Methyl 4-(bromomethyl)-3-methoxybenzoate

Preparation

Methyl 4-(bromomethyl)-3-methoxybenzoate is prepared by the following steps:A mixture of methyl 3-methoxy-4-methylbenzoate 37 (5 g, 27.8 mmol),  NBS (4.94 g, 27.8 mmol), and benoyl peroxide (0.0008 g, 0.003 mmol)  was refluxed in CCl4 (25 ml) for 10 hours. The reaction mixture was  allowed to cool and filtered. The residue was washed with CCl4 and the  combined filtrate concentrated in vacuo. Purification by column  chromatography over silica gel (5-10% EtOAc-pet ether) furnished a colourless solid (7.19  g).Yield : 100%

Uses

Methyl 4-(Bromomethyl)-3-methoxybenzoate is an intermediate used to prepare heteroarylphenyloxoacetyl and heteroarylphenylsulfonyl benzoylpiperazine analogs of BMS 378806 as HIV entry inhibitors. It is also used to synthesize steroid 5α-reductase inhibiting acylpiperidines.

Synthesis

Step 1: Methyl 4-methyl-3-methoxybenzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.09 g, 6.10 mmol) and catalytic amount of 2,2'-azobisisobutyronitrile (AIBN) were mixed in carbon tetrachloride (40 ml) and the reaction was carried out at reflux for 16 hours. After completion of the reaction, the reaction mixture was filtered and the resulting filtrate was washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-bromomethyl-3-methoxybenzoate (1.4 g, 97% yield).

References

[1] European Journal of Medicinal Chemistry, 1997, vol. 32, # 7-8, p. 547 - 570
[2] Patent: WO2009/55077, 2009, A1. Location in patent: Page/Page column 391-392
[3] Synlett, 2014, vol. 25, # 17, p. 2485 - 2487
[4] Patent: WO2005/105802, 2005, A1. Location in patent: Page/Page column 120-121
[5] Patent: US6391901, 2002, B1