Hydrochloric Acid → (R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

HRID 75865Notes

Reaction equation

HRID 75865 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:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:21][OH:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl>CO.[Pd]>[NH2:15][CH2:14][C:13]1[C:12]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:21][OH:22])=[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 11574786(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile

Product 1

HCID 67456107(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanolYield 57%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

The mixture of (R)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile (Example 6; 0.13 g, 0.33 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g) in MeOH (5 ml) was flushed with N2, evacuated, and then placed under H2 (40 psi) 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. The mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.074, 57%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.42 (m, 2H), 7.17 (d, J=11.1 Hz, 1H), 7.04-7.00 (m, 2H), 5.72 (br s, 1H), 5.18-5.08 (m, 1H), 3.89-3.72 (m, 4H), 1.87-1.83 (m, 1H), 0.94-0.92 (m, 2H), 0.69-0.65 (m, 2H). MS: Calcd.: 400. Found: [M+H]+401.

Workup

  1. customwas 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 layer was dried
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml)

Sources & evidence

ORD record
ord-47e924dd017f4560aff817ae86fbd7a3
Source dataset
uspto-grants-2014_09
Patent number
US08835465B2

Reaction notes

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