1,1'-Carbonyldiimidazole → N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide

HRID 402144Notes

Reaction equation

HRID 402144 reaction equation
[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:40](O)=[O:41])([N:34](C)[C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:47](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]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:47])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:40]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 8668084017-[2-(4-Isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-3-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid

Product 1

HCID 66811198N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamideYield 48.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560 mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 as a white powder: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J=13 Hz, 1H), 5.04 (t, J=11 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, J=10 Hz, 1H), 7.45 (s, 1H), 7.99 (d, J=10 Hz, 1H), 10.82 (broad s, 1H).

Workup

  1. temperatureat reflux under nitrogen for 2 h
  2. temperatureThis solution was heated at 50° C. for 15 h
  3. temperatureThen, the reaction mixture was cooled down at room temperature
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was partitioned between CH2Cl2 and HCl 1 N
  6. washthe organic layer was washed with brine
  7. dry with materialdried (MgSO4)
  8. customevaporated
  9. customPurification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2)

Sources & evidence

ORD record
ord-dd516b7aff984433bf3ccd7dd79b8d95
Source dataset
uspto-grants-2014_06
Patent number
US08741926B2

Reaction notes

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