Potassium Carbonate → 1,1-dimethylethyl 4-({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)-3-oxo-1-piperazinecarboxylate

HRID 2366867Notes

Reaction equation

HRID 2366867 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1.[CH3:23][CH:24]([O:26][C:27](=[O:52])[NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([C:48](=[O:50])[CH3:49])[C@@H:31]([CH3:51])[CH2:30]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:48]([N:32]1[C:33]2[C:38](=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][N:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]4=[O:22])=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[C@H:29]([NH:28][C:27]([O:26][CH:24]([CH3:25])[CH3:23])=[O:52])[CH2:30][C@@H:31]1[CH3:51])(=[O:50])[CH3:49]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 67196654Tert-butyl 4-[(4-bromophenyl)methyl]-3-oxopiperazine-1-carboxylateHCID 681853941-Methylethyl [(cis)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate

Product 1

HCID 671954891,1-dimethylethyl 4-({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)-3-oxo-1-piperazinecarboxylateYield 104%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

A flask was charged with 1,1-dimethylethyl 4-[(4-bromophenyl)methyl]-3-oxo-1-piperazinecarboxylate (for a preparation, see Intermediate 72) (111 mg, 0.3 mmol), 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (250 mg, 0.600 mmol), potassium carbonate (124 mg, 0.900 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.95 mg, 0.030 mmol) then filled with 1,4-dioxane (3 mL) and water (1 mL) and flushed with nitrogen. The resulting mixture was stirred under microwave irradiation at 120° C. for 30 min then cooled to room temperature. Most of the 1,4-dioxane was removed in vacuo and the residue was partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 5 to 25% (10% MeOH in DCM) in DCM) gave 1,1-dimethylethyl 4-({4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)-3-oxo-1-piperazinecarboxylate (180 mg, 0.311 mmol, 104% yield) which was used in the next step without further purification.

Workup

  1. customfor a preparation
  2. customfor a preparation
  3. customflushed with nitrogen
  4. temperaturethen cooled to room temperature
  5. customMost of the 1,4-dioxane was removed in vacuo
  6. customthe residue was partitioned between AcOEt and water
  7. customThe layers were separated
  8. extractionthe aqueous phase was extracted with AcOEt
  9. washThe combined organic phases were washed with brine
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated in vacuo
  12. customPurification of the residue by SP4

Sources & evidence

ORD record
ord-ce04cd9fee08475aa5a7d3451acb5bc2
Source dataset
uspto-grants-2014_04
Patent number
US08697725B2

Reaction notes

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