Cesium carbonate → (Rac)-cis-3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanol

HRID 473657Notes

Reaction equation

HRID 473657 reaction equation
F[C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:7]([C@@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 212625714-(Pyridin-2-ylamino)phenolHCID 68596116(Rac)-cis-3-(2-fluoropyridin-3-yl)cyclohexanol

Product 1

HCID 59374201(Rac)-cis-3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanol

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
180 °C

Procedure

A mixture of (rac)-cis-3-(2-fluoropyridin-3-yl)cyclohexanol (250 mg, 1.281 mmol), 4-(pyridin-2-ylamino)phenol (477 mg, 2.56 mmol), and cesium carbonate (834 mg, 2.56 mmol) in NMP (4 ml) was heated in a Biotage™ microwave reactor at 180° C. for 1.5 h. The mixture was partitioned between H2O (15 ml) and CH2Cl2 (30 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanol as a tan solid. MS (ESI, pos. ion) m/z: 362.0 (M+1). IC50 (uM) 0.011024.

Workup

  1. customThe mixture was partitioned between H2O (15 ml) and CH2Cl2 (30 ml)
  2. customthe layers were separated
  3. extractionthe aqueous layer was extracted with CH2Cl2 (3×30 ml)
  4. dry with materialThe combined organic layers were dried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customthe resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA)
  7. additionThe product containing fractions
  8. additionneutralized by the addition of solid Na2CO3
  9. extractionextracted with CH2Cl2 (3×20 mL)
  10. dry with materialThe combined organic layers were dried (MgSO4)
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-ca9eac1d425d42ca93ba53f448a5f6c3
Source dataset
uspto-grants-2014_01
Patent number
US08637500B2

Reaction notes

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