Cesium carbonate → Tert-butyl (2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)(4-methoxybenzyl)carbamate

HRID 921772Notes

Reaction equation

HRID 921772 reaction equation
[NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH2:2]1.Br[C:13]1[C:14]([Cl:40])=[C:15]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=[C:17]([O:19][CH:20]([F:22])[F:21])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:40][C:14]1[C:13]([N:1]2[CH2:4][CH:3]([N:5]3[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]3)[CH2:2]2)=[CH:18][C:17]([O:19][CH:20]([F:22])[F:21])=[CH:16][C:15]=1[N:23]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 206598001-(Azetidin-3-yl)-4-methylpiperazineHCID 117925637Tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate

Product 1

HCID 117926182Tert-butyl (2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)(4-methoxybenzyl)carbamateYield 61.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

1-(Azetidin-3-yl)-4-methylpiperazine (95 mg, 0.609 mmol), tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate (300 mg, 0.609 mmol), cesium carbonate (397 mg, 1,218 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and BINAP (56.9 mg, 0.091 mmol) were suspended in toluene (6088 μl) at room temperature. The reaction was degassed under vacuum and backfilled with N2 (4 times), and then heated to 105° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated. Column chromatography (24 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution) afforded tert-butyl (2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)(4-methoxybenzyl)carbamate (213.1 mg).

Workup

  1. customThe reaction was degassed under vacuum
  2. temperatureAfter cooling to room temperature
  3. additionthe reaction mixture was diluted with EtOAc
  4. filtrationfiltered through celite and
  5. concentrationconcentrated
  6. washColumn chromatography (24 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution)

Sources & evidence

ORD record
ord-fa9e0f842459426394974752fe025555
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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