Uses
2-Bromomethyl-6-nitrobenzoic Acid Methyl Ester is a potential cyclooxygenase inhibitor derived from thalidomide (T338850), an immunomodulatory agent used primarily in combination with dexamethasone to treat multiple myeloma.
Synthesis
Example 2 Preparation of methyl 2-bromomethyl-6-nitrobenzoate: under nitrogen protection, methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles), 1,3-dibromo-5,5-dimethylacetonitrile (DBH, 162.0 g, 0.57 moles), and methyl acetate (1.20 L) were added to a 3L three-neck flask, and the reaction temperature was maintained at 20 to 25°C. After refluxing the reaction mixture for 0.5-1 h, a solution of 2,2'-azobisisobutyronitrile (AIBN, 8.6 g, 52 mmol) dissolved in 100 mL of methyl acetate was added dropwise over 15-30 min. The reaction was continued at reflux for 6.5-8 hours until the residue of methyl 2-methyl-6-nitrobenzoate was less than 5-10%. Upon completion of the reaction, it was cooled to 15-18 °C and maintained for 50-60 min. The solid was collected by filtration and washed with cold methyl acetate (2 x 100 mL, 5-10 °C) until the amount of methyl 2-bromomethyl-6-nitrobenzoate in the solid was less than 3%. Heptane (1.00 L) was added to the filtrate and the organic phase was subsequently washed with 2% brine (2 x 500 mL) and deionized water (1-2 x 500 mL) until the percentage area of unreacted 5,5-dimethylglycolide urea was less than 0.5% by HPLC detection (210 nm). After removing about 1.80-1.90 L of methyl acetate by concentration under reduced pressure, methyl tert-butyl ether (MTBE, 300 mL) was added. The mixture was refluxed at 65-70 °C for 10-15 min and subsequently cooled to 50-55 °C over 0.5-1 h. 500 mg of methyl 2-bromomethyl-6-nitrobenzoate was added as a crystal seed. The suspension was cooled to 20-25 °C and kept for 2-3 hours. The product was collected by filtration, washed with cold heptane and MTBE (1:2 v/v, 2 x 100 mL, 5-10 °C), and dried at 20-25 °C, 100-120 torr under vacuum to constant weight. Using 200.0 g of methyl 2-methyl-6-nitrobenzoate as raw material, 185.2 g of methyl 2-bromomethyl-6-nitrobenzoate was obtained in 66% yield. The purity of the product was >98% (HPLC area percentage) and the moisture content was <0.1% (Karl Fisher titration).
References
[1] Patent: US2011/251395, 2011, A1. Location in patent: Page/Page column 15
[2] Chemical and Pharmaceutical Bulletin, 2003, vol. 51, # 9, p. 1098 - 1102
[3] Patent: US2011/87033, 2011, A1. Location in patent: Page/Page column 10-11
[4] Patent: WO2015/175773, 2015, A1. Location in patent: Paragraph 0117
[5] Patent: US9272035, 2016, B2. Location in patent: Page/Page column 28-29
