2-Bromo-5-methylpyridine → HCID 67207244, compound

HRID 2041736Notes

Reaction equation

HRID 2041736 reaction equation
Cl.[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[C@H:8]([NH2:27])[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3].Br[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=1.CC(C)([O-])C.[Na+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:24]([CH3:26])[CH3:25])=[CH:12][CH:13]=2)[C@H:8]([NH:27][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=2)[CH2:7][C@@H:6]1[CH3:28])(=[O:4])[CH3:3]

Participants

6

Reactant 4

HCID 5642162-Bromo-5-methylpyridineHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 67205065HCID 67205065, compound

Product 1

HCID 67207244HCID 67207244, compoundYield 82%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

A flask was charged with (2S,4R)-1-acetyl-2-methyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (for a preparation see Intermediate 108) (130 mg, 0.309 mmol), 2-bromo-5-methylpyridine (159 mg, 0.926 mmol), sodium tert-butoxide (148 mg, 1.544 mmol), 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (DavePhos) (243 mg, 0.617 mmol) and tris(dibenzylideneacetone)dipalladium(0) (283 mg, 0.309 mmol) then flushed with nitrogen and filled with degassed toluene (3 mL). The resulting mixture was stirred at 100° C. for 1.5 h then cooled to room temperature and filtered through celite. The insoluble material was washed with AcOEt and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between water and AcOEt and the layers were separated. The aqueous phase was extracted with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:13 to 63% AcOEt in Hexanes) gave (2S,4R)-1-acetyl-2-methyl-N-(5-methyl-2-pyridinyl)-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (120 mg, 0.252 mmol, 82% yield) as a yellow foam which was used in the next step without further purification.

Workup

  1. customthen flushed with nitrogen
  2. additionfilled with degassed toluene (3 mL)
  3. temperaturethen cooled to room temperature
  4. filtrationfiltered through celite
  5. washThe insoluble material was washed with AcOEt
  6. concentrationthe combined filtrate and washings were concentrated in vacuo
  7. customThe residue was partitioned between water and AcOEt
  8. customthe layers were separated
  9. extractionThe aqueous phase was extracted with AcOEt
  10. washthe combined organic phases were washed with water
  11. dry with materialbrine, dried over MgSO4
  12. concentrationconcentrated in vacuo
  13. customPurification of the residue by SP4

Sources & evidence

ORD record
ord-fe5ee230bf9d4e818fa9da7869fb15bb
Source dataset
uspto-grants-2013_11
Patent number
US08580957B2

Reaction notes

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