tert-Butylacetic acid → Neotame

HRID 479011Notes

Reaction equation

HRID 479011 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].[C:22]([CH2:26][C:27](O)=O)([CH3:25])([CH3:24])[CH3:23].CC(C)(C)CC=O>CO>[CH3:23][C:22]([CH2:26][CH2:27][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:25])[CH3:24]

Participants

5

Reactant 3

HCID 14057tert-Butylacetic acidHCID 763353,3-DimethylbutanalHCID 134601Aspartame

Product 1

HCID 9810996NeotameYield 98%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Aspartame (11.76 g), tertbutylacetic acid (4.64 g) and methanol (100 ml) were charged to a hydrogenation vessel. 3,3-Dimethylbutyraldehyde (4.0 g) was added. The vessel was pressure purged with nitrogen (4×), and 0.48 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was pressure purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (50 ml) was used to rinse the reaction vessel and the filter cake. The filtrate and wash were combined, and methanol was evaporated under reduced pressure. The solution was reduced to 75 ml total volume, and 75 g of deionized water was added. The remaining methanol was evaporated from the solution under reduced pressure. The resulting solution was stirred at room temperature for 12 hours. Hexane (75 ml) was added, and the solution was stirred for 3 hours at room temperature. The crystallized solid was isolated by filtration and washed with 50 ml deionized water and 50 ml of hexane. The wet product was dried in air to give 8.1 g of neotame (>98% by HPLC).

Workup

  1. custompurged with nitrogen (4×), and 0.48 g of 4% palladium on carbon (containing 50% water)
  2. additionwas added
  3. customAfter pressure purging the reactor with nitrogen (4×)
  4. customAfter completion of the reaction
  5. custompurged with nitrogen (4×)
  6. customThe catalyst was removed from the reaction mixture by filtration through powdered cellulose
  7. washto rinse the reaction vessel
  8. washThe filtrate and wash
  9. custommethanol was evaporated under reduced pressure
  10. additionwas added
  11. customThe remaining methanol was evaporated from the solution under reduced pressure
  12. additionHexane (75 ml) was added
  13. stirringthe solution was stirred for 3 hours at room temperature
  14. customThe crystallized solid was isolated by filtration
  15. washwashed with 50 ml
  16. customThe wet product was dried in air

Sources & evidence

ORD record
ord-5f3f14cfe8b04d6693fbbc75f79407fd
Source dataset
uspto-grants-2003_11
Patent number
US06642406B2

Reaction notes

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