Boron trifluoride etherate → US9611269, Example 33

HRID 2363338Notes

Reaction equation

HRID 2363338 reaction equation
B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:33]2[CH:37]=[C:36]([C:38]3[C:39]4[CH:46]=[CH:45][N:44](COCC[Si](C)(C)C)[C:40]=4[N:41]=[CH:42][N:43]=3)[CH:35]=[N:34]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[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:33]2[CH:37]=[C:36]([C:38]3[C:39]4[CH:46]=[CH:45][NH:44][C:40]=4[N:41]=[CH:42][N:43]=3)[CH:35]=[N:34]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C:26]3([C:29]([F:31])([F:30])[F:32])[CH2:27][CH2:28]3)=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11]

Participants

7

Reactant 4

HCID 8000Boron trifluoride etherateHCID 14923Ammonium HydroxideHCID 516892Sodium BicarbonateHCID 711436195-{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-[1-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide

Product 1

HCID 71143530US9611269, Example 33Yield 96.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

Boron trifluoride etherate (0.52 mL, 4.1 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-[1-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide (0.90 g) in acetonitrile (20 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 4 h. LCMS (M+H)+: m/z=539.2. The mixture was cooled to 0° C., water (10. mL) was added. After 30 min., 5.0 M ammonium hydroxide in water (2.5 mL) was added slowly at 0° C. in 5 min. Then the reaction mixture was stirred at room temperature overnight. The reaction 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 dichloromethylene (0-5%) to afford the desired product (0.69 g, 63%). LCMS (M+H)+: m/z=509.0. 1H NMR (300 MHz, DMSO-d6): δ 12.71 (br, 1H), 9.16 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1H), 8.68 (d, J=1.2 Hz, 1H), 8.60 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.83 (dd, J=3.2, 2.5 Hz, 1H), 7.28 (dd, J=3.4, 1.4 Hz, 1H), 4.85 (d, J=9.8 Hz, 2H), 4.59 (d, J=10.0 Hz, 2H), 3.82 (s, 2H), 1.29 (m, 2H), 1.17 (m, 2H).

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 dichloromethylene (0-5%)

Sources & evidence

ORD record
ord-72775be4732c48428d912e1274d8b873
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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