1,3-Diethyl 2-oxopropanedioate → (1S)-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide

HRID 643529Notes

Reaction equation

HRID 643529 reaction equation
N[CH:2]1[CH2:6][C@@:5]([CH:26]([CH3:28])[CH3:27])([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])[CH:4]=[CH:3]1.[O:29]=C(C(OCC)=O)C(OCC)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:22]([O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[CH2:10][NH:9][C:7]([C@:5]1([CH:26]([CH3:28])[CH3:27])[CH2:6][C:2](=[O:29])[CH:3]=[CH:4]1)=[O:8])([CH3:25])([CH3:24])[CH3:23]

Participants

5

Reactant 3

HCID 691051,3-Diethyl 2-oxopropanedioateHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 58617203(1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]1-isopropylcyclopent-2-ene-1-carboxamide

Product 1

HCID 58617127(1S)-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamideYield 91.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of (1S)-4-amino-N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]1-isopropylcyclopent-2-ene-1-carboxamide (35 g, 88 mmol) and diethyl oxomalonate (31 g, 176 mmol) in toluene (350 mL) was refluxed until no more starting material left as judged by HPLC. The reaction mixture was cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (27 g, 176 mmol) was added. The reaction mixture was then warmed to r.t. and stirred at this temperature for 1 hr before being quenched with 1M HCl and vigorously stirred for 1 hr. The reaction mixture was diluted with EtOAc and the two layers were separated. The aqueous phase was then extracted with EtOAc (5×). The organics were combined, dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography on silica gel eluting with hexane:EtOAc (11:1) to yield 32 g of (1S)—N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-isopropyl-4-oxocyclopent-2-ene-1-carboxamide as a pale yellow solid.

Workup

  1. temperaturewas refluxed until
  2. waitleft
  3. temperatureThe reaction mixture was then warmed to r.t.
  4. custombefore being quenched with 1M HCl
  5. stirringvigorously stirred for 1 hr
  6. additionThe reaction mixture was diluted with EtOAc
  7. customthe two layers were separated
  8. extractionThe aqueous phase was then extracted with EtOAc (5×)
  9. dry with materialdried over sodium sulfate
  10. customevaporated to dryness
  11. customThe crude was purified by column chromatography on silica gel eluting with hexane:EtOAc (11:1)

Sources & evidence

ORD record
ord-2b00d085bee44daf85e4f90228af435b
Source dataset
uspto-grants-2010_04
Patent number
US07700591B2

Reaction notes

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