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Sodium hydride → (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-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 921187
Notes
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Reaction equation

HRID 921187 reaction equation
[I-].[CH2:2]([O:9][C:10]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:41]([O:45][C@@H:46]([C:52]1[C:53]([CH3:95])=[N:54][C:55]2[N:56]([N:90]=[C:91]([CH:93]=O)[CH:92]=2)[C:57]=1[N:58]1[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:89])([CH3:88])[CH3:87])([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH3:71])([CH3:64])[CH2:60][CH2:59]1)[C:47]([O:49][CH2:50][CH3:51])=[O:48])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH2:2]([O:9][C:10]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH:13]=[CH:93][C:91]1[CH:92]=[C:55]2[N:54]=[C:53]([CH3:95])[C:52]([C@H:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:57]([N:58]3[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:87])([CH3:88])[CH3:89])([C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[C:80]4[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=4)[CH3:71])([CH3:64])[CH2:60][CH2:59]3)[N:56]2[N:90]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 118307148(2-(Benzyloxy)-4,5-difluorophenethyl)triphenylphosphonium iodide saltHCID 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)acetate

Product 1

HCID 131734921
(S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-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
Yield 84%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of (2-(benzyloxy)-4,5-difluorophenethyl)triphenylphosphonium iodide salt (289 mg, 0.454 mmol) in THF (4 ml) at 0° C. was added NaH (18.61 mg, 0.465 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to 0° 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 (175 mg, 0.227 mmol) dissolved in THF (4 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h then warmed to rt 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%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-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 (190 mg, 0.190 mmol, 84% yield) as mixture of E and Z isomers. LCMS (M+H)=1002.0.

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. additionwas added dropwise
  3. stirringthe mixture was stirred at 0° C. for 1 h
  4. temperaturethen warmed to rt
  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%-30% EtOAc/hexane)

Sources & evidence

ORD record
ord-85b1b0eb162f43b08685862f792073ba
Source dataset
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09273067B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes