Toluene → Tepilamide fumarate

HRID 1482768Notes

Reaction equation

HRID 1482768 reaction equation
[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].C1(C)C=CC=CC=1.[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18].C(N(CC)CC)C>O>[C:4]([O:6][CH2:21][C:20](=[O:23])[N:19]([CH2:24][CH3:25])[CH2:17][CH3:18])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]

Participants

6

Reactant 4

HCID 1140TolueneHCID 8471TriethylamineHCID 16844Chloro-N,N-diethylacetamideHCID 21721168(E)-4-methoxy-4-oxobut-2-enoate

Product 1

HCID 46179632Tepilamide fumarate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
15 °C

Procedure

At a temperature of about 50-70° C., under a nitrogen atmosphere, a slurry of mono-methyl fumarate (130 g), toluene (800 mL) and N,N-diethylchloroacetamide (157 g) is added to triethylamine (1.07 g). The temperature is adjusted to 85-95° C. and maintained there for 4 hours. Then the temperature is then adjusted to 15-25° C. and the mixture is subjected to vigorous agitation. After 30 minutes of vigorous agitation in 200 mL of water, the agitation is stopped and the phases are allowed to separate for 30 minutes. The upper organic phase is washed with additional deionized water (75 mL) with vigorous agitation for 30 minutes. The agitation is then stopped and the phases are allowed to separate for 30 minutes. The organic layer is dried over anhydrous sodium sulfate (25 g) for 2 hours. The reaction is filtered and the solution is cooled to 10-20° C. Heptane (1600 mL), at −5 to −20° C. is added over 5 minutes. The reaction is cooled to −5° C. to −10° C. for 24 to 48 hours. The resulting product is air dried for 12 hours. XRPD analysis confirms product is form 4.

Workup

  1. customis adjusted to 85-95° C.
  2. temperaturemaintained there for 4 hours
  3. customis then adjusted to 15-25° C.
  4. customto separate for 30 minutes
  5. washThe upper organic phase is washed with additional deionized water (75 mL) with vigorous agitation for 30 minutes
  6. customto separate for 30 minutes
  7. dry with materialThe organic layer is dried over anhydrous sodium sulfate (25 g) for 2 hours
  8. filtrationThe reaction is filtered
  9. additionHeptane (1600 mL), at −5 to −20° C. is added over 5 minutes
  10. temperatureThe reaction is cooled to −5° C. to −10° C. for 24 to 48 hours
  11. customdried for 12 hours

Sources & evidence

ORD record
ord-512f2694ed41480e858a84e50321c611
Source dataset
uspto-grants-2016_08
Patent number
US09416096B2

Reaction notes

Loading…