Triethylamine → 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide

HRID 1895451Notes

Reaction equation

HRID 1895451 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:26]([OH:28])=O)=[CH:11][C:12]3[N:16]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:15]=[N:14][C:13]=3[C:24]=2[F:25])=[C:4]([Cl:29])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH:47]([O:49][CH2:50][CH2:51][O:52][NH2:53])=[CH2:48].CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH:47]([O:49][CH2:50][CH2:51][O:52][NH:53][C:26]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:29])=[C:24]([F:25])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:28])=[CH2:48]

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 211141606-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acidHCID 21867017O-(2-(Vinyloxy)ethyl)hydroxylamine

Product 1

HCID 865905266-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amideYield 79%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid 11r (0.11 g, 0.23 mmol) is dissolved in N,N-dimethylformamide (2 mL). HOBT (0.037 g, 0.27 mmol) and triethylamine (0.094 mL, 0.68 mmol) are added. Then O-(2-vinyloxy-ethyl)-hydroxylamine (0.028 g, 0.27 mmol) and EDCI (0.056 g, 0.29 mmol) are added and the reaction mixture is stirred at room temperature under N2 until HPLC shows the reaction is complete (2-3 days). 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 successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×), dried (Na2SO4) and concentrated under reduced pressure. The resulting solid is purified by FCC (eluting with 15:1 methylene chloride:methanol) to yield 0.039 g (79%) of the pure desired product as an off-white solid. MS ESI (+) m/z 567, 569 (M+, Br pattern) detected.

Workup

  1. custom(2-3 days)
  2. additionThe reaction mixture is poured into a separatory funnel
  3. customthe layers separated
  4. washThe ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting solid is purified by FCC (eluting with 15:1 methylene chloride:methanol)

Sources & evidence

ORD record
ord-856a52844918487aa5d27d9d873382c4
Source dataset
uspto-grants-2013_08
Patent number
US08513293B2

Reaction notes

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