Potassium Carbonate → 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester

HRID 217036Notes

Reaction equation

HRID 217036 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:7]=2[CH:6]=1)=[O:4]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 1419172-(Bromomethyl)tetrahydro-2H-pyranHCID 11749905Methyl 6-((4-bromo-2-chlorophenyl)amino)-7-fluoro-1H-benzo[d]imidazole-5-carboxylate

Product 1

HCID 688190776-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.25 g, 0.63 mmol) is dissolved in N,N-dimethylformamide (5 mL). 2-Bromomethyl-tetrahydro-pyran (0.34 g, 1.88 mmol) and potassium carbonate (0.26 g, 1.88 mmol) are added and the reaction mixture is stirred at 60° C. for 12 hours under N2. The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting solid residue is triturated with diethyl ether to yield a pale yellow solid (N3 regioisomer by NMR) and a yellow filtrate (mixture of N1 and N3 regioisomers by NMR). The solids are collected and washed with diethyl ether to yield 0.12 g (37%) of the pure desired N3 regioisomeric product as a pale yellow solid. MS ESI (+) m/z 496, 498 (M+, Br pattern) detected.

Workup

  1. additionThe reaction mixture is poured into a separatory funnel
  2. customthe layers separated
  3. washThe ethyl acetate layer is washed with water and brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting solid residue is triturated with diethyl ether
  7. customto yield a pale yellow solid (N3 regioisomer by NMR)
  8. additiona yellow filtrate (mixture of N1 and N3 regioisomers by NMR)
  9. customThe solids are collected
  10. washwashed with diethyl ether

Sources & evidence

ORD record
ord-9ce1e5452c0646028a2e8070f14bb6ab
Source dataset
uspto-grants-2012_06
Patent number
US08193231B2

Reaction notes

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