Cesium fluoride → HCID 117843278, compound

HRID 2209069Notes

Reaction equation

HRID 2209069 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[F-].[Cs+].[CH3:23][N:24]1[C:28]2[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[S:31][C:27]=2[CH:26]=[N:25]1.[SnH4]>O1CCOCC1>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:30]3[S:31][C:27]4[CH:26]=[N:25][N:24]([CH3:23])[C:28]=4[CH:29]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1

Participants

6

Reactant 4

HCID 25953Cesium fluoride2×HCID 123161StannaneHCID 71143890HCID 71143890, compoundHCID 117843294(R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one

Product 1

HCID 117843278HCID 117843278, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
67.5 °C

Procedure

Intermediate 2.06 (29 mg, 0.098 mmol), Pd-PEPPSI-IPent precatalyst (4 mg, 0.005 mmol), cesium fluoride (32 mg, 0.21 mmol) and powdered 4 Å molecular sieves (25 mg) were taken up in dioxane (1 mL) under Ar. 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (46 μL, 0.13 mmol) was added and the resulting mixture was heated to 65-70° C. After 2 h, the reaction temperature was increased to 80° C. After 18 additional hours, additional Pd-PEPPSI-IPent precatalyst (3 mg, 0.004 mmol), CsF (35 mg, 0.23 mmol) and stannane (23 μL, 0.065 mmol) were added and the reaction was heated to 80° C. After an additional 3 h, additional Pd-PEPPSI-IPent precatalyst (5 mg, 0.006 mmol) was added and the reaction was stirred at 80° C. overnight. After 16 additional hours, the reaction mixture was partitioned between EtOAc and water. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (MeOH in DCM) to provide (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.23. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H21N6O2S: 397.1; found: 397.2. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=0.7 Hz, 1H), 7.35 (d, J=0.7 Hz, 1H), 5.74-5.65 (m, 1H), 5.53 (s, 1H), 4.06 (s, 3H), 4.02 (d, J=0.4 Hz, 3H), 3.66-3.58 (m, 1H), 3.45-3.39 (m, 1H), 3.02-2.88 (m, 1H), 2.63-2.48 (m, 2H), 1.52 (d, J=6.3 Hz, 3H).

Workup

  1. temperaturethe reaction temperature was increased to 80° C
  2. temperaturethe reaction was heated to 80° C
  3. waitAfter an additional 3 h
  4. customAfter 16 additional hours, the reaction mixture was partitioned between EtOAc and water
  5. customThe phases were separated
  6. extractionthe aqueous phase was extracted with EtOAc
  7. dry with materialThe combined organic phase was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto afford a crude residue that
  11. customwas purified by silica gel chromatography (MeOH in DCM)

Sources & evidence

ORD record
ord-dd5fa17ef4a143fb91f378f73f2028b3
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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