Trifluoroacetic acid → 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide

HRID 2363315Notes

Reaction equation

HRID 2363315 reaction equation
[C:1]([CH2:3][C:4]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:7][N:6]([C:8]2[C:21]([F:22])=[CH:20][C:11]([C:12]([NH:14][C@@H:15]([CH:17]3[CH2:19][CH2:18]3)[CH3:16])=[O:13])=[C:10]([F:23])[CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:7][N:6]([C:8]2[C:21]([F:22])=[CH:20][C:11]([C:12]([NH:14][C@@H:15]([CH:17]3[CH2:18][CH2:19]3)[CH3:16])=[O:13])=[C:10]([F:23])[CH:9]=2)[CH2:5]1)#[N:2]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 712079354-{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)-1-cyclopropylethyl]-2,5-difluorobenzamide

Product 1

HCID 711557114-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamideYield 64.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

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}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide (0.48 g) was dissolved in a solution of trifluoroacetic acid (3 mL, 40 mmol) in methylene chloride (3 mL). The solution was stirred at room temperature for 1.5 hours. It was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL). To the solution was added ethylenediamine (3 mL). The mixture was stirred at room temperature for 2 hours. After concentration the crude material was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-10%) to afford the desired product (245 mg, 24%). LCMS (M+H)+: m/z=503.2. 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 9.08 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 7.84 (dd, J=8.0, 4.0 Hz, 1H), 7.78 (m, 1H), 7.36 (dd, J=13.0, 7.0 Hz, 1H), 7.23 (m, 1H), 6.64 (dd, J=13.0, 7.0 Hz, 1H), 4.70 (d, J=8.0 Hz, 2H), 4.45 (d, J=8.0 Hz, 2H), 3.78 (s, 2H), 3.43 (m, 1H), 1.09 (d, J=6.5 Hz, 6H), 0.97 (m, 1H), 0.43 (m, 1H), 0.37 (m, 1H), 0.28 (m, 1H), 0.19 (m, 1H).

Workup

  1. concentrationIt was concentrated under reduced pressure
  2. dissolutionThe residue was dissolved in methanol (5 mL)
  3. additionTo the solution was added ethylenediamine (3 mL)
  4. stirringThe mixture was stirred at room temperature for 2 hours
  5. concentrationAfter concentration the crude material
  6. customwas purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-10%)

Sources & evidence

ORD record
ord-41e8f5bcb70a4d93bca39f3188f6d9ec
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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