Cyanomethylenetributylphosphorane → cis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine

HRID 1269939Notes

Reaction equation

HRID 1269939 reaction equation
[CH:1]([O:4][C:5]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)([CH3:3])[CH3:2].O[C@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17]1.Cl.C(OC1C(O[C@@H]2CCC[C@H](N)C2)=CC=C2C=1C=NN2)CC.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH:1]([O:4][C:5]1[C:13]([O:14][C@@H:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH2:22])[CH2:17]2)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 4622928CyanomethylenetributylphosphoraneHCID 229335444-isopropoxy-1H-indazol-5-olHCID 60011725trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dioneHCID 69433087cis-3-[(4-propoxy-1H-indazol-5-yl)oxy]cyclohexanamine hydrochloride

Product 1

HCID 69428641cis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamineYield 60.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Under a nitrogen atmosphere, the 4-isopropoxy-1H-indazol-5-ol (118 mg, 0.614 mmol) obtained in Example 638 and the trans-2-(3-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (100 mg, 0.408 mmol) obtained in Example 385, (b) were added to a solution of 90%-cyanomethylenetri-n-butylphosphorane (155 mg, 0.614 mmol) in toluene (4 ml) at room temperature, and the resulting mixture was heated to 100° C. After 4.5 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was diluted with chloroform and washed with a 1M-aqueous sodium hydroxide solution. The aqueous layer was re-extracted with chloroform and then the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). To the resulting oil was added a 30%-methylamine-ethanol solution at room temperature, and the resulting mixture was refluxed. After 4 hours, the mixture was concentrated under reduced pressure at room temperature, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain cis-3-[(4-isopropoxy-1H-indazol-5-yl)oxy]cyclohexanamine (71.0 mg, 60%).

Workup

  1. concentrationthe reaction solution was concentrated under reduced pressure
  2. additionthe resulting residue was diluted with chloroform
  3. washwashed with a 1M-aqueous sodium hydroxide solution
  4. extractionThe aqueous layer was re-extracted with chloroform
  5. dry with materialthe organic layer was dried over anhydrous magnesium sulfate
  6. customThe organic layer dried
  7. concentrationwas concentrated under reduced pressure
  8. customthe resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate)
  9. additionTo the resulting oil was added a 30%-methylamine-ethanol solution at room temperature
  10. temperaturethe resulting mixture was refluxed
  11. waitAfter 4 hours
  12. concentrationthe mixture was concentrated under reduced pressure at room temperature
  13. customthe resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia))

Sources & evidence

ORD record
ord-21c51ea8581b4917a77b231ab5ab33ea
Source dataset
uspto-grants-2007_04
Patent number
US07199147B2

Reaction notes

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