Cesium fluoride → {4-{6-[(3R)-1-Aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-2-nitro-phenyl}-carbamic Acid tert-butyl Ester

HRID 970014Notes

Reaction equation

HRID 970014 reaction equation
Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:19])[CH3:18].[F-].[Cs+]>O1CCOCC1.CN(C=O)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([O:21][C:22](=[O:42])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:7]=[N:6][C:5]([O:8][C@@H:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)=[CH:4][CH:3]=2)=[CH:26][C:25]=1[N+:39]([O-:41])=[O:40])([CH3:20])([CH3:18])[CH3:19]

Participants

8

Reactant 3

HCID 25953Cesium fluorideHCID 59737239Tert-butyl 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamateHCID 86598842(3R)-3-[(6-chloropyridazin-3-yl)oxy]quinuclidine

Product 1

HCID 67070172{4-{6-[(3R)-1-Aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-2-nitro-phenyl}-carbamic Acid tert-butyl Ester

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

The product of Example 33A (240 mg, 1 mmol) was coupled with the product of Example 34B (0.72, 2 mmol) under the catalysis of Pd2(dba)3 (24 mg, 0.025 mmol) and (tBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) in dioxane (8 mL) and DMF (Aldrich, 1 mL) at 80° C. under N2 for 16 hours. After the reaction went to completion, it was cooled down to room temperature and diluted with EtOAc (50 mL), washed with brine (2×10 mL). The organic solution was and concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.3) as yellow solid (350 mg, 79%). 1H NMR (300 MHz, MeOH-D4) δ 1.40 (s, 9 H), 1.51-1.70 (m, 1 H), 1.70-1.98 (m, 2 H), 2.00-2.23 (m, 1 H), 2.37-2.51 (m, 1 H), 2.71-3.18 (m, 5 H), 3.47-3.69 (m, 1 H), 5.33-5.49 (m, 1 H), 7.30 (d, J=9.2 Hz, 1 H), 7.54 (d, J=8.5 Hz, 1 H), 7.62 (s, 1 H), 8.14 (d, J=9.5 Hz, 1 H), 8.37 (dd, J=8.1, 2.0 Hz, 1 H), 8.80 (d, J=2.0 Hz, 1 H) ppm. MS (DCl/NH3): 442 (M+H)+.

Workup

  1. washwashed with brine (2×10 mL)
  2. concentrationconcentrated under reduced pressure
  3. customthe title compound was purified by chromatography (SiO2, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.3) as yellow solid (350 mg, 79%)

Sources & evidence

ORD record
ord-2a202ec0d2d44181b08ffd596f5a96c6
Source dataset
uspto-grants-2007_12
Patent number
US07309699B2

Reaction notes

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