Cesium carbonate → N-(3-chloro-4-fluorophenyl)-7-(piperidin-1-ylmethyl)-2-(pyridin-3-yl)quinazolin-4-amine

HRID 1520328Notes

Reaction equation

HRID 1520328 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)=[N:7][C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[F:25]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23706007Borate(1-), trifluoro(1-piperidinylmethyl)-, potassium (1:1), (T-4)-HCID 672983267-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine

Product 1

HCID 67297889N-(3-chloro-4-fluorophenyl)-7-(piperidin-1-ylmethyl)-2-(pyridin-3-yl)quinazolin-4-amineYield 22.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 21881883Oxolane--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

A dry 15 mL sealed tube was charged with 7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol), potassium 1-trifluoroboratomethylpiperidine (52.5 mg, 0.256 mmol), cesium carbonate (227.5 mg, 0.698 mmol), Pd(OAc)2 (1.6 mg, 3 mol %) and XPhos (6.7 mmol, 6 mol %) in THF/water (10:1, 3.3 mL). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered through a pad of Celite and solvent was removed in vacuo. The crude product was purified by ISCO (silica, 12 g column, 97% dichloromethane-3% methanol-0.1% NH4OH) to yield the desired compound as a yellow solid (23.3 mg, 22%). LCMS m/z=448.0 (M+1) (Method C) (retention time=1.95 min). 1H NMR (300 MHz, CD3OD) δ 9.40 (d, J=1.4 Hz, 1H), 8.70-8.62 (m, 1H), 8.56 (dd, J=4.9, 1.6 Hz, 1H), 8.18-8.09 (m, 2H), 7.69 (ddd, J=6.8, 4.1, 2.1 Hz, 2H), 7.54-7.45 (m, 2H), 7.23 (t, J=9.0 Hz, 1H), 3.61 (s, 2H), 2.47 (s, 4H), 1.64 (dd, J=13.9, 8.9 Hz, 5H), 1.49 (d, J=4.1 Hz, 2H).

Workup

  1. customA dry 15 mL sealed tube
  2. filtrationThe reaction mixture was filtered through a pad of Celite and solvent
  3. customwas removed in vacuo
  4. customThe crude product was purified by ISCO (silica, 12 g column, 97% dichloromethane-3% methanol-0.1% NH4OH)

Sources & evidence

ORD record
ord-5d441d1d3c7140668acfbfe226773a39
Source dataset
uspto-grants-2015_07
Patent number
US09073890B2

Reaction notes

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