6-Bromo-N-methyl-2-naphthalenecarboxamide

Uses

6-Bromo-N-methyl-2-naphthamide is used as a reactant in the synthesis process for orteronel (TAK-700), a potenital inhibitor that could be used for the treatment of prostate cancer.

Synthesis

1. 6-Bromo-2-naphthoic acid (10.1 g, 40.1 mmol) and N,N-dimethylformamide (4.75 g, 65.0 mmol) were dissolved in toluene (80 mL). 2. Thionyl chloride (5.7 g, 48.2 mmol) was slowly added dropwise to the reaction mixture at 45 to 50 °C with continuous stirring for 1 hour and then cooled to room temperature. 3. In another vessel, a solution was prepared by dissolving triethylamine (11.4 g, 112.4 mmol) and 40% methylamine methanol solution (8.1 g, 104.4 mmol) in toluene (80 mL). 4. The reaction mixture from step 2 was slowly added dropwise to the solution prepared in step 3 at 10 to 25°C with stirring for 1 hour at room temperature. 5. Water (50 mL) was added dropwise to the reaction mixture and stirring was continued at room temperature. 6. The crystals formed were collected by filtration and washed with a solvent mixture of methanol/water (2:8) (25 mL) to obtain wet crystals. 7. Dissolve the wet crystals in N,N-dimethylacetamide (70 mL) and heat to 60 °C to dissolve completely. 8. After cooling to room temperature, water (140 mL) was added slowly and dropwise to the reaction mixture. 9. The crystals were collected by filtration and washed with water (80 mL) to obtain wet crystals. 10. Suspend the wet crystals in ethyl acetate (25 mL) and stir at room temperature. 11. The crystals were collected by filtration and washed with ethyl acetate (5 mL). 12. The resulting wet crystals were dried under reduced pressure to afford 6-bromo-N-methyl-2-naphthalenecarboxamide (9.4 g, 35.6 mmol) in 89% yield. 13. 13. Product characterization: 1H NMR (500 MHz, DMSO-d6) δ 2.84 (d, J = 4.4 Hz, 3H), 7.71 (dd, J = 8.8, 2.2 Hz, 1H), 7.93-8.03 (m, 3H), 8.28 (d, J = 1.9 Hz, 1H), 8.44 (s, 1H), 8.62 (d, J = 4.1 Hz, 1H). 4.1 Hz, 1H); HRMS (ESI) m/z Calculated C12H11BrNO [M + H]+: 264.0024, measured: 264.0019; Elemental Analysis Calculated C12H10NOBr: C, 54.57; H, 3.82; N, 5.30; Br, 30.25; Measured C, 54.56; H, 3.70; N, 5.25. 3.70; N, 5.34; Br, 30.23.

References

[1] Patent: WO2012/173280, 2012, A1. Location in patent: Page/Page column 32-33
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6356 - 6374
[3] Patent: EP1471056, 2004, A1. Location in patent: Page 32