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Sodium t-butoxide → n-(2,5-Di-1-cyclohexen-1-yl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine

HRID 1431362
Notes
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Reaction equation

HRID 1431362 reaction equation
[C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 23676156Sodium t-butoxideHCID 59631251HCID 59631251, compoundHCID 59631437HCID 59631437, compoundHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 50906992n-(2,5-Di-1-cyclohexen-1-yl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine

Reagents, catalysts & solvents

2
HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A stirred mixture of mostly 2,5-dicyclohexenylpyridin-3-amine (0.047 g, 0.19 mmol), 4-bromo-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.085 g, 0.26 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.019 g, 0.039 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.018 g, 0.019 mmol), and sodium tert-butoxide (0.056 g, 0.58 mmol) in dry toluene (2.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 2.5 h, the reaction was cooled to rt. After extracting twice with EtOAc, the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-10% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM) to afford an impure light yellow film. The light yellow film was further purified with HPLC 10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution. The desired fractions (Prep. HPLC Retention time was −14.1 min) were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as N-(2,5-di-1-cyclohexen-1-yl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, ddd, J=4.9, 1.7, 1.0 Hz), 8.23 (1H, d, J=2.0 Hz), 7.91 (1H, m), 7.85 (1H, m), 7.62 (1H, ddd, J=9.7, 2.4, 1.1 Hz), 7.38 (1H, ddd, J=7.4, 4.8, 1.2 Hz), 7.33 (1H, d, J=11.5 Hz), 7.00 (1H, ddd, J=13.6, 8.6, 2.6 Hz), 6.86 (1H, d, J=2.0 Hz), 6.18 (1H, m), 6.14 (1H, m), 2.48 (2H, br. s.), 2.33 (2H, br. s.), 2.29 (2H, m), 2.22 (2H, m), 2.14 (3H, s), 1.88 (2H, m), 1.79 (4H, m), 1.67 (2H, m). Mass Spectrum ESI (pos.) m/e: 509.2 (M+H)+.

Workup

  1. customwas purged three times with argon
  2. temperaturethe reaction was cooled to rt
  3. extractionAfter extracting twice with EtOAc
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationAfter filtration and concentration the residue
  6. customwas purified on silica gel (0-10% of 89:9:1 DCM:MeOH:ammonium hydroxide solution in DCM)
  7. customto afford an impure light yellow film
  8. customThe light yellow film was further purified with HPLC 10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution
  9. concentrationThe desired fractions (Prep. HPLC Retention time was −14.1 min) were concentrated
  10. additionthen diluted with EtOAc
  11. washAfter washing twice with satd aq. sodium bicarbonate solution and once with brine
  12. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-96946175d62b4ec3a4a77ecb62a685ba
Source dataset
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08940724B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes