HCID 59226506, compound → HCID 59226433, compound

HRID 73573Notes

Reaction equation

HRID 73573 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:9]=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH:10]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]1

Participants

5

Reactant 2

HCID 59226506HCID 59226506, compoundHCID 178418361HCID 178418361, compound

Product 1

HCID 59226433HCID 59226433, compoundYield 53%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 176Acetic AcidSolvent

Conditions

Temperature
45 °C

Procedure

A solution of 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (1.0 eq) in acetic acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.1 eq) was added. The reaction mixture was stirred at 45° C., 300 psi hydrogen atmosphere in a steel bomb overnight and at 65° C., 300 psi for 5 hours. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. Organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione (53%). LC/MS (m/z): MH+=350.3, Rt=0.78 min. The enantiomerically pure 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 2-((1S,5S)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione were resolved by chiral HPLC (For analysis Rt=7.53 min and 13.11 min respectively; hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 100×4.6 mm at 1 mL/min. For preparative separation, hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 250×20 mm at 20 mL/min) 1H NMR (CDCl3): δ 8.04 (s, 1H), 8.00 (d, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.06 (d, 1H), 4.54 (m, 1H), 3.71 (m, 2H), 2.89 (m, 1H), 2.23-2.44 (m, 2H), 1.90 (m, 1H), 1.20-1.60 (m, 3H), 1.18 (s, 3H), 1.07 (s, 3H).

Workup

  1. customSolids were removed by filtration over celite
  2. washrinsed with EtOAc and MeOH
  3. concentrationThe filtrate was concentrated
  4. additiondiluted with EtOAc
  5. washwashed 2× with sat. aq. 2M Na2CO3
  6. dry with materialOrganic layer was dried with MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes)

Sources & evidence

ORD record
ord-afb81f9f177c45bd866957a563f4064d
Source dataset
uspto-grants-2014_09
Patent number
US08829193B2

Reaction notes

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