1,8-Diazabicyclo(5.4.0)undec-7-ene → Ethyl 4-bromo-1-{3-(cyanomethyl)-1-[2,5-difluoro-4-({[(1S)-2,2,2-trifluoro-1-methylethyl]amino}carbonyl)phenyl]azetidin-3-yl}-1H-pyrazole-3-carboxylate

HRID 1049150Notes

Reaction equation

HRID 1049150 reaction equation
[Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.N12CCCN=C1CCCCC2.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]2[C:44]([F:45])=[CH:43][C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])=[O:35])=[C:32]([F:46])[CH:31]=2)[CH2:27]1)#[N:24]>C(O)(C)C>[Br:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:5]([C:26]2([CH2:25][C:23]#[N:24])[CH2:29][N:28]([C:30]3[CH:31]=[C:32]([F:46])[C:33]([C:34]([NH:36][C@@H:37]([CH3:42])[C:38]([F:39])([F:41])[F:40])=[O:35])=[CH:43][C:44]=3[F:45])[CH2:27]2)[CH:6]=1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 1177001494-[3-(Cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamideHCID 178470483HCID 178470483, compound

Product 1

HCID 117699944Ethyl 4-bromo-1-{3-(cyanomethyl)-1-[2,5-difluoro-4-({[(1S)-2,2,2-trifluoro-1-methylethyl]amino}carbonyl)phenyl]azetidin-3-yl}-1H-pyrazole-3-carboxylate

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a microwave vial was added isopropyl alcohol (10 mL), ethyl 4-bromo-1H-pyrazole-3-carboxylate (from ChemBridge) (788 mg, 3.60 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (48.9 μL, 0.327 mmol) and 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (from Example 4 step 4, 1.13 g, 3.27 mmol). The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified with flash chromatography (eluting with 0-35% ethyl acetate in hexanes) to give the desired product as white foam. 1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 7.34 (dd, J=12.5 and 6.3 Hz, 1H), 6.62 (dd, J=11.9 and 7.3 Hz, 1H), 4.76 (dt, J=15.5 and 7.8 Hz, 1H), 4.61 (d, J=9.2 Hz, 2H), 4.39 (d, J=8.0 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.31 (m, 6H) ppm. LCMS calculated for C21H20BrF5N5O3 (M+H)+: m/z=564.1. Found: 563.8.

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe solvent was removed in vacuo
  3. customThe residue was purified with flash chromatography (eluting with 0-35% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-fad7d4ec2a5644249c209a25c0d719b5
Source dataset
uspto-grants-2016_07
Patent number
US09382231B2

Reaction notes

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