Sodium hydride → (S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-bromo-4-(trifluoromethyl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921107Notes

Reaction equation

HRID 921107 reaction equation
[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Br:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[CH2:46]Br.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:46][C:37]4[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:45])[F:44])=[CH:41][C:36]=4[Br:35])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 149499362-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzeneHCID 118318735(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118321378(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-bromo-4-(trifluoromethyl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 66.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.200 g, 0.421 mmol) and 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (0.268 g, 0.843 mmol) in DMF (1 mL) was added sodium hydride (0.051 g, 1.264 mmol). The mixture was stirred at rt. After 30 min, the reaction was quenched with water and extracted with EtOAc (3×'s). The organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 25 CV) to give the title compound (0.200 g, 0.281 mmol, 66.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=0.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.59 (dd, J=8.6, 1.0 Hz, 1H), 6.59 (s, 1H), 6.02 (ddt, J=17.0, 10.4, 5.1 Hz, 1H), 5.95-5.85 (m, 1H), 5.53-5.39 (m, 1H), 5.19 (dd, J=10.5, 1.7 Hz, 1H), 4.87 (s, 2H), 4.77 (s, 2H), 4.30-4.14 (m, 2H), 4.02 (d, J=5.1 Hz, 2H), 2.62 (s, 3H), 2.06-1.61 (m, 3H), 1.35 (s, 3H), 1.25 (s, 12H) 5 piperidine protons not visible. LCMS (M+H) calcd for C33H43BrF3N4O5: 712.33. found: 713.4.

Workup

  1. customthe reaction was quenched with water
  2. extractionextracted with EtOAc (3×'s)
  3. washwashed with brine
  4. customdried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 25 CV)

Sources & evidence

ORD record
ord-603c5a211c524ae48832e074cc94946a
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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