Benzoic acid, ethylidenehydrazide (6CI,7CI,8CI,9CI) synthesis

Yield:-

Reaction Conditions:

in ethanol at 20; for 2 h;

Steps:

1.21b Methyl 3-(2-benzoylhydrazinyl)-2-(bicyclo[2.2.1]heptan-2-yl)-2-methylbutanoate

To a solution of benzohydrazide (50 mmol, 6.8 g) in 50 mL of EtOH was added acetaldehyde (1.1 eq, 55 mmol, 3.1 mL) and the reaction mixture was stirred at room temperature for 2 h. The precipitated product was filtered off, washed with cold EtOH and dried in vacuum to afford N′-ethylidenebenzohydrazide (4 g, 50% yield) which was used further crude. (0311) To a suspension of N′-ethylidenebenzohydrazide (1.5 g, 9.2 mmol) and scandium (III) triflate (0.1 eq, 0.92 mmol, 453 mg) in 20 mL of anhydrous acetonitrile at -20° C. was added dropwise a solution of (2-(bicyclo[2.2.1]heptan-2-yl)-1-methoxyprop-1-enyloxy)trimethylsilane (Compound 4, Example 1.21c) (1.5 eq, 13.85 mmol, 3.5 g) in 5 mL of anhydrous acetonitrile. The reaction mixture was stirred at -20° C. for 2 h, warmed to room temperature and stirred for 18 hours. The reaction was quenched with saturated NaHCO₃ solution (50 ml) and extracted with EtOAc (3×30 ml). The organic layers were combined, washed with brine (40 ml), dried over MgSO₄ and concentrated under vacuum. The resulting residue was purified by column chromatography (Hexane/EtOAc 20%; R_f=0.5) to obtain the title compound (2.4 g; 77%) as a white powder, mixture of four isomers. (0312) ¹H NMR (400 MHz, DMSO-d₆) δ 9.96-9.93 (m, 0.5NH), 9.91-9.88 (m, 0.5NH), 7.91-7.72 (m, 2H), 7.57-7.34 (m, 3H), 5.01 (t, J=7.6 Hz, 0.25H), 4.94 (t, J=7.6 Hz, 0.25H), 4.85 (t, J=7.6 Hz, 0.25H), 4.80 (t, J=7.6 Hz, 0.25H), 3.57 (s, 0.75H), 3.56 (s, 0.75H), 3.55 (s, 0.75H), 3.53 (s, 0.75H), 3.40-3.18 (m, 1H), 2.16 (bs, 0.5H), 2.11 (bs, 1H), 2.05-1.97 (m, 0.75H), 1.88 (t, J=7.8 Hz, 0.25H), 1.78 (t, J=8.0 Hz, 0.25H), 1.64 (t, J=7.7 Hz, 0.25H), 1.37-1.52 (m, 3H), 1.20-1.37 (m, 2H), 1.17 (s, 0.75H), 1.15-1.04 (m, 3H), 1.09 (s, 1.5H), 1.05 (s, 0.75H), 1.03-0.90 (m, 3H). MS 343 (MH⁺).

References:

US2015/376136,2015,A1 Location in patent:Paragraph 0310-0312