Diisopropylethylamine → (S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino) nicotinonitrile

HRID 2189864Notes

Reaction equation

HRID 2189864 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.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1>CCCCO>[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]([NH:38][C@H:36]([C:33]4[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=4)[CH3:37])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 16097531(S)-1-(5-Fluoropyridin-2-yl)ethanamineHCID 674265316-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile

Product 1

HCID 24952274(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino) nicotinonitrileYield 62%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Conditions

Temperature
130 °C

Procedure

A suspension of 6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,5-difluoronicotinonitrile (Method 32, 5.75 g, 22.0 mmol), in n-BuOH (28.75 ml) was prepared at room temperature in a 48 ml sealed tube. DIEA (4.98 ml, 28.6 mmol) was then added, followed by the addition of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 4.0 g, 28.6 mmol). The tube was then sealed, and the suspension was heated to 130° C. over 45 minutes. The reaction was then allowed to stir at 130° C. for 18 hours. The reaction was then cooled to room temperature and concentrated by rotary evaporation at 60° C. to remove n-BuOH. The remaining oil was then taken up in DCM (100 ml) and washed with water (2×100 ml). The combined aqueous fractions were then extracted with DCM (100 ml), and the combined organic fractions were dried over Na2SO4, filtered and concentrated. The resulting oil was then purified by column chromatography (DCM, then DCM-MeOH=100:1) to give the title compound (5.2 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=2.5 Hz, 1H), 7.60-7.34 (m, 3H), 6.09-5.63 (m, 1H), 5.24 (q, J=7.0 Hz, 1H), 1.91 (septet, 1H), 1.58 (d, J=6.6 Hz, 3H), 1.08-0.90 (m, 2H), 0.79-0.70 (m, 2H). MS: Calcd.: 381. Found: [M+H]+ 382.

Workup

  1. customsealed tube
  2. customThe tube was then sealed
  3. temperatureThe reaction was then cooled to room temperature
  4. concentrationconcentrated by rotary evaporation at 60° C.
  5. customto remove n-BuOH
  6. washwashed with water (2×100 ml)
  7. extractionThe combined aqueous fractions were then extracted with DCM (100 ml)
  8. dry with materialthe combined organic fractions were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe resulting oil was then purified by column chromatography (DCM

Sources & evidence

ORD record
ord-77a66b95138a45c3803468951175eff4
Source dataset
uspto-grants-2012_12
Patent number
US08324252B2

Reaction notes

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