1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 7-(2,4-Dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide

HRID 500564Notes

Reaction equation

HRID 500564 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[CH:15][N:16]=[N:17]2)=[CH:12][C:11]=1[C:22](O)=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH:47]([O:49][CH2:50][CH2:51][O:52][NH2:53])=[CH2:48]>CN(C=O)C.CCOC(C)=O>[CH:47]([O:49][CH2:50][CH2:51][O:52][NH:53][C:22]([C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([F:20])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[N:17]=[N:16][CH:15]=[C:14]2[CH3:21])=[O:23])=[CH2:48]

Participants

7

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 27960291-Hydroxybenzotriazole hydrateHCID 21867017O-(2-(Vinyloxy)ethyl)hydroxylamineHCID 686378117-(2,4-Dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid

Product 1

HCID 865986387-(2,4-Dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amideYield 39%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (31 mg, 0.086 mmol), EDCI (28 mg, 0.14 mmol), and HOBt-H2O (21 mg, 0.14 mmol) in DMF (1 mL) was stirred for 45 minutes at room temperature. O-(2-Vinyloxy-ethyl)-hydroxylamine (18 mg, 0.18 mmol) and TEA (0.030 mL, 0.21 mmol) were added. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by Biotage (1.5 to 3% MeOH in CH2Cl2) to afford 9 mg (39%) of 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide. A mixture of the vinyl ether (9 mg, 0.020 mmol) and 1 N aqueous HCl (0.040 mL, 0.040 mmol) in EtOH (3 mL) was stirred for 1 hour at room temperature. The pH of the reaction mixture was adjusted to 6 to 7 with 2 N aqueous NaOH. The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 7-(2,4-dichlorophenylamino)-8-fluoro-4-methyl-cinnoline-6-carboxylic acid (2-hydroxyethoxy)-amide (6 mg, 71%). MS APCI (+) m/z 425, 427 (M+, Cl pattern) detected; 1H NMR (400 MHz, CD3OD) δ 9.26 (s, 1H), 8.30 (s 1H), 7.48 (d, 1H), 7.22 (dd, 1H), 6.90 (dd, 1H), 4.08 (t, 2H), 3.99 (t, 2H), 2.80 (s, 3H).

Workup

  1. stirringThe resulting mixture was stirred for 16 hours at room temperature
  2. washwashed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto give the crude material which
  7. customwas purified by Biotage (1.5 to 3% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-e8074d4624d24f6aa82a199d3d67edbe
Source dataset
uspto-grants-2010_08
Patent number
US07772234B2

Reaction notes

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