Sodium hydride → (S)-ethyl 2-(2-(3-(2-bromo-4-fluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921153Notes

Reaction equation

HRID 921153 reaction equation
[I-].[Br:2][C:3]1[CH:29]=[C:28]([F:30])[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+].[C:33]([O:37][C@@H:38]([C:44]1[C:45]([CH3:87])=[N:46][C:47]2[N:48]([N:82]=[C:83]([CH:85]=O)[CH:84]=2)[C:49]=1[N:50]1[CH2:55][CH2:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]([O:64][Si:65]([C:78]([CH3:81])([CH3:80])[CH3:79])([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH3:63])([CH3:56])[CH2:52][CH2:51]1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Br:2][C:3]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:4]=1[CH2:5][CH:6]=[CH:85][C:83]1[CH:84]=[C:47]2[N:46]=[C:45]([CH3:87])[C:44]([C@H:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:49]([N:50]3[CH2:55][CH2:54][C:53]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]([O:64][Si:65]([C:78]([CH3:79])([CH3:80])[CH3:81])([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C:72]4[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=4)[CH3:63])([CH3:56])[CH2:52][CH2:51]3)[N:48]2[N:82]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 131734911(S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetateHCID 131734912HCID 131734912, compound

Product 1

HCID 131734913(S)-ethyl 2-(2-(3-(2-bromo-4-fluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 88%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of (2-bromo-4-fluorophenethyl)triphenylphosphonium, iodide salt (705 mg, 1.193 mmol) in THF (8 ml) at 0° C. was added NaH (48.9 mg, 1.223 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to −78° C. and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (460 mg, 0.597 mmol) dissolved in THF (8 ml) was added dropwise and the mixture was stirred at −78° C. for 1 h then warmed to rt and stirred 1 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%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-bromo-4-fluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (500 mg, 0.523 mmol, 88% yield) as inseparable mixture of E and Z isomers. LCMS (M+2H)=957.2.

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 rt
  5. stirringstirred 1 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%-30% EtOAc/hexane)

Sources & evidence

ORD record
ord-a8c94a93862b4b2aa3b236010bbb409b
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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