1,1'-Carbonyldiimidazole → N-[17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl]-[(ethyl)(methyl)amino]sulfonamide

HRID 1516671Notes

Reaction equation

HRID 1516671 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])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:46]1N=C[N:48]([C:51](N2C=NC=C2)=O)[CH:47]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([N:70](C)[SH:71](=[O:73])=[O:72])C>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]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:70][S:71]([N:48]([CH2:47][CH3:46])[CH3:51])(=[O:73])=[O:72])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[CH:12][C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 2733832Lithium HexamethyldisilazideHCID 6741069117-[2-(4-Isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acidHCID 178465506HCID 178465506, compound

Product 1

HCID 67410198N-[17-[2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl]-[(ethyl)(methyl)amino]sulfonamideYield 13.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
65 °C

Procedure

A mixture of 17-[2-(4-isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (35, 60 mg, 0.095 mmol) and CDI (0.23 mmol) in dry THF (5 mL) was heated at 65° C. in a reflux setup for 1 h, and then cooled to RT. The formation of the stable intermediate 36 was observed. Then, a solution of lithium bis(trimethylsilyl)amide (460 μL of 1.0M in THF) and N-ethyl-N-methylsulfonamide (62.5 mg, 0.45 mmol) in THF (7 mL), was added. After 1 h, the reaction was quenched with water, evaporated, diluted with THF, acidified with HCl in dioxane, and evaporated. Purification by flash chromatography (YMC silica, gradient MeOH/CH2Cl2, 2 to 5%) gave 9.6 mg of the title product as white solids. LCMS: tR=3.51 min, >95%, m/z (API-ES+)=753 (M+1), 1H NMR (400 MHz, CDCl3) major rotamer □ 1.16-1.28 (m, 5H), 1.36 (m, 1H), 1.39 (d, 6H, J=6.4 Hz), 1.42 (m, 1H), 1.62 (m, 1H), 1.70 (m, 1H), 1.87 (dd, 1H, J=8.2 Hz, 5.8 Hz), 2.00 (m, 1H), 2.20-2.31 (m, 1H), 2.33-2.44 (m, 2H), 2.50-2.62 (m, 2H), 2.88-2.94 (m, 4H), 3.04 (s, 3H), 3.17-3.28 (m, 2H), 3.38-3.45 (m, 3H), 3.97 (s, 3H), 4.60 (m, 1H), 5.04 (m, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.23 (s, 1H), 7.04 (d, 1H, J=1.2 Hz), 7.12 (dd, 1H, J=8.8, 2.8 Hz), 7.37 (d, 1H, J=2.8 Hz), 7.51 (m, 1H), 8.03 (d, 1H, J=8.8 Hz), 10.53 (s, 1H).

Workup

  1. temperaturecooled to RT
  2. customthe reaction was quenched with water
  3. customevaporated
  4. additiondiluted with THF
  5. customevaporated
  6. customPurification by flash chromatography (YMC silica, gradient MeOH/CH2Cl2, 2 to 5%)

Sources & evidence

ORD record
ord-bfb7ca0f402b430b8b2184daae161c39
Source dataset
uspto-grants-2012_07
Patent number
US08227407B2

Reaction notes

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