Diisopropylethylamine → Methyl 2-[(4-methoxy-1,4-dioxobutyl)amino]-4-(trifluoromethyl)benzoate

HRID 2387973Notes

Reaction equation

HRID 2387973 reaction equation
[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:16]CN(C(C)C)C(C)C.Cl[C:26](=[O:32])[CH2:27][CH2:28][C:29]([O-:31])=[O:30]>C(Cl)Cl.C1COCC1>[CH3:16][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:26]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:32]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 12601886Methyl 2-Amino-4-(trifluoromethyl)benzoateHCID 22177264HCID 22177264, compound

Product 1

HCID 59405012Methyl 2-[(4-methoxy-1,4-dioxobutyl)amino]-4-(trifluoromethyl)benzoateYield 100%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A 22 L reactor equipped with an overhead stirrer and a temperature probe was charged with methyl 2-amino-4-(trifluoromethyl)benzoate (680 g, 3.1 mol). DCM (5.4 L, 8 vol) was added to it and the resulting solution was cooled in an ice-water bath. DIEA (1.08 L, 6.2 mol, 2 equiv) was added to the solution. A solution of 4-chloro-4-oxo-butyrate (568 mL, 4.65 mol, 1.5 equiv) in DCM (1.4 L, 2 vol) was added dropwise maintaining the internal temperature below 15° C. (3 h). The ice-water bath was removed and the reaction was stirred for 3 h. The reaction was judged complete by HPLC analysis. Water (3.4 L, 5 vol) was added to the reaction and the biphasic mixture was stirred at ambient temperature overnight. The water layer was removed and saturated aqueous NaHCO3 (3.4 L, 5 vol) was added to the DCM layer. The mixture was stirred for 30 min. The two layers were separated and another 3.4 L (5 vol) of saturated aqueous NaHCO3 was added to the DCM layer. The mixture was stirred for 30 min. The two layers were separated and a 1:1 mixture of brine/water (3.4 L, 5 vol) was added to the DCM layer. The biphasic mixture was stirred for 30 min. The two layers were separated and the DCM layer was pumped down to a low volume (ca. 1.4 L, 2 vol). THF (6.8 L, 10 vol) was added to the solution and the solvent was evaporated under reduced pressure to a low volume (ca. 1.4 L) to obtain Methyl 2-(4-methoxy-4-oxobutanamido)-4-(trifluoromethyl)benzoate [1.032 kg, theoretical yield, 3.1 mol] as a solution in THF.

Workup

  1. customA 22 L reactor equipped with an overhead stirrer
  2. temperaturethe resulting solution was cooled in an ice-water bath
  3. temperaturemaintaining the internal temperature below 15° C. (3 h)
  4. customThe ice-water bath was removed
  5. additionWater (3.4 L, 5 vol) was added to the reaction
  6. stirringthe biphasic mixture was stirred at ambient temperature overnight
  7. customThe water layer was removed
  8. additionsaturated aqueous NaHCO3 (3.4 L, 5 vol) was added to the DCM layer
  9. stirringThe mixture was stirred for 30 min
  10. customThe two layers were separated
  11. additionanother 3.4 L (5 vol) of saturated aqueous NaHCO3 was added to the DCM layer
  12. stirringThe mixture was stirred for 30 min
  13. customThe two layers were separated
  14. additiona 1:1 mixture of brine/water (3.4 L, 5 vol)
  15. additionwas added to the DCM layer
  16. stirringThe biphasic mixture was stirred for 30 min
  17. customThe two layers were separated
  18. additionTHF (6.8 L, 10 vol) was added to the solution
  19. customthe solvent was evaporated under reduced pressure to a low volume (ca. 1.4 L)

Sources & evidence

ORD record
ord-8e3381e74fac47fbaf4a9588e1d79e13
Source dataset
uspto-grants-2012_09
Patent number
US08268992B2

Reaction notes

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