1-Butanol → N-{5-[1-({3-Cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}cyclopropanecarboxamide

HRID 75915Notes

Reaction equation

HRID 75915 reaction equation
[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.ClC1C([NH:40][C@H:41]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH3:42])=NC(NC2C=C(OC(C)C)NN=2)=C([N+]([O-])=O)C=1.CC[N:52](C(C)C)C(C)C.[CH2:59]([OH:63])[CH2:60][CH2:61][CH3:62]>>[C:14]([C:13]1[C:12]([NH:40][CH:41]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[C:47]([NH:52][C:59]([CH:60]3[CH2:62][CH2:61]3)=[O:63])[CH:48]=2)[CH3:42])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]

Participants

5

Reactant 4

HCID 2631-ButanolHCID 81531DiisopropylethylamineHCID 674265316-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrileHCID 178458644HCID 178458644, compound

Product 1

HCID 67426455N-{5-[1-({3-Cyano-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyridin-2-yl}amino)ethyl]-2-fluorophenyl}cyclopropanecarboxamide

Conditions

Temperature
150 °C

Procedure

To a 10-ml microwave reaction vessel was added 6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile (Method 32, 431 mg, 1.65 mmol), N-[5-(1-aminoethyl)-2-fluorophenyl]cyclopropanecarboxamide (Method 69, 550 mg, 2.5 mmol), and DIEA (1.15 ml, 6.6 mmol) in n-butanol (5 ml). The resulting suspension was set to microwave heating (CEM Discover System) at 150° C. for 3 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 25-35% EtOAc (20% v/v MeOH) in hexanes to give 267 mg (35% isolated yield) of the title compound. 1H NMR: 11.99 (s, 1H) 9.91 (s, 1H) 9.42 (s, 1H) 7.88 (d, J=6.03 Hz, 1H) 7.59 (d, J=10.55 Hz, 1H) 6.95-7.20 (m, 3H) 5.99 (s, 1H) 5.02-5.21 (m, 1H) 1.89-2.03 (m, 1H) 1.76-1.89 (m, 1H) 1.45 (d, J=7.54 Hz, 3H) 0.87 (t, J=8.67 Hz, 2H) 0.75 (d, J=6.03 Hz, 4H) 0.54-0.66 (m, 2H). MS: Calcd.: 463. Found: [M+H]+ 464.

Workup

  1. concentrationThe reaction was concentrated in vacuo
  2. custompurified by silica gel chromatography (Biotage Horizon System)
  3. washa gradient elution of 25-35% EtOAc (20% v/v MeOH) in hexanes
  4. customto give

Sources & evidence

ORD record
ord-a8260e3073f640dd924bc947c8842824
Source dataset
uspto-grants-2014_09
Patent number
US08835465B2

Reaction notes

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