Boron trifluoride etherate → 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamide

HRID 2363283Notes

Reaction equation

HRID 2363283 reaction equation
B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:30]2[CH:34]=[C:33]([C:35]3[C:36]4[CH:43]=[CH:42][N:41](COCC[Si](C)(C)C)[C:37]=4[N:38]=[CH:39][N:40]=3)[CH:32]=[N:31]2)[CH2:16][N:15]([C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[CH:19][C:18]=2[F:29])[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:30]2[CH:34]=[C:33]([C:35]3[C:36]4[CH:43]=[CH:42][NH:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH:32]=[N:31]2)[CH2:16][N:15]([C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[CH:19][C:18]=2[F:29])[CH2:14]1)#[N:11]

Participants

7

Reactant 4

HCID 8000Boron trifluoride etherateHCID 14923Ammonium HydroxideHCID 516892Sodium BicarbonateHCID 711436454-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamide

Product 1

HCID 711436174-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamideYield 87.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

Boron trifluoride etherate (2.0 mL, 16 mmol) was added to a solution of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamide (2.20 g, 3.74 mmol) in acetonitrile (30.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature overnight. The reaction was cooled to 0° C., water (5 mL) was added. After stirring at room temperature for 30 minutes, 5.0 M ammonium hydroxide in water (9 mL, 50 mmol) was added slowly at 0° C. over a period of 5 minutes. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%) to afford the desired product (1.50 g, 63%) which was further purified by re-crystallization from acetone to afford the pure product (1.25 g, purity: 99.96%). The product was then converted to TFA salt. LCMS (M+H)+: m/z=459.2. 1H NMR (300 Hz, DMSO-d6): δ 12.73 (s, 1H), 9.11 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (t, J=2.5 Hz, 1H), 7.64 (s, 1H), 7.60 (t, J=2.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 6.72 (t, J=9.0 Hz, 1H), 4.66 (d, J=7.0 Hz, 2H), 4.41 (d, J=7.0 Hz, 2H), 4.04 (m, 1H), 3.73 (s, 2H), 1.12 (d, J=6.5 Hz, 6H).

Workup

  1. temperatureThe reaction was cooled to 0° C.
  2. stirringAfter stirring at room temperature for 30 minutes
  3. stirringThen the reaction mixture was stirred at room temperature overnight
  4. extractionextracted with ethyl acetate (3×20 mL)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%)

Sources & evidence

ORD record
ord-d8ba39030f4a40fd940dd3a5b582e138
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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