Formic Acid → HCID 21904688, compound

Temperature

0 °C

Pentafluorophenol (852 mg, 4.64 mmol) was dissolved in diethyl ether (15 mL) and the solution cooled to 0° C. Formic acid (209 μL, 5.56 mol) was added followed by DCCl (956 mg, 4.64 mmol) and the mixture was stirred for 10 min. The white suspension was filtered off and the filtrate was cooled to 0° C. and treated with a solution of the product from Example 1 (640 mg, 2.32 mmol) in DCM (10 mL) and triethylamine (323 μL, 2.32 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. The solvents were then removed under reduced pressure and the residue was basified with water (10 mL)/880 NH3 (1 mL) and extracted with DCM (4×15 mL). The combined organic extracts were dried (MgSO4) and evaporated to an oily-solid residue (844 mg, ca. 100%); δH (CDCl3, 400 MHz) 2.42 (3H, s), 3.87 (3H, s), 4.55 (2H, s), 5.98 (1H, brs), 6.50 (1H, dd), 6.59 (1H, d), 7.17 (1H, d), 7.31 (1H, d), 8.21 (1H, s), 8.29 (1H, s), 8.38 (1H, d). This material was carried on directly to the reduction stage without further purification. The crude formamide was dissolved in THF (10 mL) and treated with borane-THF complex (1M in THF, 7 mL, 7 mmol). The resulting pale yellow solution was heated at reflux under nitrogen for 3.5 h. After cooling to room temperature, the reaction was quenched by the careful addition of 6 M HCl (7 mL) and the mixture was subsequently heated to reflux for 3 h. Most of the THF was removed by evaporation and the resulting aqueous solution was washed with diethyl ether (2×10 mL) and then basified by the addition of 880 NH3. Extraction with DCM (4×10 mL) followed by drying of the combined extracts (MgSO4) and evaporation afforded a clear oil. Purification by flash chromatography [SiO2; DCM/MeOH/880 NH3 (95:5:0.5)] gave the desired compound as a colourless oil. A portion of this material (300 mg) was dissolved in DCM (5 mL) and treated with 1M HCl in diethyl ether (5 mL) and the resulting mixture was evaporated to dryness twice from DCM. The resulting yellow oil was dissolved in DCM (5 mL) and treated with diethyl ether dropwise to induce precipitation. The solvents were removed under reduced pressure and the resulting pale yellow solid was dried under vacuum (345 mg); Bis HCl salt: δH (CD3OD, 400 MHz) 2.39 (3H, s), 2.87 (3H, s), 3.85 (3H, s), 4.58 (2H, s), 6.87 (1H, dd), 6.95 (1H, d), 7.29 (1H, d), 8.06 (1H, d), 8.28 (1H, s), 8.58 (1H, d); MS m/z (TS+) 291 (MH+).

1. filtrationThe white suspension was filtered off
2. temperaturethe filtrate was cooled to 0° C.
3. customThe resulting reaction mixture
4. stirringwas stirred at room temperature for 6 h
5. customThe solvents were then removed under reduced pressure
6. extractionextracted with DCM (4×15 mL)
7. dry with materialThe combined organic extracts were dried (MgSO4)
8. customevaporated to an oily-solid residue (844 mg, ca. 100%)
9. customwithout further purification
10. dissolutionThe crude formamide was dissolved in THF (10 mL)
11. temperatureThe resulting pale yellow solution was heated
12. temperatureat reflux under nitrogen for 3.5 h
13. temperatureAfter cooling to room temperature
14. customthe reaction was quenched by the careful addition of 6 M HCl (7 mL)
15. temperaturethe mixture was subsequently heated
16. temperatureto reflux for 3 h
17. customMost of the THF was removed by evaporation
18. washthe resulting aqueous solution was washed with diethyl ether (2×10 mL)
19. additionbasified by the addition of 880 NH3
20. extractionExtraction with DCM (4×10 mL)
21. dry with materialby drying of the combined extracts (MgSO4) and evaporation
22. customafforded a clear oil
23. customPurification by flash chromatography [SiO2; DCM/MeOH/880 NH3 (95:5:0.5)]

ORD record

ord-9c39876dc58949b9ba3a67af5b3575e6

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07129234B2