4-Methylquinoline → HCID 11339121, compound

HRID 1713338Notes

Reaction equation

HRID 1713338 reaction equation
[N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[F:20][C:21]([F:38])([F:37])[C:22](=[O:36])[CH2:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[O:27][CH2:26][CH2:25]1>C1COCC1.C1COCC1.C(C1C=CC=CC=1)C.CCCCCCC>[F:38][C:21]([F:20])([F:37])[C:22]([CH2:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[CH:2][CH:3]=1)([OH:36])[CH2:23][C:24]1([CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[O:27][CH2:26][CH2:25]1

Participants

6

Reactant 3

HCID 102854-MethylquinolineHCID 2724682Lithium diisopropylamideHCID 57809915HCID 57809915, compound

Product 1

HCID 11339121HCID 11339121, compoundYield 6.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22742125Tetrahydrofuran heptane ethylbenzolSolvent

Conditions

Temperature
-30 °C

Procedure

To a chilled (−78° C.) solution of 105.2 μL (0.79 mmol) of lepidine in 5 mL of THF at −78° C. was added 398 μL (0.79 mmol) of a 2 M solution of lithium diisopropyl amide in THF/ethyl benzene/heptane. The reaction was then warmed to −30° C. After 30 minutes, the mixture was cooled to −78° C. and then 200 mg (0.724 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 1 μL of THF was added. The reaction mixture was warmed to room temperature for 1 hour and monitored by TLC. The reaction mixture was then cooled to −78° C., quenched with saturated ammonium chloride solution, warmed to room temperature, and THF was removed by concentrating in vacuo. The residue was extracted with diethyl ether, dried over sodium sulfate, and concentrated. The residue was purified on PLC plate (hexanes-EtOAc (6:4)) to afford a mixture of two diastereomers. The diastereomers were partially purified by a second PLC plate (CH2Cl2-MeOH (95:5)). One of the diastereomers was triturated with diethyl ether and the solid was collected by filtration to afford 20 mg (6%) of the title compound as a single diastereomer (M+1=420). The other diastereomer was chromatographed a second time on a PLC plate (CH2Cl2-MeOH (95:5)). The solids were triturated with diethyl ether and collected by filtration to afford 10 mg (3%) of the second diastereomer (M+1=420).

Workup

  1. temperaturethe mixture was cooled to −78° C.
  2. temperatureThe reaction mixture was warmed to room temperature for 1 hour
  3. temperatureThe reaction mixture was then cooled to −78° C.
  4. customquenched with saturated ammonium chloride solution
  5. temperaturewarmed to room temperature
  6. customTHF was removed
  7. concentrationby concentrating in vacuo
  8. extractionThe residue was extracted with diethyl ether
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated
  11. customThe residue was purified on PLC plate (hexanes-EtOAc (6:4))
  12. customto afford
  13. additiona mixture of two diastereomers
  14. customThe diastereomers were partially purified by a second PLC plate (CH2Cl2-MeOH (95:5))
  15. customOne of the diastereomers was triturated with diethyl ether
  16. filtrationthe solid was collected by filtration

Sources & evidence

ORD record
ord-e0d244a0286b4f4cb1ed3154b0dd9a54
Source dataset
uspto-grants-2010_09
Patent number
US07795272B2

Reaction notes

Loading…