Cesium carbonate → Methyl 5-bromo-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzoate

HRID 1504451Notes

Reaction equation

HRID 1504451 reaction equation
[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29](I)=[CH:28][C:27]=2[F:35])=[CH:22][C:21]=1[CH3:36].COC1CCCC1>CC(O)C.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:29]2[C:30]([O:32][CH3:33])=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([CH3:36])[CH:22]=3)=[C:27]([F:35])[CH:28]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 138539Cyclopentyl methyl etherHCID 736224Methyl 2-amino-5-bromobenzoateHCID 1177369494'-Chloro-2-fluoro-4-iodo-5-methoxy-3'-methyl-1,1'-biphenyl

Product 1

HCID 117736886Methyl 5-bromo-2-((4'-chloro-2-fluoro-5-methoxy-3'-methyl-[1,1'-biphenyl]-4-yl)amino)benzoateYield 95%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
100 °C

Procedure

A sealable vial was charged vial with methyl 2-amino-5-bromobenzoate (3.63 g, 15.80 mmol), cesium carbonate (8.75 g, 26.9 mmol), Pd2(dba)3 (0.362 g, 0.395 mmol), xantphos (0.457 g, 0.790 mmol), and 4′-chloro-2-fluoro-4-iodo-5-methoxy-3′-methyl-1,1′-biphenyl (7.14 g, 18.96 mmol). The vial was sealed with septum cap and CPME (31.6 ml) was added. The mixture was heated at 100° C. for 2 h. The mixture was cooled and partitioned between water (30 mL) and EtOAc (50 mL). There was an insoluble solid that was suspended between the layers. The organic layer and the solid were collected together and the mixture was concentrated. The resulting yellow solid was taken up in DCM (100 mL) and filtered through a plug of celite. The mother liquor was concentrated to give a yellow solid that was slurried in IPA (100 mL) and collected by vacuum filtration to provide methyl 5-bromo-2-((4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)amino)benzoate (7.15 g, 14.94 mmol, 95% yield) as a yellow solid. (ESI) 476.1 (M−H)−.

Workup

  1. customThe vial was sealed with septum
  2. customcap
  3. temperatureThe mixture was cooled
  4. custompartitioned between water (30 mL) and EtOAc (50 mL)
  5. customThe organic layer and the solid were collected together
  6. concentrationthe mixture was concentrated
  7. filtrationfiltered through a plug of celite
  8. concentrationThe mother liquor was concentrated
  9. customto give a yellow solid
  10. filtrationcollected by vacuum filtration

Sources & evidence

ORD record
ord-78cc0b176f844fac9f93e73c792a76f3
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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