Isopropanol → AZD 1080

HRID 423153Notes

Reaction equation

HRID 423153 reaction equation
O[N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][N:14]=2)=[C:3]1[OH:26].C(O)(C)C>C(O)(=O)C.[Fe]>[OH:26][C:3]1[NH:2][C:10]2[C:5]([C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:15][N:14]=1)=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2

Participants

5

Reactant 2

HCID 3776IsopropanolHCID 135900033HCID 135900033, compound

Product 1

HCID 135564570AZD 1080Yield 81%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 176Acetic AcidSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 1,2-Dihydroxy-3-(5-morpholin-4-ylmethyl-pyridin-2-yl)-1H-indole-5-carbonitrile (1.0 g, 94% pure, 10.73 mmol) in acetic acid (60 ml) at 60° C. was added iron powder (1.8 g, 32.19 mmol) and the resulting dark green solution stirred at 60° C. for 3 hrs. The suspension was removed from the oil bath and cooled to room temperature. Celite® (10 g) was added and the mixture concentrated to dryness. The mixture was then purified by silica column chromatography eluting with dichloromethane/methanol (1% ammonium hydroxide) 5:1 to give an orange solid; which was reslurried with isopropanol, filtered and then washed with isopropanol. After drying at 50° C. under vacuum gave, 2.89 g, 81% yield of 2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile as a yellow powder. 1H NMR (400 MHz; CDCl3,): δ 14.76 (br s, 1H), 10.9 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.77 (m, 2H), 7.26 (dd, J=1.08, 7.97 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.55 (m, 4H), 3.35 (s, 2H), 2.35 (br s, 4H); 13C NMR: (100 MHz, CDCl3): δ 169.2, 148.9, 142.5, 1367.5, 136.4, 125.7, 124.5, 122.8, 121.8, 121.5, 119.3, 118.8, 101.8, 84.9, 66.6, 58.8, 53.3 ppm; MS (ESI) m/z [M+1]+ 335.

Workup

  1. customThe suspension was removed from the oil bath
  2. temperaturecooled to room temperature
  3. additionCelite® (10 g) was added
  4. concentrationthe mixture concentrated to dryness
  5. customThe mixture was then purified by silica column chromatography
  6. washeluting with dichloromethane/methanol (1% ammonium hydroxide) 5:1
  7. customto give an orange solid
  8. filtrationfiltered
  9. washwashed with isopropanol
  10. customAfter drying at 50° C. under vacuum
  11. customgave

Sources & evidence

ORD record
ord-d246d845faf740abaa7e212b2269aec6
Source dataset
uspto-grants-2012_01
Patent number
US08101750B2

Reaction notes

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