Sodium hydride → 1-(4-Chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol

HRID 244395Notes

Reaction equation

HRID 244395 reaction equation
[F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[C:19]1[C:20]([Cl:34])=[C:21]2[CH:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[N:23][CH:24]=1.[Li]CCCC.[Na]>C1COCC1.[Cl-].[NH4+]>[Cl:34][C:20]1[C:19]([C:3]([C:5]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)([OH:4])[C:2]([F:1])([F:14])[F:15])=[CH:24][N:23]=[C:22]2[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:21]=12

Participants

8

Reactant 5

HCID 24758Sodium hydrideHCID 5360545SodiumHCID 57078082,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone2×HCID 684797205-bromo-4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridineHCID 178418339Butyllithium

Product 1

HCID 249587271-(4-Chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanolYield 46%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

To a chilled (ice-bath) solution of 369 mg (1.72 mmol) of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone in 10 mL of THF was added 70 mg (1.75 mmol) of 60% sodium hydride in mineral oil and the mixture was then chilled to −78° C. In another flask, to a chilled (−78° C.) solution of 508 mg (1.65 mmol) of 5-bromo-4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine (prepared according to the procedures in Misra, Bioorg. Med. Chem. Lett. 2003, 13, 2405, and Nakai in Chem. Pharm. Bull. 2004, 52, 1098) in 10 mL of anhydrous THF was added 670 μL (1.68 mmol) of a 2.5 M solution of n-BuLi in hexanes. The mixture stirred for 5 minutes and was then added to the sodium salt of 2,2,2-trifluoro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone. The reaction was monitored by TLC [ethyl acetate-hexanes (6:4)] indicating a new more polar product than both starting materials. After 1 hour, the mixture was diluted with 30 mL of saturated aqueous ammonium chloride and extracted with three 30 mL portions of ethyl acetate. The combined organic layers were washed with three 30 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using dichloromethane to load the sample and then eluting with ethyl acetate-hexanes (10-50% gradient) to afford 337 mg (44%) of title compound. Trituration with ether afforded 85 mg of the title compound as a white solid. MS m/z 444.38 (MH+).

Workup

  1. customprepared
  2. waitAfter 1 hour
  3. extractionextracted with three 30 mL portions of ethyl acetate
  4. washThe combined organic layers were washed with three 30 mL portions of brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude residue was chromatographed on silica gel
  9. washeluting with ethyl acetate-hexanes (10-50% gradient)

Sources & evidence

ORD record
ord-0b42e52c0dde4f62af5e244619827c6c
Source dataset
uspto-grants-2014_02
Patent number
US08658637B2

Reaction notes

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