Boron trifluoride etherate → US9611269, Example 30

HRID 2363330Notes

Reaction equation

HRID 2363330 reaction equation
B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:32]2[CH:36]=[C:35]([C:37]3[C:38]4[CH:45]=[CH:44][N:43](COCC[Si](C)(C)C)[C:39]=4[N:40]=[CH:41][N:42]=3)[CH:34]=[N:33]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:32]2[CH:36]=[C:35]([C:37]3[C:38]4[CH:45]=[CH:44][NH:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH:34]=[N:33]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@H:26]([CH3:31])[C:27]([F:28])([F:29])[F:30])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11]

Participants

7

Reactant 4

HCID 8000Boron trifluoride etherateHCID 14923Ammonium HydroxideHCID 516892Sodium BicarbonateHCID 712079615-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide

Product 1

HCID 71155891US9611269, Example 30Yield 58%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

Boron trifluoride etherate (0.078 mL, 0.62 mmol) was added to a solution of 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide in acetonitrile (4.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 3 h. [LCMS (M+H)+: m/z=527.2]. The mixture was cooled to 0° C., water (1.6 mL) was added. After 30 min., 5.0 M ammonium hydroxide in water (0.38 mL, 1.9 mmol) was added slowly at 0° C. over 5 min. Then the reaction mixture was stirred at room temperature overnight. The mixture was worked up with saturated aqueous NaHCO3, 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 methanol in dichloromethane (0-5%) to afford the desired product (60 mg, 58%). LCMS (M+H)+: m/z=497.1. 1H NMR (400 MHz, DMSO-d6): δ 12.73 (br, 1H), 9.13 (s, 1H), 8.87 (s, 1H), 8.83 (d, J=9.2 Hz, 1H), 8.68 (d, J=1.4 Hz, 1H), 8.58 (s, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.82 (dd, J=3.1, 2.2 Hz, 1H), 7.27 (dd, J=3.3, 1.3 Hz, 1H), 4.83 (d, J=9.8 Hz, 2H), 4.81 (m, 1H), 4.58 (d, J=9.9 Hz, 2H), 3.80 (s, 2H), 1.36 (d, J=7.1 Hz, 3H).

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. waitAfter 30 min.
  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 methanol in dichloromethane (0-5%)

Sources & evidence

ORD record
ord-3fcc582e8a3a41f6b1cdcc5a0bc76682
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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