Synthesis
General procedure for the synthesis of 8-bromo-3,4-dihydro-2H-benzo[B]oxoheptatrien-5-one from 4-(3-bromophenoxy)butyric acid: a mixture of polyphosphoric acid (590 g), diatomaceous earth (400 g) and toluene (1.5 L) was stirred for 0.5 h under nitrogen protection. Subsequently, 4-(3-bromophenoxy)butyric acid (135.8 g, 0.5264 mol) was added to the mixture. The reaction mixture was refluxed for 2.5 hours and then cooled to room temperature. The reaction mixture was filtered and the diatomaceous earth/polyphosphoric acid residue was washed with ethyl acetate (1.5 L). The organic phase was washed sequentially with 1N sodium hydroxide solution (3 x 0.75 L), water (1 L) and saturated saline, and then dried over anhydrous sodium sulfate. Concentration of the combined organic layers afforded 94.3 g (75% yield) of 8-bromo-3,4-dihydro-2H-benzo[b]oxepinacotrien-5-one. This product was combined with 85.0 g of 8-bromo-3,4-dihydro-2H-benzo[b]oxepinacotrien-5-one (total weight 173.3 g) from other experiments and distilled using a Kugelrohr apparatus (oven temperature 130 ± 5°C) to give a final 158.4 g of 8-bromo-3,4-dihydro-2H-benzo[b]oxepinacotrien-5-one , boiling point: 38.8-39.0°C (0.20 mmHg), melting point: 38.4-38.5°C. The final product is a mixture of the following substances.
References
[1] Patent: WO2004/69245, 2004, A1. Location in patent: Page/Page column 89
[2] Patent: US2012/238549, 2012, A1. Location in patent: Page/Page column 127
[3] European Journal of Medicinal Chemistry, 1995, vol. 30, # 5, p. 377 - 386
[4] Patent: WO2015/89337, 2015, A1. Location in patent: Paragraph 0515; 0527
[5] Patent: WO2018/191577, 2018, A1. Location in patent: Page/Page column 142
