Synthesis
Bromine (6.56 mL, 128 mmol) was added dropwise to a stirred solution of 4-iodoacetophenone 1 (30.0 g, 122 mmol) in dioxane (200 mL) under ice-bath conditions. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by LC/MS. Upon completion of the reaction (about 1 hour), the solvent was removed by rotary evaporation and the residue was dried under vacuum to afford 2-bromo-4'-iodoacetophenone 2 (40 g, 100% yield).
To a solution of Cbz-D-Ala-OH 3 (5.0 g, 22.4 mmol) in NMP (100 mL) was added cesium carbonate (3.72 g, 11.4 mmol). After stirring at room temperature for 1 hour, 2-bromo-4'-iodoacetophenone 2 (7.60 g, 22.4 mmol) was added. The reaction mixture was stirred at room temperature and monitored by LC/MS to form intermediate 4. The reaction solution was diluted with xylene (100 mL) and ammonium acetate (9.25 g, 120 mmol) followed by stirring at 120 °C for 4 h. The reaction mixture was then stirred for 1 h at room temperature. Depending on the course of the reaction, up to 50 additional equivalents of ammonium acetate may need to be added. It is critical to keep a solid present in the flask during the reaction.
After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL).The EtOAc solution was washed twice with saturated sodium bicarbonate solution (200 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and stirred for 1 h to precipitate. Solid 5 (4.0 g) was collected by filtration and dried under vacuum. The mother liquor was concentrated by rotary evaporation and the residue was purified by a Biotage system (eluent: hexane/EtOAc = 1:1 to pure EtOAc) to give additional 5 (100% yield). The two products were combined and dried under vacuum to give the final compound 5 (5.8 g, 58% yield).
References
[1] Patent: WO2005/107762, 2005, A2. Location in patent: Page/Page column 265-266
[2] Patent: WO2007/56056, 2007, A2. Location in patent: Page/Page column 60; 69
[3] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 246 - 253
[4] Patent: US2005/101602, 2005, A1. Location in patent: Page/Page column 45
[5] Patent: US2005/159597, 2005, A1. Location in patent: Page/Page column 30-31
