Hydrochloric Acid → HCID 131732649, compound

HRID 882286Notes

Reaction equation

HRID 882286 reaction equation
[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:28])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CC(C)([O-])C.[Na+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[ClH:71]>O1CCOCC1.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]>[ClH:71].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:28][C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 783452-BromopyrimidineHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 70976636HCID 70976636, compound

Product 1

HCID 131732649HCID 131732649, compoundYield 36.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
100 °C

Procedure

To a flask charged with 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (for a preparation see Intermediate 32) (197 mg, 0.5 mmol), 2-bromopyrimidine (238 mg, 1.500 mmol), sodium tert-butoxide (240 mg, 2.500 mmol), 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (197 mg, 0.500 mmol) and tris(dibenzylideneacetone)dipalladium(0) (229 mg, 0.250 mmol) was added degassed toluene (4 mL) and the resulting mixture was stirred under nitrogen at 100° C. After 2 h the mixture was cooled to room temperature and most of the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with saturated aqueous NaHCO3 (×3), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DCM and loaded on a SCX column (20 g). The cartridge was eluted with DCM then ammonia in MeOH (2N). The methanolic ammonia fractions were concentrated in vacuo and further purified on by chromatography (25 g column, elution with 2N ammonia in MeOH/DCM gradient) to give a residue which was dissolved in 1,4-dioxane (4 ml) and the solution treated with hydrogen chloride in 1,4-dioxane (4N, 0.5 mL). The precipitate which formed was isolated by filtration and dried at 60° C. under vacuum for 2 h to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide, hydrochloride (93 mg, 0.183 mmol, 36.5% yield) as a pale yellow solid. LCMS (HpH, 2 min), Rt=0.79 min, MH+=473.

Workup

  1. additionwas added
  2. customdegassed toluene (4 mL)
  3. temperatureAfter 2 h the mixture was cooled to room temperature and most of the solvent
  4. customwas evaporated in vacuo
  5. customThe residue was partitioned between EtOAc and saturated NaHCO3 solution
  6. customthe layers were separated
  7. extractionThe aqueous phase was extracted with EtOAc
  8. washthe combined organic phases were washed with saturated aqueous NaHCO3 (×3)
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated in vacuo
  11. dissolutionThe residue was dissolved in DCM
  12. washThe cartridge was eluted with DCM
  13. concentrationThe methanolic ammonia fractions were concentrated in vacuo
  14. customfurther purified on by chromatography (25 g column, elution with 2N ammonia in MeOH/DCM gradient)
  15. customto give a residue which
  16. customThe precipitate which formed
  17. customwas isolated by filtration
  18. customdried at 60° C. under vacuum for 2 h

Sources & evidence

ORD record
ord-2dd5fd05b34148b689cfccd837e54655
Source dataset
uspto-grants-2015_03
Patent number
US08993554B2

Reaction notes

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