1,1'-Carbonyldiimidazole → N-[[18-[2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide

HRID 1669552Notes

Reaction equation

HRID 1669552 reaction equation
[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41](O)=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 75050637HCID 75050637, compound

Product 1

HCID 75050636N-[[18-[2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamideYield 72.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 18-[2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (12, 54 mg, 0.083 mmol) and carbonyldiimidazole (20 mg, 0.125 mmol, 1.5 eq) in dry THF (4 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (15 mg, 0.125 mmol) and DBU (19 mg, 0.125 mmol) were added. This solution was heated at 50° C. for 16 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography (gradient of EtOAc (0 to 50%) in DCM) afforded 45 mg (72%) of the title product which was recrystallized from water to give 12 mg of the desired product as a slightly yellow powder. m/z=751 (M+H)+. 1H NMR (CDCl3): 0.8-1.9 (m, 21H), 2.17 (m, 1H), 2.28-2.56 (m, 4H), 2.65 (m, 1H), 2.86, (m, 1H), 3.55 (m, 1H), 3.87 (m, 4H), 4.10 (m, 1H), 4.57 (m, 1H), 4.94 (t, J=9.5 Hz, 1H), 5.43 (m, 2H), 5.64 (m, 1H), 6.92 (broad s, 1H), 6.98 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.28 (m, 2H), 7.37 (s, 1H), 7.80 (d, J=9.0 Hz, 1H).

Workup

  1. temperatureat reflux under nitrogen for 2 h
  2. customcan be isolated
  3. temperatureThis solution was heated at 50° C. for 16 h
  4. temperatureThen, the reaction mixture was cooled down at room temperature
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was partitioned between CH2Cl2 and HCl 1N
  7. washthe organic layer was washed with brine
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated
  10. customPurification by flash chromatography (gradient of EtOAc (0 to 50%) in DCM)

Sources & evidence

ORD record
ord-41dc9ae3a4644294bfd4d7920a148b61
Source dataset
uspto-grants-2011_08
Patent number
US07989471B2

Reaction notes

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