Cesium carbonate → (S)-2-tert-Butoxycarbonylamino-3-{2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester

HRID 391768Notes

Reaction equation

HRID 391768 reaction equation
[CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[CH:18][CH:17]=2)[CH2:14][OH:15])=[C:8](Br)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>[CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=4)=[CH:18][CH:17]=3)[CH2:14][O:15][C:8]=2[CH:7]=1

Participants

5

Reactant 2

HCID 10796Cesium carbonateHCID 58327516(S)-3-(3-Bromo-4-{1-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester

Product 1

HCID 58327497(S)-2-tert-Butoxycarbonylamino-3-{2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl esterYield 142.2%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 2734941(1,1'-Binaphthalen)-2-yldi-tert-butylphosphineCatalyst

Conditions

Temperature
52 °C

Procedure

(S)-3-(3-Bromo-4-{1-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (8.0 g), palladium acetate (224 mg), racemic 2-(di-tert-butylphosphino)1,1′-binaphthalene (480 mg), and cesium carbonate (5.86 g) were placed into a 100 mL round-bottom flask. The flask was evacuated and flushed with nitrogen twice. Anhydrous toluene (40 mL) was added and the resulting suspension was heated for 48 h at 52° C. After concentration of the reaction mixture to a brown oil, the residue was purified by silica gel chromatography (ethyl acetate/hexanes to give the desired product 10 g as a fluffy white solid. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.44 (d, 1H), 7.33 (m, 3H), 7.26 (m, 1H), 6.98 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 6.62 (dd, 1H), 5.04 (s, 2H), 4.98 (m, 1H), 4.56 (m, 1H), 4.28 (dd, 1H), 3.98 (m, 1H), 3.74 (s, 3H), 3.0 (m, 2H), 1.42 (s, 9H).

Workup

  1. customThe flask was evacuated
  2. customflushed with nitrogen twice
  3. additionAnhydrous toluene (40 mL) was added
  4. customAfter concentration of the reaction mixture to a brown oil, the residue was purified by silica gel chromatography (ethyl acetate/hexanes

Sources & evidence

ORD record
ord-ab9d3ec893044e26beb37a4224b9cf01
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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