2-Bromopyridine → HCID 67207476, compound

HRID 2041758Notes

Reaction equation

HRID 2041758 reaction equation
Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C@H:15]([NH2:35])[CH2:14][C@@H:13]1[CH3:36])(=[O:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].BrC1C=CC=CN=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].C1(C)C=CC=CC=1>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C@H:15]([NH:35][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:14][C@@H:13]1[CH3:36])(=[O:11])[CH3:10]

Participants

8

Reactant 5

HCID 79732-BromopyridineHCID 881004-Bromopyridinium chloride2×HCID 634876Binap, (A+-)-3×HCID 23676156Sodium t-butoxide2×HCID 67195867HCID 67195867, compound

Product 1

HCID 67207476HCID 67207476, compoundYield 13.88%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A flask was charged with 4-bromopyridine hydrochloride (61.8 mg, 0.318 mmol), (cis)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 25) (100 mg, 0.265 mmol), racemic BINAP (8.25 mg, 0.013 mmol), sodium tert-butoxide (30.5 mg, 0.318 mmol) and tris(dibenzylideneacetone)dipalladium(0) (12.13 mg, 0.013 mmol) then filled with toluene (2.5 mL). The resulting mixture was stirred at 110° C. under nitrogen for 20 h then cooled to room temperature. An extra 1.2 equivalent of 4-bromopyridine hydrochloride (60 mg) and sodium tert-butoxide (30 mg) were added as well as racemic BINAP (0.05 equivalent, 8 mg) and the resulting mixture was stirred at 110° C. for 5 h. After the mixture was cooled to room temperature, a further 1.2 eq of bromopyridine (62 mg) was added and the reaction mixture stirred at 110° C. for 16 h then cooled to room temperature. An extra 0.05 eq of racemic BINAP (8 mg) and tris(dibenzylideneacetone)dipalladium(0) (12 mg) were added and the resulting mixture stirred at 110° C. for 5 h then cooled to room temperature and loaded onto a 5 g SCX column then eluted with MeOH (2 column volume (CV)) followed by 2M NH3 in MeOH (4 CV). The ammonia fractions were combined and concentrated in vacuo. Purification of the residue by MDAP (modifier: trifluoroacetic acid) gave cis-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-N-4-pyridinyl-1,2,3,4-tetrahydro-4-quinolinamine (22 mg, 0.037 mmol, 13.88% yield).

Workup

  1. temperaturethen cooled to room temperature
  2. stirringthe resulting mixture was stirred at 110° C. for 5 h
  3. temperatureAfter the mixture was cooled to room temperature
  4. stirringthe reaction mixture stirred at 110° C. for 16 h
  5. temperaturethen cooled to room temperature
  6. stirringthe resulting mixture stirred at 110° C. for 5 h
  7. temperaturethen cooled to room temperature
  8. washthen eluted with MeOH (2 column volume (CV))
  9. concentrationconcentrated in vacuo
  10. customPurification of the residue by MDAP (modifier: trifluoroacetic acid)

Sources & evidence

ORD record
ord-48d80bf2d37a4b9487a81e09ef8355ba
Source dataset
uspto-grants-2013_11
Patent number
US08580957B2

Reaction notes

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