Cesium carbonate → 2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

Temperatur

60 °C

To a 2 L, 3-necked, round-bottomed flask equipped with an overhead mechanical stirrer, thermocouple probe, heating mantle, reflux condenser, and nitrogen inlet were added 2-fluoro-6-iodobenzoic acid (127.6 g, 480 mmol), copper iodide (4.57 g, 24 mmol), and Cs2CO3 (312.6 g, 959 mmol). To these solids were added dioxane (640 mL), then water (2.6 mL, 144 mmol), then 1H-1,2,3-triazole (55.6 mL, 959 mmol), and finally trans-1,2-dimethylcyclohexane-1,2-diamine (15.1 mL, 96 mmol). The mixture was then warmed to 60° C. for 30 min, then to 83° C. for 30 min, and then to 100° C. for 3 h. After the 3 h at 100° C., the mixture was cooled and then 1 L of MTBE and 1 L of water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 1.72 with ˜148 mL of concentrated hydrochloric acid. The aqueous was then extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide a dark oil. The oil was stirred overnight in EtOAc (450 mL) and the resulting precipitate was removed by filtration. The mother-liquors were concentrated to a brown solid (106.21 g, 75 wt % by quantitative HPLC, 79.7 g, 80%). 1H NMR (400 MHz, DMSO-d6): 8.22-8.13 (bs, 2H), 7.84-7.80 (m, 1H), 7.74-7.65 (m, 1H), 7.50-7.41 (m, 1H).

1. customTo a 2 L, 3-necked, round-bottomed flask equipped with an overhead mechanical stirrer
2. temperaturethermocouple probe, heating mantle
3. temperaturereflux condenser, and nitrogen inlet
4. waitto 100° C. for 3 h
5. temperatureAfter the 3 h at 100° C., the mixture was cooled
6. customAfter vigorous mixing, the layers were separated
7. extractionThe aqueous was then extracted twice with EtOAc
8. dry with materialThe combined organic layers were dried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated
11. customto provide a dark oil
12. customthe resulting precipitate was removed by filtration
13. concentrationThe mother-liquors were concentrated to a brown solid (106.21 g, 75 wt % by quantitative HPLC, 79.7 g, 80%)

ORD-Eintrag

ord-981c61d9dafa411d9b659a00eb4c898c

Quelldatensatz

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08653263B2