Hydrochloric Acid → 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]-(dimethylamino)sulfonamide

HRID 1516670Notes

Reaction equation

HRID 1516670 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].C1N=C[N:48]([C:51](N2C=NC=C2)=O)[CH:47]=1.C1CCN2C(=NCCC2)CC1.CN[N:71](NC)[SH:72](=[O:74])=[O:73].Cl>C1COCC1.O1CCOCC1>[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:71][S:72]([N:48]([CH3:51])[CH3:47])(=[O:74])=[O:73])=[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

8

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 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 178486254HCID 178486254, compound

Product 1

HCID 67411494N-[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]-(dimethylamino)sulfonamideYield 9.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 312751,4-DioxaneSolvent

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, 39.8 mg, 0.063 mmol) and CDI (22 mg, 0.136 mmol) in dry THF (4 mL) was heated at 65° C. in a reflux setup. After 1.75 h the reaction mixture was cooled to room temperature. The formation of the stable intermediate 36 was observed. Then, a solution of DBU (30 μL, 0.20 mmol) and N,N-dimethylaminosulfonamide (23.4 mg, 0.19 mmol) in THF (1 mL), was added. The reaction was heated overnight at 55° C., then acidified with a 4 M solution of HCl (200 μL) in dioxane and evaporated. Purification by flash chromatography (YMC silica, gradient MeOH/AcOEt, 1:100 to 5:95) gave 4.3 mg of the title product 37 as light yellow solids: LCMS: tR=3.64 min, >99% (Method Flow: 0.8 mL/min. UV 220 nm, ACE C8 3×50 mm; Mobile phase A: 10 mM NH4Ac in 90% water, B: 10 mM NH4Ac in 90% MeCN; Gradient: 5 to 99% B in 3 min, then 99% B for 2 min), m/z=739 (M+H)+. 1H NMR (500 MHz, CDCl3) major rotamer 1.2-1.4 (m, 3H), 1.39 (d, 6H, J=6.0 Hz), 1.46 (dd, 1H, J=9.7, 6.2 Hz), 1.66-1.80 (m, 2H), 1.87 (m, 1H), 1.99 (m, 1H), 2.22-2.32 (m, 1H), 2.32-2.46 (m, 2H), 2.50-2.62 (m, 2H), 2.80-2.84 (m, 1H), 2.98 (s, 3H), 3.04 (s, 3H), 3.20 (m, 1H), 3.40-3.44 (m, 2H), 3.77 (s, 3H), 3.97 (s, 3H), 4.6 (m, 1H), 5.05 (m, 1H), 5.37 (m, 1H), 5.68 (m, 1H), 6.39 (s, 1H), 7.05 (d, 1H, J=1.0 Hz), 7.13 (dd, 1H, J=9.0, 2.5 Hz), 7.38 (d, 1H, J=2.5 Hz), 7.51 (s, 1H), 8.04 (d, 1H, J=9.0 Hz), 10.62 (s, 1H).

Workup

  1. temperatureAfter 1.75 h the reaction mixture was cooled to room temperature
  2. temperatureThe reaction was heated overnight at 55° C.
  3. customevaporated
  4. customPurification by flash chromatography (YMC silica, gradient MeOH/AcOEt, 1:100 to 5:95)

Sources & evidence

ORD record
ord-80309a1719e24093b6ed10b145b5d2e1
Source dataset
uspto-grants-2012_07
Patent number
US08227407B2

Reaction notes

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