Diisopropylamine → 5-hydroxy-1-[3-(quinolin-5-yl)phenyl]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one

HRID 571078Notes

Reaction equation

HRID 571078 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14]CC3C=CC(OC)=CC=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:5]=[CH:6][CH:7]=1.[N:31]1[C:40]2[C:35](=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.[Na+].O.S(C1C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=CC=1)([O-])(=O)=O.[Na+].[Na+].C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[OH:14][C:12]1[C:11](=[O:24])[CH:10]=[C:9]([CH:25]([OH:30])[C:26]([F:29])([F:27])[F:28])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:36]3[CH:37]=[CH:38][CH:39]=[C:40]4[C:35]=3[CH:34]=[CH:33][CH:32]=[N:31]4)[CH:3]=2)[CH:13]=1

Participants

8

Reactant 4

HCID 7912DiisopropylamineHCID 5153389Quinolin-5-ylboronic acidHCID 53487040Sodium 3,3',3''-phosphinetriyltribenzenesulfonate hydrateHCID 674175711-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one

Product 1

HCID 674179895-hydroxy-1-[3-(quinolin-5-yl)phenyl]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-oneYield 81.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (400 mg, 0.826 mmol), quinolin-5-ylboronic acid (171 mg, 0.991 mmol), tris(3-sulfonatophenyl)phosphine hydrate sodium salt (79 mg, 0.124 mmol) and palladium(II)acetate (9.27 mg, 0.041 mmol), under nitrogen, were added DMF (6 mL), diisopropylamine (0.353 mL, 2.478 mmol) and water (1 mL). The reaction mixture was stirred at 60° C. under nitrogen for 1.5 h. After cooling to room temperature the reaction mixture was partitioned between half-saturated aqueous NH4Cl and EtOAc. Layers were separated and the aqueous solution was extracted with EtOAc (3×). Combined organic solutions were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2-TFA (1:1, 6 mL), allowed to stand at room temperature for 10 min and then concentrated. Purification was done by preparative HPLC (5-95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 OBD Sunfire 30×150 mm). The desired fractions were loaded onto a Strata-X—C cation exchange column. After washing the column with water and MeOH, the column was eluted with 5% NH4OH in MeOH to give 5-hydroxy-1-[3-(quinolin-5-yl)phenyl]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one as tan solid (277 mg, 81%). 1H NMR (DMSO-d6, 400 MHz) □ 8.97-8.96 (m, 1H), 8.27 (dd, J=28.8, 8.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.87 (t, J=7.5 Hz, 1H), 7.81-7.69 (m, 2H), 7.63-7.53 (m, 4H), 7.28 (br m, 1H), 6.54 (d, J=12.1 Hz, 1H), 4.84-4.73 (m, 1H). HRMS Calc (M+H)+ 413.1035. Found 413.1102.

Workup

  1. temperatureAfter cooling to room temperature the reaction mixture
  2. customwas partitioned between half-saturated aqueous NH4Cl and EtOAc
  3. customLayers were separated
  4. extractionthe aqueous solution was extracted with EtOAc (3×)
  5. dry with materialCombined organic solutions were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe resulting residue was dissolved in CH2Cl2-TFA (1:1, 6 mL)
  9. waitto stand at room temperature for 10 min
  10. concentrationconcentrated
  11. customPurification
  12. customover 20 min
  13. addition0.05% added TFA
  14. washAfter washing the column with water and MeOH
  15. washthe column was eluted with 5% NH4OH in MeOH

Sources & evidence

ORD record
ord-9eb701d8cdb445fa816ac84cce6f7e74
Source dataset
uspto-grants-2015_05
Patent number
US09024032B2

Reaction notes

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