Triethylamine → rel-5-Bromo-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3,4-difluorobenzaldehyde

HRID 225439Notes

Reaction equation

HRID 225439 reaction equation
[Br:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:7](F)=[CH:6][C:3]=1C=O.C(N(CC)CC)C.[CH3:20][C@H:21]1[O:26][C@@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.[C:28](=[O:31])(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:6]([C:7]([N:23]2[CH2:24][C@H:25]([CH3:27])[O:26][C@H:21]([CH3:20])[CH2:22]2)=[C:8]([F:11])[C:9]=1[F:10])[CH:28]=[O:31]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 6415002,6-Dimethylmorpholine, cis-HCID 86614498HCID 86614498, compound

Product 1

HCID 86614497rel-5-Bromo-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3,4-difluorobenzaldehyde

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

2-Bromo-3,4,5-trifluorobenzaldehyde (133.15 grams, 0.56 mol) was dissolved in 1000 ml dry acetonitrile. Triethylamine (118.65 ml, 0.85 mol) was added, followed by cis-2,6-dimethylmorpholine (Lancaster, 71.64 grams, 0.62 mol), and 125 ml additional acetonitrile. The mixture was refluxed for 24 hours, then cooled to room temperature, and poured into 1500 ml saturated sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with 500 ml ethyl acetate. The combined organic portions were washed twice with 500 ml brine and then dried over magnesium sulfate. After filtering and rotary evaporation, 199.7 grams of oil was recovered. The oil was diluted to ˜300 ml with heptane to induce solidification and placed in the freezer overnight. The resulting yellow solid was filtered to yield 111.7 grams, 99.8% purity (HPLC) of title compound. Mp 88.1-92.0° C. HPLC analysis done on a Chromolith Performance column, RP-18e, 100-4.6 mm; Mobile phase: A=MeOH, B=0.1N TEAA (pH=7); Gradient: 60% A to 100% A over 5 minutes; wavelength: 254 nm; Retention time: 1.94 minutes.

Workup

  1. temperatureThe mixture was refluxed for 24 hours
  2. customThe phases were separated
  3. extractionthe aqueous phase extracted twice with 500 ml ethyl acetate
  4. washThe combined organic portions were washed twice with 500 ml brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationAfter filtering
  7. customrotary evaporation, 199.7 grams of oil
  8. customwas recovered
  9. additionThe oil was diluted to ˜300 ml with heptane
  10. customplaced in the freezer overnight
  11. filtrationThe resulting yellow solid was filtered

Sources & evidence

ORD record
ord-8bf6747b4edb4c30961534386aba6d3f
Source dataset
uspto-grants-2009_07
Patent number
US07557100B2

Reaction notes

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