Triethylamine → (1R,3S,5R)-3-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

HRID 1527598Notes

Reaction equation

HRID 1527598 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[F:30][C:31]1[C:37]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][C:39]([F:40])([F:41])[F:42])[C:31]=2[F:30])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 10928Ethyl chloroformateHCID 11020613(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acidHCID 252105032-Fluoro-3-(trifluoromethoxy)aniline

Product 1

HCID 68283686(1R,3S,5R)-3-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.83 g, 8.07 mmol) in dry THF (45 mL) at −20° C. under nitrogen atmosphere was added triethylamine (3.32 mL, 23.8 mmol) followed by ethylchloroformate (0.775 mL, 8.07 mmol) dropwise. The reaction mixture was stirred at −20° C. for 90 min and a solution of 2-fluoro-3-(trifluoromethoxy)aniline (prepared as described in Part C, 1.5 g, 7.69 mmol) in dry THF (5 mL) was added. The reaction mixture was further stirred at −20° C. for 1 h, warmed up to RT and stirred at 65° C. for 16 h until completion of the reaction. The reaction mixture was diluted with EtOAC, washed with a saturated aqueous solution of NaHCO3 (×3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1) to give the desired material as a colorless oil. MS: 427 [M+Na]+, 304.9 [MH−Boc]+; tR (HPLC conditions c): 5.23 min.

Workup

  1. stirringThe reaction mixture was further stirred at −20° C. for 1 h
  2. temperaturewarmed up to RT
  3. stirringstirred at 65° C. for 16 h until completion of the reaction
  4. additionThe reaction mixture was diluted with EtOAC
  5. washwashed with a saturated aqueous solution of NaHCO3 (×3) and brine
  6. customdried (phase separator)
  7. concentrationconcentrated under reduced pressure
  8. customThe crude residue was purified via flash column chromatography on silica gel (EtOAc/c-hexane 1:1)

Sources & evidence

ORD record
ord-d44c8770cdb8482b9186fce5905df2c9
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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