Sodium hydride → 4-[3-Methyl-4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester

HRID 1931626Notes

Reaction equation

HRID 1931626 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[OH:12].[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[C:27]([CH3:35])=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].[Cl-].[NH4+]>CN(C)C=O>[CH:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:12][C:5]4[CH:6]=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:4]=4[F:3])=[C:28]3[C:27]([CH3:35])=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 1231532,4,5-TrifluorophenolHCID 579649474-(4-Chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid isopropyl ester2×

Product 1

HCID 579649044-[3-Methyl-4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl esterYield 70%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Sodium hydride (60% dispersion in mineral oil; 7 mg, 0.18 mmol) was added to a solution of 2,4,5-trifluorophenol (18 mg, 0.12 mmol) in dimethylformamide (1 mL) and the mixture was stirred at room temperature for 15 min. A solution of 4-(4-chloro-3-methyl-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid isopropyl ester (Intermediate 21; 40 mg, 0.12 mmol) in dimethylformamide (1 mL) was added, and the reaction mixture was heated at 100° C. for 2 h. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layer was washed with water (3 times) and brine, dried (sodium sulfate), filtered, evaporated and purified on a flash silica column (20 mm×3″) eluting with 25-33% ethyl acetate/hexanes to give 4-[3-methyl-4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (37 mg, 70%) as a white foam. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.93-2.02 (m, 4H), 2.62 (s, 3H), 2.96-3.09 (m, 2H), 3.32 (s, 3H), 4.04-4.12 (m, 2H), 4.74-4.83 (m, 1H), 4.89-4.96 (m, 1H), 7.81-7.90 (m, 2H), 8.48 (s, 1H). Mass spectrum (ES) MH+=450.

Workup

  1. temperaturethe reaction mixture was heated at 100° C. for 2 h
  2. extractionthe mixture was extracted with ethyl acetate (3×25 mL)
  3. washThe organic layer was washed with water (3 times) and brine
  4. dry with materialdried (sodium sulfate)
  5. filtrationfiltered
  6. customevaporated
  7. custompurified on a flash silica column (20 mm×3″)
  8. washeluting with 25-33% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-31eefd54e485421a9796350fe8aaea93
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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