RARECHEM AL BF 0302

Synthesis

General procedure for the synthesis of methyl 3-bromo-5-chloro-2-hydroxybenzoate from methyl 5-chloro-2-hydroxybenzoate: Methyl 5-chloro-2-hydroxybenzoate (50.02 g) was dissolved in DMF (500 ml) and stirred at room temperature. To this solution was slowly added methyl 3-bromo-5-chloro-2-hydroxybenzoate (47.76 g) and stirring was continued overnight. After completion of the reaction, the precipitated solid was collected by filtration. When the sinter was dried under air flow, more solids were formed and needed to be collected again. The filtrate was diluted with ether (Et2O) and washed with deionized water (H2O). The ether layer is separated, dried with anhydrous sodium sulfate (Na2SO4), filtered and concentrated to a smaller volume. After cooling, the precipitated solid was collected and washed with cold ether to finally obtain the title compound methyl 3-bromo-5-chloro-2-hydroxybenzoate (68.05 g, 96% yield). It was analyzed by high performance liquid chromatography (HPLC) with a retention time (Rt) of 3.42 min and mass spectrometry detected the [M-H] peak as 265,267.

References

[1] Patent: WO2008/98978, 2008, A2. Location in patent: Page/Page column 37
[2] Patent: WO2007/113289, 2007, A1. Location in patent: Page/Page column 35-36
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4343 - 4348
[4] Patent: US2014/275172, 2014, A1. Location in patent: Paragraph 0608