Cyclohexanone → 4-Chloro-2-(4-cyclohexylpiperazin-1-yl)-5,7-difluoro-3-methylquinoline

HRID 1431646Notes

Reaction equation

HRID 1431646 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].C(N(CC)CC)C.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.ClC(Cl)C.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][N:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:23][CH2:22]2)[C:10]=1[CH3:27]

Participants

9

Reactant 6

HCID 7967CyclohexanoneHCID 8471TriethylamineHCID 5003444Sodium cyanoborohydride2×HCID 5049666Sodium triacetoxyborohydrideHCID 22036585Dichloroethane methanolHCID 866495114-Chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate

Product 1

HCID 596312584-Chloro-2-(4-cyclohexylpiperazin-1-yl)-5,7-difluoro-3-methylquinoline

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

The 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate (75 mg, 0.18 mmol), triethylamine (0.025 mL, 0.18 mmol) and cyclohexanone (0.019 mL, 0.18 mmol) were added to 3 mL of a 2:1 dichlorethane/MeOH mixture. The sodium triacetoxyborohydride (120 mg, 0.55 mmol) was added and the slurry was stirred at rt for 4.5 h. Sodium cyanoborohydride (55 mg, 0.87 mmol) was then added and the slurry was stirred at rt for 4.5 h. Another aliquot of sodium cyanoborohydride (55 mg, 0.87 mmol) was added and the reaction was heated to 80° C. and stirred overnight. The reaction was cooled and then diluted with DCM and water. The layers were separated and the aq. layer was extracted (2×75 mL) with EtOAc. The layers were combined and washed with brine (1×50 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 100% EtOAc:hexanes) to give 4-chloro-2-(4-cyclohexylpiperazin-1-yl)-5,7-difluoro-3-methylquinoline. Mass Spectrum (ESI) m/e=298.1 (M+1).

Workup

  1. stirringthe slurry was stirred at rt for 4.5 h
  2. temperaturethe reaction was heated to 80° C.
  3. stirringstirred overnight
  4. temperatureThe reaction was cooled
  5. customThe layers were separated
  6. extractionthe aq. layer was extracted (2×75 mL) with EtOAc
  7. washwashed with brine (1×50 mL)
  8. dry with materialdried over magnesium sulfate
  9. customThe crude product was purified by medium pressure chromatography (silica gel, 0 to 100% EtOAc:hexanes)

Sources & evidence

ORD record
ord-3e2ef791a2f34b7f90e22d669ad9cc6e
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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