Diisopropylethylamine → 4-(3-fluoro-4-{[(quinoxalin-2-ylamino)carbonyl]amino}phenoxy)-N-methyl-pyridine-2-carboxamide

HRID 658497Notes

Reaction equation

HRID 658497 reaction equation
[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[F:19].ClC(Cl)(O[C:24](=[O:30])OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:51]=[N:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=1>C1COCC1.CN(C=O)C>[F:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH:1][C:24]([NH:41][C:42]1[CH:51]=[N:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=1)=[O:30])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 2245732-AminoquinoxalineHCID 468352194-(4-Amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide

Product 1

HCID 599874944-(3-fluoro-4-{[(quinoxalin-2-ylamino)carbonyl]amino}phenoxy)-N-methyl-pyridine-2-carboxamideYield 27.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
75 °C

Procedure

To a solution of 4-[4-amino-3-(fluoro)phenoxy]-N-methylpyridine-2-carboxamide (150.0 mg, 0.57 mmol) in anhydrous THF (5.7 mL) was added triphosgene (63 mg, 0.21 mmol, 0.37 eq) and diisopropylethyl amine (0.12 mL, 0.69 mmol, 1.2 eq), and the reaction mixture was stirred at 75° C. After 3 h a solution of 2-aminoquinoxaline (83.3 mg, 0.57 mmol, 1.0 eq) in anhydrous DMF (2.8 mL) was added, and the reaction mixture was stirred at 75° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude was absorbed onto silica and purified by MPLC (biotage) eluted with 10% MeOH/EtOAc. Trituration from DCM/MeOH afforded 25.0 mg (10.1%) of the title product as a yellow solid. 1H-NMR (DMSO-d6) δ 11.75 (s, 1H), 10.75 (s, 1H), 8.89 (s, 1H), 8.79 (br q, J=5.1 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.38 (t, J=9.0 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.82 (d, J=3.9 Hz, 2H), 7.70 to 7.64 (m, 1H), 7.47 to 7.42 (m, 2H), 7.20 (dd, J=5.4, 2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H) 2.78 (d, J=4.8 Hz, 3H); TLC (100% EA), Rf=0.20; MS LC-MS [M+H]+=433), RT=2.86 min.

Workup

  1. stirringthe reaction mixture was stirred at 75° C. for 17 h
  2. customThe reaction mixture was partitioned between EtOAc and water
  3. washthe organic layer was washed with water and brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customThe crude was absorbed onto silica
  8. custompurified by MPLC (biotage)
  9. washeluted with 10% MeOH/EtOAc

Sources & evidence

ORD record
ord-1aa21a0cfe914306b2f5c7f20f58c455
Source dataset
uspto-grants-2011_12
Patent number
US08076488B2

Reaction notes

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