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

HRID 589173Notes

Reaction equation

HRID 589173 reaction equation
[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:9]=1.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[C:51]1[CH:56]=[CH:55][C:54](B2OC(C)(C)C(C)(C)O2)=[CH:53][N:52]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:54]3[CH:53]=[N:52][C:51]([C:45]4[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=4[F:43])=[CH:56][CH:55]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:9]=1

Participants

5

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 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-carboxylateHCID 672950922-(2,6-Difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Product 1

HCID 67294707Tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-[6-(2,6-difluorophenyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylateYield 50.3%

Conditions

Temperature
95 °C

Procedure

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 (1.26 g, 1.73 mmol), 2-(2,6-difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.88 g, 2.1 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (141 mg, 0.173 mmol), and potassium carbonate (0.716 g, 5.18 mmol) were placed in a 100-mL round bottom flask equipped with a reflux condenser and rubber septa. Then, the reaction vessel was evacuated and back filled with nitrogen 3 times before adding 1,4-dioxane (3.50 mL) and water (0.933 mL). Then, the reaction was sparged with nitrogen for 8 minutes, then maintained under nitrogen with a balloon and heated at 95° C. for 6 hr. The reaction mixture was then cooled to ambient temperature, diluted with dichloromethane (100 mL), filtered through a plug of Magnesol (ca. 60 mL). and the filtrate was concentrated. The crude product was purified by flash chromatography, (0 to 10% ethylacetate/dichloromethane) to afford the title compound (690 mg, 50%) as an ivory foam.

Workup

  1. customequipped with a reflux condenser
  2. customThen, the reaction vessel was evacuated
  3. additionback filled with nitrogen 3 times
  4. additionbefore adding 1,4-dioxane (3.50 mL) and water (0.933 mL)
  5. customThen, the reaction was sparged with nitrogen for 8 minutes
  6. temperaturemaintained under nitrogen with a balloon
  7. temperatureThe reaction mixture was then cooled to ambient temperature
  8. additiondiluted with dichloromethane (100 mL)
  9. filtrationfiltered through a plug of Magnesol (ca. 60 mL)
  10. concentrationand the filtrate was concentrated
  11. customThe crude product was purified by flash chromatography, (0 to 10% ethylacetate/dichloromethane)

Sources & evidence

ORD record
ord-294e6ed06a8d4586a8fc2fc1ce718af3
Source dataset
uspto-grants-2016_01
Patent number
US09227971B2

Reaction notes

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