(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile → (S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde

HRID 2189855Notes

Reaction equation

HRID 2189855 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)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1CC(O)=[O:37].O>[Ni]>[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]([CH:14]=[O:37])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1

Participants

4

Reactant 2

HCID 11646595(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrileHCID 69477857Pyridine-acetic acid water

Product 1

HCID 86620610(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehydeYield 45%

Reagents, catalysts & solvents 1

HCID 935NickelCatalyst

Procedure

(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl) ethylamino)nicotinonitrile (Example 1, 0.4 g, 1.1 mmol) was dissolved in the mixture pyridine-acetic acid-water (1:1:1, 18 ml total volume) at room temperature, to which was added Raney nickel (0.09 g, 1.1 mmol). The reaction was purged with nitrogen, evacuated, and then placed under hydrogen filled balloon for 18 hours. The reaction mixture was flushed with nitrogen, and filtered to remove the catalyst, which was washed with MeOH (30 ml). The filtrate was then extracted with DCM (5×50 ml), washed with aq. NaHCO3, and purified by reverse phase column chromatography (5-30% ACN) to give the title compound (0.18 g, 45%). 1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 7.45 (d, J=10.4 Hz, 1H), 7.34-7.31 (m, 2H), 7.05-7.01 (m, 2H), 6.11 (s, 1H), 5.26 (s, 1H), 1.92-1.86 (m, 1H), 1.55 (d, J=7.0 Hz, 3H), 1.00-0.98 (m, 2H), 0.71-0.64 (m, 2H). MS: Calcd.: 383. Found: [M+H]+ 384.

Workup

  1. customThe reaction was purged with nitrogen
  2. customevacuated
  3. customfor 18 hours
  4. customThe reaction mixture was flushed with nitrogen
  5. filtrationfiltered
  6. customto remove the catalyst, which
  7. washwas washed with MeOH (30 ml)
  8. extractionThe filtrate was then extracted with DCM (5×50 ml)
  9. washwashed with aq. NaHCO3
  10. custompurified by reverse phase column chromatography (5-30% ACN)

Sources & evidence

ORD record
ord-2bad1657e3c342d1948cd1af72a841d2
Source dataset
uspto-grants-2012_12
Patent number
US08324252B2

Reaction notes

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