was added. The mixture was re-heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and 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 purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (415 mg, 62%). MS (ESI): 386.4 (MH+).

Workup

  1. temperatureThe reaction mixture was cooled down to 30° C.
  2. temperatureThe mixture was re-heated to 80° C. for 2 hours
  3. temperatureThe reaction mixture was cooled
  4. extractionextracted two times with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customthe solvent was evaporated
  9. customThe residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane)

Sources & evidence

ORD record
ord-e4dede784b1d45d1add7db7199971c82
Source dataset
uspto-grants-2014_05
Patent number
US08722721B2

Linked notes

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