Sodium hydride → (S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-(2-bromophenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921103Notes

Reaction equation

HRID 921103 reaction equation
[I-].[Br:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH2:32]([O:35][C:36]1([CH3:65])[CH2:41][CH2:40][N:39]([C:42]2[N:47]3[N:48]=[C:49]([CH:51]=O)[CH:50]=[C:46]3[N:45]=[C:44]([CH3:53])[C:43]=2[C@H:54]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:38][CH2:37]1)[CH:33]=[CH2:34]>C1COCC1>[CH2:32]([O:35][C:36]1([CH3:65])[CH2:37][CH2:38][N:39]([C:42]2[N:47]3[N:48]=[C:49]([CH:51]=[CH:6][CH2:5][C:4]4[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=4[Br:2])[CH:50]=[C:46]3[N:45]=[C:44]([CH3:53])[C:43]=2[C@H:54]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:40][CH2:41]1)[CH:33]=[CH2:34]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 118307054(2-Bromophenethyl)triphenylphosphonium iodideHCID 118318786(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 123595847(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-(2-bromophenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 57%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of (2-bromophenethyl)triphenylphosphonium iodide (0.121 g, 0.212 mmol) in THF (1 ml) at 0° C. was added sodium hydride (8.68 mg, 0.217 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to −78° C. and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.106 mmol) dissolved in THF (1 ml) was added dropwise and the mixture was stirred at −78° C. for 1 h then warmed to room temperature and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV) to give the title compound (0.0386 g, 0.060 mmol, 57.0% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.28-7.20 (m, 1H), 7.17-7.05 (m, 1H), 6.73-6.55 (m, 1H), 6.54-6.44 (m, 1H), 6.11-5.74 (m, 3H), 5.56-4.97 (m, 2H), 4.33-4.11 (m, 4H), 4.07-3.98 (m, 1H), 3.94 (d, J=4.4 Hz, 1H), 2.62 (s, 3H), 2.01-1.79 (m, 3H), 1.77-1.64 (m, 1H), 1.29-1.19 (m, 15H), (4 piperidine protons not visible in NMR). LCMS (M+H) calcd for C33H43BrN4O4: 640.24. found: 641.4.

Workup

  1. temperatureThe mixture was cooled to −78° C.
  2. additionwas added dropwise
  3. stirringthe mixture was stirred at −78° C. for 1 h
  4. temperaturethen warmed to room temperature
  5. stirringstirred 2 h
  6. customThe reaction was quenched with water
  7. extractionthe product was extracted with EtOAc
  8. washThe organic phase was washed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV)

Sources & evidence

ORD record
ord-a5a7b94b91734dec940df607425d03b7
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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