Cesium fluoride → (S)-2-((3-(3-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-N-(1-(p-tolyl)ethyl)acetamide

HRID 402491Notes

Reaction equation

HRID 402491 reaction equation
Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:26])[N:3]=1.[F-].[Cs+].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.[F:47][C:48]1[C:49]([Sn](CCCC)(CCCC)CCCC)=[N:50][CH:51]=[CH:52][CH:53]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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(Cl)Cl>[F:47][C:48]1[C:49]([C:2]2[C:10]3[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH3:18])=[O:15])=[CH:8][C:9]=3[CH3:11])[N:4]([CH3:26])[N:3]=2)=[N:50][CH:51]=[CH:52][CH:53]=1

Participants

9

Reactant 5

HCID 25953Cesium fluorideHCID 516892Sodium BicarbonateHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 164271503-Fluoro-2-(tributylstannyl)pyridineHCID 67209749(S)-2-((3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-N-(1-(p-tolyl)ethyl)acetamide

Product 1

HCID 70817062(S)-2-((3-(3-fluoropyridin-2-yl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-N-(1-(p-tolyl)ethyl)acetamideYield 6.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a sealed tube were added (S)-2-((3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)-N-(1-(p-tolyl)ethyl)acetamide (50 mg, 0.13 mmol), Pd[P(tBu)3)]2 (3.4 mg, 6.7 μmol), CsF (45 mg, 0.30 mmol), [(t-Bu)3PH]BF4 (3.9 mg, 0.013 mmol) and Pd2(dba)3 (6.1 mg, 6.7 μmol). The tube was evacuated and flushed 3 times with argon and then 3-fluoro-2-tributylstannyl-pyridine (104 mg, 0.27 mmol) in dioxane (1 ml) was added and the suspension heated at 100° C. for 16 h. After cooling to rt, CH2Cl2 and NaHCO3 solution were added and the phases separated. The organic layers were washed with water, dried over Na2SO4 and the solvents removed under reduced pressure. Purification using preparative reverse phase chromatography (LC SunFire C18 OBD column) followed by liberation of the free base (SPE cartridge SCX-1, eluent 7M NH3 in methanol) yielded the title compound (3.7 mg, 6%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.59 (d, 1H), 8.54 (d, 1H), 7.91 (t, 1H), 7.62-7.58 (m, 1H), 7.18 (d, 2H), 7.08 (d, 2H), 6.64 (s, 1H), 4.96 (q, 1H), 4.87 (d, 1H), 4.84 (d, 1H), 3.89 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.37 (d, 3H); HPLC-MS RtJ=1.08 min; [M+H]+=434.1]

Workup

  1. customThe tube was evacuated
  2. customflushed 3 times with argon
  3. temperatureAfter cooling to rt
  4. customthe phases separated
  5. washThe organic layers were washed with water
  6. dry with materialdried over Na2SO4
  7. customthe solvents removed under reduced pressure
  8. customPurification

Sources & evidence

ORD record
ord-d5bcafd19315461abfb5697f3568c343
Source dataset
uspto-grants-2014_06
Patent number
US08742106B2

Reaction notes

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