Ethylene Dichlorides

Example 54

To a mixture of 1-methyl-3-{[4-(piperidin-4-yl)phenyl]amino}-5-(1,3-thiazol-2-yl)pyrazin-2-one (24 mg, 0.065 mmol) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde (24 mg, 0.065 mmol) in 1,2-dichloroethane (1.0 mL) was added sodium triacetoxyborohydride (41 mg, 0.20 mmol). After 30 minutes, additional portions of 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde (24 mg, 0.065 mmol) and sodium triacetoxyborohydride (41 mg, 0.20 mmol) were added. After 30 more minutes, water was added and the mixture was extracted twice with dichloromethane. The combined organic layers were concentrated then purified by preparative TLC eluted with 10% MeOH/DCM to provide 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[4-(4-{[4-methyl-3-oxo-6-(1,3-thiazol-2-yl)pyrazin-2-yl]amino}phenyl)piperidin-1-yl]methyl}piperidin-1-yl)isoindole-1,3-dione (0.017 g, 35%).

Example 51

[Figure (not displayed)]
1) Synthesis of Compound 52

[Figure (not displayed)]

In a dry single-necked flask, Compound 36-4 (300 mg), Compound 52-1 (129 mg), sodium carbonate (102 mg), 1,2-dichloroethane (2.1 mL), and water (0.9 mL) were added. After nitrogen purge, dichlorobis(triphenylphosphine)palladium (40 mg) was added, and the resulting mixture was refluxed at 100° C. and reacted for 16 h. The reaction mixture was concentrated, and the residue obtained from the concentration was purified successively by a preparative TLC plate and preparative HPLC method to obtain Compound 52. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.52-9.55 (m, 1H), 8.93 (d, J=2.89 Hz, 1H), 7.98-8.04 (m, 2H), 7.92 (d, J=0.88 Hz, 1H), 7.86-7.91 (m, 1H), 7.59 (dd, J=9.91, 2.13 Hz, 1H), 6.60 (dd, J=2.89, 1.63 Hz, 1H), 3.20 (q, J=7.53 Hz, 2H), 1.73 (s, 5H), 1.67-1.77 (m, 1H), 1.50 (t, J=7.59 Hz, 3H). LCMS (ESI) m/z: 554 (M+1).

Example 4

[Figure (not displayed)]

2,2′-(1,2-Bis((E)-3-bromoacryloyl)hydrazine-1,2-diyl)diacetic acid (210 mg, 0.509 mmol) in dichloroethane (15 ml) was added (COCl)₂ (505 mg, 4.01 mmol), followed by addition of 0.040 ml of DMF. After stirred at RT for 2 h, the mixture was concentrated and co-evaporated with dichloroethane (2×20 ml) and toluene (2×15 ml) to dryness to afford the title crude product (which is not stable) for the next step without further purification (245 mg, 107% yield). MS ESI m/z calcd for C10H₉Br₂Cl₂N₂O₄ [M+H]⁺ 448.82, 450.82, 452.82, 454.82, found 448.60, 450.60, 452.60, 454.60.