Potassium Phosphate, Tribasic → (S)-(1-(2-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol

HRID 1055151Notes

Reaction equation

HRID 1055151 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39][N:40]2[CH:44]=[C:43]([CH2:45][OH:46])[N:42]=[N:41]2)[C:34]([F:51])=[CH:33][N:32]=1.OCC1N=NNC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:51][C:34]1[C:35]([NH:37][C@@H:38]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39][N:40]2[CH:44]=[C:43]([CH2:45][OH:46])[N:42]=[N:41]2)=[N:36][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:9]=2)=[N:32][CH:33]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 672856905-fluoro-1-((4-methylphenyl)sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo(2,3-b)pyridine2×HCID 86714791(S)-(1-(2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanolHCID 178519888HCID 178519888, compound

Product 1

HCID 71251336(S)-(1-(2-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 962WaterSolvent

Conditions

Temperature
115 °C

Procedure

A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.158 g, 0.380 mmol), (S)-(1-(2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol, 217a, (0.100 g, 0.304 mmol) and K3PO4 (0.520 g, 2.440 mmol) in 2-methyl THF (8 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.008 g, 0.018 mmol) and Pd2(dba)3 (0.006 g, 0.006 mmol) were added and the reaction mixture was heated at 115° C. in a pressure vial for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-70% EtOAc/Hexanes gradient) to afford 120 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.90 (d, J=3.0 Hz, 1H), 5.37 (m, 1H), 4.92 ? 4.83 (m, 1H), 4.78-4.69 (m, 2H), 4.44 (dd, J=13.9, 11.3 Hz, 1H), 2.32 (s, 3H), 1.11 (s, 9H); LCMS Gradient 60-98%, 0.1% formic acid, 7 minutes, C18/ACN, Retention Time=1.29 minutes (M+H) 583.33

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated in vacuo
  4. dissolutionThe residue was dissolved in EtOAc (50 mL)
  5. washwashed with water
  6. dry with materialThe organic layer was dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude residue was purified via silica gel chromatography (0-70% EtOAc/Hexanes gradient)

Sources & evidence

ORD record
ord-3a3d8773d56a4a519b79b3e8b92863f2
Source dataset
uspto-grants-2016_07
Patent number
US09394302B2

Reaction notes

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