Sodium Carbonate → Tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 589178Notes

Reaction equation

HRID 589178 reaction equation
C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:25]1[CH:26]=[CH:27][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[N:29][CH:30]=1.[CH3:35][Si:36]([CH3:76])([CH3:75])[CH2:37][CH2:38][O:39][CH2:40][N:41]([CH2:67][O:68][CH2:69][CH2:70][Si:71]([CH3:74])([CH3:73])[CH3:72])[C:42]1[N:47]2[N:48]=[CH:49][C:50](I)=[C:46]2[N:45]=[C:44]([CH:52]2[CH2:58][CH:57]3[N:59]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH:54]([CH2:55][CH2:56]3)[CH2:53]2)[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:74][Si:71]([CH3:72])([CH3:73])[CH2:70][CH2:69][O:68][CH2:67][N:41]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:35])([CH3:76])[CH3:75])[C:42]1[N:47]2[N:48]=[CH:49][C:50]([C:25]3[CH:30]=[N:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:46]2[N:45]=[C:44]([CH:52]2[CH2:58][CH:57]3[N:59]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH:54]([CH2:55][CH2:56]3)[CH2:53]2)[CH:43]=1

Participants

8

Reactant 5

HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 154863922-(5-Bromopyridin-2-yl)propan-2-olHCID 67294720Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Product 1

HCID 67299289Tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylateYield 56.2%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent2×

Procedure

Potassium acetate (1.383 g, 14.09 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (168 mg, 0.230 mmol), bis(pinacolato)diboron (1.40 g, 5.49 mmol), and 2-(5-bromopyridin-2-yl)propan-2-ol (1.099 g, 5.086 mmol) were combined in a microwave tube equipped with a stir bar. The headspace was exchanged for dry nitrogen (×3), and 1,4-dioxane (10 mL) was added. The vessel was lowered into a 90° C. oil bath, and stirred rapidly for 2.5 h. The mixture was cooled to room temperature and tert-butyl 3-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate (1.774 g, 2.431 mmol) in 1,4-dioxane (6 mL, 80 mmol), and aqueous sodium carbonate (2.0 M, 3.3 mL, 6.6 mmol) were added. The organic layer became homogeneous, and the aq. becomes milky. The reaction was again lowered into the 90° C. bath, and stirred vigorously for 16 h, at which point HPLC shows the reaction to be complete. The mixture was cooled and partitioned between ethyl acetate (200 mL) and water (50 mL). The organics were washed with water (50 mL), brine (50 mL), dried with MgSO4, filtered through celite, and concentrated. The crude material was purified by flash chromatography (20-100% ethyl acetate in hexanes). The title compound (1.01 g) was isolated as a brown oil.

Workup

  1. customequipped with a stir bar
  2. additionwas added
  3. customwas lowered into a 90° C.
  4. customwas again lowered into the 90° C. bath
  5. stirringstirred vigorously for 16 h, at which point HPLC
  6. customthe reaction
  7. temperatureThe mixture was cooled
  8. custompartitioned between ethyl acetate (200 mL) and water (50 mL)
  9. washThe organics were washed with water (50 mL), brine (50 mL)
  10. dry with materialdried with MgSO4
  11. filtrationfiltered through celite
  12. concentrationconcentrated
  13. customThe crude material was purified by flash chromatography (20-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-d625412c96a847288be3d32712aba77e
Source dataset
uspto-grants-2016_01
Patent number
US09227971B2

Reaction notes

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