Uses
2-Chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene is a reagent used in the synthesis of novel indole-2-carboxamide derivative as anti-inflammatory agents used in the treatment of sepsis. Also an intermediate of Niraparib (N481400), a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.
Synthesis
Example 1a: General procedure for the synthesis of 3-chloro-4-(3-fluorobenzyloxy)nitrobenzene from 3-chloro-4-fluoronitrobenzene and 3-fluorobenzyl alcohol. First, 3-fluorobenzyl alcohol (0.30 kg, 2.39 mol, 1.05 eq.) was dissolved in acetonitrile (ACN, 6.0 L), followed by addition of potassium hydroxide flakes (85%, 0.16 kg, 1.25 eq.). The resulting suspension was heated to 35 °C. A solution of 3-chloro-4-fluoronitrobenzene (0.40 kg, 2.28 mol) dissolved in acetonitrile (ACN, 2.0 L) was slowly added in the temperature range of 35-40 °C. The reaction mixture was kept at this temperature for 18 hours. After completion of the reaction, the mixture was cooled to 20-25 °C and the reaction was quenched with water (8 L). The resulting slurry was filtered and the solid product was washed with water (2 x 0.40 L). Finally, the product was dried at 45 °C and 10 mmHg pressure for 25 h to give 0.59 kg of the target compound 3-chloro-4-(3-fluorobenzyloxy)nitrobenzene in 92% yield.
References
[1] Patent: US2006/270668, 2006, A1. Location in patent: Page/Page column 16
[2] Patent: US2006/270669, 2006, A1. Location in patent: Page/Page column 19-20
[3] Patent: WO2009/63054, 2009, A1. Location in patent: Page/Page column 37; 68
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555
[5] Patent: WO2011/2523, 2011, A1. Location in patent: Page/Page column 43
