Cesium carbonate → HCID 16063829, compound

HRID 421262Notes

Reaction equation

HRID 421262 reaction equation
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][C@@H:41]([CH2:43][OH:44])[CH2:40][N:39]2C[CH2:46][CH2:47][CH2:48][C@H:38]12.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.[Pd]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[C@@H:41]([CH2:43][OH:44])[CH2:40][N:39]4[CH2:46][CH2:47][CH2:48][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl2×HCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamideHCID 66658814HCID 66658814, compound

Product 1

HCID 16063829HCID 16063829, compoundYield 27.8%

Reagents, catalysts & solvents 2

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalyst2×HCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

The title compound was prepared starting from 323 mg (0.608 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 1.216 mg (0.160 mmol) of (3R,9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-3-ylmethanol (Tetrahedron Asymmetry, 1996, 7(7), 1999-2005), 35 mg of bis(dibenzylideneacetone)palladium (0.061 mmol), 57 mg of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.145 mmol), 297 mg (0.912 mmol) of cesium carbonate; the reagents were dissolved in 10 ml of toluene and stirred at 140° C. in a closed vial for 4 hours. More dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (57 mg 0.145 mmol), and bis(dibenzylideneacetone)palladium (35 mg, 0.061 mmol) were added and the reaction kept at 140° C. for additional 4 hours. The crude material was loaded on a SCX cartridge, the neutral fractions were washed with methanol and the basic eluted with 2M ammonia in methanol and collected. The solvent was removed and the residue purified by chromatography (Silica) eluting with ethyl acetate, followed by a gradient from methylene chloride to methylene chloride:methanol 95:5. The cleanest fractions were purified further by chromatography on an NH2 silica cartridge with a gradient cyclohexane to cyclohexane:ethyl acetate 70:30, affording 29 mg of the title compound as pale yellow solid.

Workup

  1. customThe title compound was prepared
  2. waitthe reaction kept at 140° C. for additional 4 hours
  3. washthe neutral fractions were washed with methanol
  4. washthe basic eluted with 2M ammonia in methanol
  5. customcollected
  6. customThe solvent was removed
  7. customthe residue purified by chromatography (Silica)
  8. washeluting with ethyl acetate
  9. customThe cleanest fractions were purified further by chromatography on an NH2 silica cartridge with a gradient cyclohexane to cyclohexane:ethyl acetate 70:30

Sources & evidence

ORD record
ord-32835da4aa2b40bf94904b10956e77cc
Source dataset
uspto-grants-2012_01
Patent number
US08097618B2

Reaction notes

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