Carbon Dioxide → 4-Bromo-2-fluoro-3-methoxybenzoic acid

Temperature

0 °C

Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 56.0 mL, 89.6 mmol) to a stirred solution of diisopropylamine (13.7 mL, 96.9 mmol) in tetrahydrofuran (150 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, 0° C. for 15 min, and then cooled again to −78° C. A solution of 1-bromo-3-fluoro-2-methoxybenzene (15.28 g, 74.5 mmol) in tetrahydrofuran (40 mL) is added dropwise to the previous solution over a period of 30 min. to give an amber solution. After stirring this solution at −78° C. for 1.5 h, dry ice (˜125 g) is added, and the resulting mixture is allowed to warm slowly (˜1 h) to room temperature with stirring as it degasses. The reaction mixture is acidified to pH ˜1 by addition of a 5% aqueous solution of hydrochloric acid (˜500 mL), and the product is extracted with diethyl ether (6×100 mL). The combined organic extracts are washed with brine (100 mL), and the product extracted with a saturated solution of aqueous sodium bicarbonate (3×100 mL). The combined aqueous extracts (pH ˜9) are washed with diethyl ether (3×100 mL) and acidified slowly to pH ˜1 by addition of a 37% aqueous solution of hydrochloric acid (˜50 mL). The product is extracted with diethyl ether (3×200 mL), and the combined organic extracts are washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 12 as an off-white solid. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. mp 168-170° C. 1H NMR (CD3OD): δ 3.92 (d, JH-F=1.0 Hz, 3H, OCH3), 7.44 (dd, JH-H=8.5 Hz, JH-F=1.5 Hz, 1H, H-5), 7.55 (dd, JH-H=8.5 Hz, JH-F=7.0 Hz, 1H, H-6). 19F{1H} NMR (CD3OD): δ −127.0 (s). 13C{1H} NMR (CD3OD): 662.1 (d, JC-F=4.5 Hz, OCH3), 121.5 (d, JC-F=8.5 Hz, C-1), 123.6 (d, JC-F=2.0 Hz, C-4), 128.0 (s, C-6), 129.0 (d, JC-F=4.5 Hz, C-5), 147.7 (d, JC-F=13.5 Hz, C-3), 157.1 (d, JC-F=263.5 Hz, C-2), 166.3 (d, JC-F=3.0 Hz, CO2H). HRMS m/z calcd for C8H679BrFNaO3 270.9382 ([M+Na]+). Found 270.9377.

1. temperaturecooled again to −78° C
2. customto give an amber solution
3. stirringAfter stirring this solution at −78° C. for 1.5 h
4. temperatureto warm slowly (˜1 h) to room temperature
5. stirringwith stirring as it
6. extractionthe product is extracted with diethyl ether (6×100 mL)
7. washThe combined organic extracts are washed with brine (100 mL)
8. extractionthe product extracted with a saturated solution of aqueous sodium bicarbonate (3×100 mL)
9. washThe combined aqueous extracts (pH ˜9) are washed with diethyl ether (3×100 mL)
10. additionacidified slowly to pH ˜1 by addition of a 37% aqueous solution of hydrochloric acid (˜50 mL)
11. extractionThe product is extracted with diethyl ether (3×200 mL)
12. washthe combined organic extracts are washed with brine (100 mL)
13. dry with materialdried over anhydrous magnesium sulfate
14. concentrationconcentrated under reduced pressure

ORD record

ord-6396a439d8ed477f9e9bbdde6e1f66d7

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08114888B2