Cesium carbonate → HCID 59215784, compound

HRID 2074934Notes

Reaction equation

HRID 2074934 reaction equation
[CH2:1]1[NH:6][C@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][CH2:11][C@H:2]12.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.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:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32]([N:6]3[C@H:5]([CH2:7][OH:8])[CH2:4][N:3]4[CH2:9][CH2:10][CH2:11][C@@H:2]4[CH2:1]3)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:15]=[C:14]([C:13]([F:47])([F:12])[F:46])[CH:19]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamideHCID 66658706HCID 66658706, compound

Product 1

HCID 59215784HCID 59215784, compoundYield 4.4%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
140 °C

Procedure

(3S,8aR)-Octahydropyrrolo[1,2-a]pyrazin-3-ylmethanol (Tetrahedron Asymmetry, 1996, 7(7), 1999-2005, 230 mg, 1.47 mmol) and 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (570 mg, 1.07 mmol) were dissolved in 12 mL of toluene. 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (ligand) (78 mg, 0.20 mmol), Pd(dba)2 (45 mg, 0.08 mmol) and, at last, caesium carbonate (697 mg, 2.14 mmol) were added. The reaction vessel was sealed and nitrogen bubbled through the solution for 15 min. The reaction mixture was heated to 140° C. for 15 h. The mixture was diluted with 100 mL of EtOAc and extracted with water. The aqueous phase was extracted again with dichloromethane. The combined organics were dried and the solvent removed. Product purified by flash chromatography: silica, cyclohexane:EtOAc 50:50 to 0:100. Further purification by HPLC (prep. conditions: Column: Gemini C18 5 μm, 100×19 mm; Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CN, Gradient: 50% (B) for 1 min, from 50% (B) to 65% (B) in 12 min, 95% (B) for 6 min; Flow rate: 17 ml/min; UV wavelength range: 210-350 nm; Mass range: 100-900 amu; Ionization: ES+. Isolated 31 mg of the title compound.

Workup

  1. customThe reaction vessel was sealed
  2. customnitrogen bubbled through the solution for 15 min
  3. additionThe mixture was diluted with 100 mL of EtOAc
  4. extractionextracted with water
  5. extractionThe aqueous phase was extracted again with dichloromethane
  6. customThe combined organics were dried
  7. customthe solvent removed
  8. customProduct purified by flash chromatography
  9. customFurther purification by HPLC (prep
  10. waitfrom 50% (B) to 65% (B) in 12 min
  11. wait95% (B) for 6 min

Sources & evidence

ORD record
ord-cad21843a81f4ca6b4f6016fb0b8098a
Source dataset
uspto-grants-2011_04
Patent number
US07919491B2

Reaction notes

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