Cesium fluoride → HCID 178434231, compound

HRID 1441420Notes

Reaction equation

HRID 1441420 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.[F-].[Cs+].O1[CH2:24][CH2:23]OCC1>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]>[CH3:4][C:5]1[C:23]2[C:24](=[CH:10][CH:9]=[C:14]([C:2]3[N:7]=[N:6][C:5]([O:8][C@@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)[CH:13]=2)[NH:7][N:6]=1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 312751,4-DioxaneHCID 86598842(3R)-3-[(6-chloropyridazin-3-yl)oxy]quinuclidine

Product 1

HCID 178434231HCID 178434231, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

The product of Example 9A (120 mg, 0.5 mmol) was coupled with the product of Example 20A (278 mg, 0.7 mmol) under the catalysis of by Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol) and (tBu3P)2 Pd (Strem Chemicals, 26 mg, 0.05 mmol) with CsF (Strem Chemicals, 152 mg, 1 mmol) in dioxane (10 ml) at 80° C. under N2 for 16 hours. After the reaction went to completion, it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was concentrated under vacuum and the residue was treated with TFA (1 mL) in CH2Cl2 (5 mL) at ambient temperature for 2 hours. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (68 mg, 41%). 1H NMR (MeOH-D4, 300 MHz) 1.50-1.66 (m, 1H) 1.70-1.94 (m, 2H) 2.01-2.15 (m, 1H) 2.29-2.37 (m, 1H) 2.62 (s, 3H) 2.81-3.04 (m, 5H) 3.44-3.56 (m, 1H) 5.28-5.36 (m, 1H) 7.28 (d, J=9.2 Hz, 1H) 7.59 (d, J=8.8 Hz, 1H) 8.05 (dd, J=8.8, 1.4 Hz, 1H) 8.16 (d, J=9.2 Hz, 1H) 8.31 (s, 1H) ppm. MS (DCI/NH3) m/z 336 (M+H)+.

Workup

  1. washwashed with brine (2×10 mL)
  2. concentrationThe organic solution was concentrated under vacuum
  3. additionthe residue was treated with TFA (1 mL) in CH2Cl2 (5 mL) at ambient temperature for 2 hours
  4. concentrationIt was then concentrated
  5. customThe title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (68 mg, 41%)

Sources & evidence

ORD record
ord-5bc933eadca04509aef07918e25ac014
Source dataset
uspto-grants-2010_02
Patent number
US07655657B2

Reaction notes

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