Reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15]N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=O)[CH2:19][CH2:18]2.S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]2[NH:15][C:20]3[CH:21]4[CH2:24][CH2:25][N:17]([CH2:18][C:19]=3[C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:23][CH2:22]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1Participants
Conditions
- Temperature
- 80 °C
Procedure
Under nitrogen, (2-(benzyloxy)phenyl)hydrazine (214 mg, 1.0 mmol, International Publication No. WO2009001129) was mixed with the product of Example 1A (139 mg, 1.0 mmol) and sulfuric acid (0.2 mL, 3.76 mmol; J. T. Baker) in dry dioxane (10 mL). Then the mixture was heated to 80° C. and stirred for 16 hours in a sealed tube. The mixture was concentrated and basified with 1.0 M NaOH and then extracted with ethyl acetate (3×20 mL). The organic phase was concentrated and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.01-2.13 (m, 4 H), 3.01-3.13 (m, 3 H), 3.17-3.28 (m, 2 H), 4.22 (s, 2 H), 5.21 (s, 2 H), 6.66 (dd, J=7, 2 Hz, 1 H), 6.83-6.93 (m, 2 H), 7.28-7.41 (m, 3 H), 7.48-7.55 (m, 2 H); MS (DCI/NH3) m/z 319 (M+H)+.
Workup
- concentrationThe mixture was concentrated
- extractionextracted with ethyl acetate (3×20 mL)
- concentrationThe organic phase was concentrated
- custompurified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)]
Sources & evidence
- ORD record
- ord-5ffb9df5b0114c95ba3a02ea3d88c1c5
- Source dataset
- uspto-grants-2013_09
- Patent number
- US08524703B2
Linked notes
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