What is the synthesis and application of 5-Bromo-2-methylbenzoic acid?

Background and Overview^[1]

5-Bromo-2-methylbenzoic acid is a pharmaceutical intermediate that can be obtained by brominating 2-methylbenzoic acid. It has been reported in the literature that it can be used to prepare caragliatin.

Synthesis^[1-2]

Report 1

Starting from 2-methylbenzoic acid, 5-Bromo-2-methylbenzoic acid is synthesized with a yield of over 85% by adding 1.05 molar equivalents of liquid bromine to the reaction mixture containing Fe powder and the superacid catalyst trifluoromethanesulfonic acid, and treating the solvent bromine with molecular sieve for absolute anhydrous pretreatment.

Report 2

Under a N₂ atmosphere, 2-methylbenzoic acid (40.0g, 290mmol) is added to a suspension of Br2 (160mL) and iron powder (3.20g, 57.0mol) in an ice bath. The mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction mixture is poured into water and the red solid is collected by filtration. The solid is dried under vacuum at 50°C. The solid is dissolved in 400mL of methanol, followed by the addition of 640mL of 0.1N hydrochloric acid at room temperature. The mixture is stirred to obtain a white solid. The solid is recrystallized from ethanol to obtain 5-Bromo-2-methylbenzoic acid (12.0g, 19%). 1H NMR (300 MHz, CDCl3): δ8.17 (d, J=2.1, 1H), 7.56 (dd, J=8.1, 2.1, 1H), 7.15 (d, J=8.1, 1H), 2.59 (s, 3H).

Application^[2]

2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene is an important intermediate for the synthesis of caragliatin. It can be used directly as a synthetic raw material for caragliatin or prepared into another important raw material, 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene. CN201510287802.X reports a method for the preparation of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, which involves the coupling reaction of 2-bromothiophene with p-bromofluorobenzene to obtain 2-(4-fluorophenyl)thiophene, followed by the Finkelstein reaction of 2-(4-fluorophenyl)thiophene with 5-Bromo-2-methylbenzoic acid to obtain 5-bromo-2-methylbenzyl-2-(4-fluorophenyl)thiophene ketone, and finally the reduction reaction of 5-bromo-2-methylbenzyl-2-(4-fluorophenyl)thiophene ketone to obtain 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene. This invention uses inexpensive and readily available p-bromofluorobenzene and 5-Bromo-2-methylbenzoic acid as raw materials to synthesize caragliatin intermediates. The product is easy to purify, easy to operate, low in cost, and environmentally friendly.

References

[1] CN201410153116.9 Synthesis process of caragliatin

[2] [Chinese invention, Chinese invention authorization] CN200880123501.1 Quinoline regulator of ATP-binding cassette transporters

[3] CN201510287802.X Method for preparing 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene