(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 → (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)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 921180Notes

Reaction equation

HRID 921180 reaction equation
[I-].[CH2:2]([O:9][C:10]1[C:15]([CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:14]([F:37])[C:13]([F:38])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:39]([O:43][C@@H:44]([C:50]1[C:51]([CH3:93])=[N:52][C:53]2[N:54]([N:88]=[C:89]([CH:91]=O)[CH:90]=2)[C:55]=1[N:56]1[CH2:61][CH2:60][C:59]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][C@H:68]([O:70][Si:71]([C:84]([CH3:87])([CH3:86])[CH3:85])([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH3:69])([CH3:62])[CH2:58][CH2:57]1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH2:2]([O:9][C:10]1[C:15]([CH2:16][CH:17]=[CH:91][C:89]2[CH:90]=[C:53]3[N:52]=[C:51]([CH3:93])[C:50]([C@H:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:55]([N:56]4[CH2:61][CH2:60][C:59]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][C@H:68]([O:70][Si:71]([C:84]([CH3:85])([CH3:86])[CH3:87])([C:72]5[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:78]5[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=5)[CH3:69])([CH3:62])[CH2:58][CH2:57]4)[N:54]3[N:88]=2)=[C:14]([F:37])[C:13]([F:38])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

4

Reactant 2

HCID 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 131734919(6-(Benzyloxy)-2,3-difluorophenethyl)triphenylphosphonium, iodide salt

Product 1

HCID 131734920(S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)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 50.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a suspension of (6-(benzyloxy)-2,3-difluorophenethyl)triphenylphosphonium, iodide salt (217 mg, 0.340 mmol) in THF (5 ml) at 0° C. was added n-Buli (0.213 ml, 0.340 mmol) and the resulting mixture was heated at 60° C. for 1 h. The mixture was then cooled to rt 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 (175 mg, 0.227 mmol) dissolved in THF (5 ml) was added dropwise and the mixture was stirred rt for 5 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-(6-(benzyloxy)-2,3-difluorophenyl)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 (114 mg, 0.114 mmol, 50% yield) as mixture of E and Z isomers. LCMS (M+H)=1001.8.

Workup

  1. additionwas added n-Buli (0.213 ml, 0.340 mmol)
  2. temperatureThe mixture was then cooled to rt
  3. additionwas added dropwise
  4. customThe reaction was quenched with water
  5. extractionthe product was extracted with EtOAc
  6. washThe organic phase was washed with brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane)

Sources & evidence

ORD record
ord-fbfa54e0f31b4c5080117cbf87b0a198
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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