Reaction #312621

Reaction equation

sodium bicarbonate

Triethylamine

2-Bromo-3,4,5-trifluorobenzaldehyde

cis-2,6-dimethylmorpholine

→

title compound

3-Bromo-6-(2,6-cis-dimethylmorpholin-4-yl)-4,5-difluorobenzaldehyde

Solvents

acetonitrile

acetonitrile

Conditions

Workup

1. 1
   TemperatureThe mixture was refluxed for 24 hours
2. 2
   OtherThe phases were separated
3. 3
   Extractionthe aqueous phase extracted twice with 500 ml ethyl acetate
4. 4
   WashThe combined organic portions were washed twice with 500 ml brine
5. 5
   Dryingdried over magnesium sulfate
6. 6
   FiltrationAfter filtering
7. 7
   Otherrotary evaporation, 199.7 grams of oil
8. 8
   Otherwas recovered
9. 9
   workup.ADDITIONThe oil was diluted to ˜300 ml with heptane
10. 10
    Otherplaced in the freezer overnight
11. 11
    FiltrationThe resulting yellow solid was filtered

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.

Source