Water → 2-Fluoro-N-methyl-4-(3-(1-(quinolin-2-YL)azetidin-3-YL)pyrazin-2-YL)benzamide

HRID 624521Notes

Reaction equation

HRID 624521 reaction equation
Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[C:29](=[O:32])[NH:30][CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[F:22][C:23]1[CH:24]=[C:25]([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[C:29]([NH:30][CH3:31])=[O:32]

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 447174673-Fluoro-4-(methylcarbamoyl)benzeneboronic acidHCID 585467412-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinoline

Product 1

HCID 727148502-Fluoro-N-methyl-4-(3-(1-(quinolin-2-YL)azetidin-3-YL)pyrazin-2-YL)benzamideYield 73%

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.072 g, 0.243 mmol; see preparation in WO2011143365), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (0.076 g, 0.388 mmol, Combi-blocks), potassium phosphate (0.129 g, 0.607 mmol, Alfa Aesar), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.017 g, 0.024 mmol, Aldrich), water (0.3 mL) and dioxane (1.2 mL) was purged with Argon gas. The mixture was heated at 100° C. for 30 min in microwave reactor, then the heating was stopped and the mixture was cooled to room temperature. The mixture was diluted with saturated Na2CO3 and extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography (12 g, 0%-100% EtOAc-CH2Cl2). The product was further purified by reverse phase HPLC (Shimazu; Gemini 10 μM C18 110A AXIA, 100×50 mm column, 10-55% MeCN in water with 0.1% TFA in 26 min). The collected fractions were neutralized with solid Na2CO3 and extracted with CH2Cl2 three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as a white solid (73 mg, 73%). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.10 (d, J=4.69 Hz, 3 H) 4.30-4.55 (m, 5 H) 6.63 (d, J=8.80 Hz, 1 H) 6.83 (d, J=7.04 Hz, 1 H) 7.23 (t, J=7.34 Hz, 1 H) 7.37 (d, J=12.32 Hz, 1 H) 7.42 (dd, J=8.02, 1.17 Hz, 1 H) 7.50-7.57 (m, 1 H) 7.61 (d, J=7.82 Hz, 1 H) 7.73 (d, J=8.41 Hz, 1 H) 7.89 (d, J=8.80 Hz, 1 H) 8.28 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.35 Hz, 1 H) 8.64 (d, J=2.35 Hz, 1 H). m/z=414 (M+1).

Workup

  1. customwas purged with Argon gas
  2. temperaturethe mixture was cooled to room temperature
  3. additionThe mixture was diluted with saturated Na2CO3
  4. extractionextracted with EtOAc three times
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe crude was purified by silica gel chromatography (12 g, 0%-100% EtOAc-CH2Cl2)
  8. customThe product was further purified by reverse phase HPLC (Shimazu; Gemini 10 μM C18 110A AXIA, 100×50 mm column, 10-55% MeCN in water with 0.1% TFA in 26 min)
  9. extractionextracted with CH2Cl2 three times
  10. dry with materialThe organic phase was dried over Na2SO4
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-b63d59daaf734261bc62b07326c87514
Source dataset
uspto-grants-2016_04
Patent number
US09303028B2

Reaction notes

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