Hydrochloric Acid → (S)-3-(Aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine

HRID 75860Notes

Reaction equation

HRID 75860 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]([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.Cl>[Pd].CO>[NH2:15][CH2:14][C:13]1[C:12]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH3:21])=[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

Participants

5

Reactant 2

HCID 313Hydrochloric AcidHCID 11646595(S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile

Product 1

HCID 67454991(S)-3-(Aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamineYield 58.5%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

To a MeOH solution (5 ml) was added (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1; 0.15 g, 0.4 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g). The mixture was then flushed with N2, evacuated, and then placed under 40 psi of H2 for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na2CO3 (100 ml) was added, and the mixture was shaken vigorously for 30 min. The layers were then allowed to separate, and the aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were dried, filtered and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=9:1) to give the title compound (0.09 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.38 (m, 2H), 7.15 (d, J=11. Hz, 1H), 7.02-6.97 (m, 2H), 5.15-5.08 (m, 1H), 3.74 (s, 2H), 1.88-1.81 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.93-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 384. Found: [M+H]+ 385.

Workup

  1. customThe mixture was then flushed with N2
  2. customevacuated
  3. customThe reaction was then evacuated
  4. customflushed with N2
  5. filtrationfiltered
  6. washwashed with MeOH (3×30 ml)
  7. concentrationconcentrated
  8. dissolutionThe resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml)
  9. additiona saturated aqueous solution of Na2CO3 (100 ml) was added
  10. customto separate
  11. extractionthe aqueous layer was extracted with DCM (3×100 ml)
  12. customThe combined organic layers were dried
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe resulting solid was purified by column chromatography (DCM-MeOH=9:1)

Sources & evidence

ORD record
ord-597128b604ea4ade8899e46c27a30320
Source dataset
uspto-grants-2014_09
Patent number
US08835465B2

Reaction notes

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