Tetrabutylammonium Fluoride → (2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-fluoro-2-pyridyl)-3-(3-hydroxyazetidin-1-yl)propanamide

HRID 1098062Notes

Reaction equation

HRID 1098062 reaction equation
[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]1[CH2:30][N:29]([CH2:31][C@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[Cl:59])[N:51]=[CH:52][C:45]=23)[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)=[O:34])[CH2:28]1)(C(C)(C)C)(C)C>O1CCCC1>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[N:50]1[C:46]2[N:47]=[CH:48][N:49]=[C:44]([O:43][C@@H:32]([CH2:31][N:29]3[CH2:30][CH:27]([OH:26])[CH2:28]3)[C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=3)=[O:34])[C:45]=2[CH:52]=[N:51]1

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 57504561(2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide

Product 1

HCID 46175433(2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-fluoro-2-pyridyl)-3-(3-hydroxyazetidin-1-yl)propanamideYield 73.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of tetrabutylammonium fluoride (1M in THF) (7.14 mL, 7.14 mmol) was added in one portion to a stirred solution of (2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (Intermediate AX1) (4.27 g, 7.14 mmol) in tetrahydrofuran (100 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (30 mL), concentrated to approximately 50 mL and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc to afford the product (2.54 g, 73.6%). 1H NMR (400 MHz, CDCl3) δ 2.35 (1H, s), 3.15-3.21 (3H, m), 3.27-3.31 (1H, m), 3.84-3.91 (2H, m), 4.50-4.57 (1H, m), 5.90-5.93 (1H, m), 7.41-7.54 (4H, m), 7.61-7.63 (1H, m), 8.14 (1H, d), 8.23-8.26 (1H, m), 8.37 (1H, s), 8.59 (1H, s), 9.74 (1H, s); m/z (ES+) (M+H)+=484.17; HPLC tR=1.65 min.

Workup

  1. customThe reaction mixture was quenched with saturated NH4Cl (30 mL)
  2. concentrationconcentrated to approximately 50 mL
  3. additiondiluted with water (50 mL) and EtOAc (100 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous layer extracted with EtOAc (100 mL)
  6. dry with materialThe combined organics were dried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customto afford crude product
  10. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc

Sources & evidence

ORD record
ord-9697db5667354a5590bdace2aedc6a2a
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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