Diisopropylethylamine → (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

HRID 625595Notes

Reaction equation

HRID 625595 reaction equation
CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C@@H:20]2[C@H:18]1[CH2:19]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29]>C(#N)C>[C@@H:18]12[CH2:19][C@@H:20]1[CH2:21][C@@H:22]([C:23]([O:25][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29])=[O:24])[N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 5195852-Bromo-1-(3-bromophenyl)ethan-1-oneHCID 11020613(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

Product 1

HCID 58209509(1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylateYield 99.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

DIPEA (2.79 mL, 16.0 mmol) was added to a stirring slurry of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.00 g, 8.80 mmol) and 2-bromo-1-(3-bromophenyl)ethanone (2.22 g, 8.00 mmol) in acetonitrile (25 mL) (the solution became clear and amber colored) and the reaction mixture was stirred overnight. The reaction was concentrated and purified via BIOTAGE® (80 g SiO2, 10-25% EtOAc/hexanes) to yield (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.37 g, 7.94 mmol) as a viscous light yellow oil. LC-MS retention time 1.853 min; m/z 423 and 425.98 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a waters XTERRA® MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=1.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0, 7.8 Hz, 1H), 5.58-5.10 (m, 2H), 4.23 (br s, 1H), 3.62-3.39 (m, 1H), 2.58 (dt, J=13.3, 6.5 Hz, 1H), 2.46 (dd, J=13.3, 9.5 Hz, 1H), 1.73-1.51 (m, 1H), 1.47 (s, 9H), 0.85 (br s, 1H), 0.51 (s, 1H).

Workup

  1. concentrationThe reaction was concentrated
  2. custompurified via BIOTAGE® (80 g SiO2, 10-25% EtOAc/hexanes)

Sources & evidence

ORD record
ord-2a3df9a19afb44908dda8a6d4a828086
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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