Carbon Dioxide → HCID 118435585, compound

Temperature

-58 °C

A mixture of 2,4-dibromo-1,3-thiazole (11.85 g, 48.78 mmol) in toluene (90 mL) and chlorobenzene (90 mL) was cooled to −58° C. (internal temperature) and treated in a drop-wise manner with n-butyllithium (1.6 M solution in hexanes, 29 mL, 46 mmol), while maintaining the internal reaction temperature at −55° C. In a separate flask, a solution of P1 (5.00 g, 35.4 mmol) in toluene (25 mL) was cooled to 0° C. and slowly treated with boron trifluoride dibutyl etherate (11.0 mL, 53.2 mmol), while keeping the temperature of the solution below 5° C. The solution of P1 was then added in a drop-wise manner to the lithiated thiazole solution, while maintaining the internal reaction temperature between −54° C. and −58° C. After 10 minutes, carbon dioxide vapor (from 50 g of dry ice pellets, previously blasted with a strong nitrogen stream to remove any frost coating the pellets) was introduced to the reaction via bubbling it in under the surface of the liquid. After 20 minutes of bubbling, the reaction mixture was treated with water (5 volumes). The organic layer was washed twice with aqueous sodium carbonate solution (10%, 5 volumes), and with saturated aqueous sodium chloride solution (5 volumes). Solvent was removed under reduced pressure (50 mm mercury, bath temperature 60° C.; then 35 mm mercury, bath temperature 80° C.), and the resulting oil was treated with a solution of ethyl acetate in heptane (10%, 80 mL). Silica gel (15 g) was added, and the mixture was stirred at room temperature for 90 minutes, whereupon it was filtered; the filter cake was washed with a solution of ethyl acetate in heptane (25%, 4×30 mL), and the combined filtrates were concentrated in vacuo to a volume of ˜30 mL. This material was granulated at room temperature for 4 hours. The solid was collected via filtration and washed with heptane to afford the product as a yellow solid. Yield: 8.16 g, 26.7 mmol, 75%. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 6.43 (br s, 1H), 3.97 (AB quartet, upfield doublet is broadened, JAB=12.6 Hz, ΔνAB=13.6 Hz, 2H), 3.75 (br d, half of AB quartet, J=7.5 Hz, 1H), 3.69 (dd, half of ABX pattern, J=7.4, 4.8 Hz, 1H), 3.66-3.75 (m, 1H), 3.38 (ddd, J=11.8, 6.7, 4.8 Hz, 1H), 1.89 (ddd, J=14.1, 6.9, 2.1 Hz, 1H), 1.42 (ddd, J=14.1, 11.8, 11.7 Hz, 1H), 1.27 (d, J=6.2 Hz, 3H).

1. temperaturewhile maintaining the internal reaction temperature at −55° C
2. customthe temperature of the solution below 5° C
3. temperaturewhile maintaining the internal reaction temperature between −54° C. and −58° C
4. customto remove any frost coating the pellets)
5. additionwas introduced to the reaction
6. customvia bubbling it in under the surface of the liquid
7. customAfter 20 minutes of bubbling
8. additionthe reaction mixture was treated with water (5 volumes)
9. washThe organic layer was washed twice with aqueous sodium carbonate solution (10%, 5 volumes)
10. customSolvent was removed under reduced pressure (50 mm mercury, bath temperature 60° C.
11. additionthen 35 mm mercury, bath temperature 80° C.), and the resulting oil was treated with a solution of ethyl acetate in heptane (10%, 80 mL)
12. additionSilica gel (15 g) was added
13. filtrationwas filtered
14. washthe filter cake was washed with a solution of ethyl acetate in heptane (25%, 4×30 mL)
15. concentrationthe combined filtrates were concentrated in vacuo to a volume of ˜30 mL
16. waitThis material was granulated at room temperature for 4 hours
17. filtrationThe solid was collected via filtration
18. washwashed with heptane

ORD record

ord-171e5e6fe4d34d55a79a2dc977c20bbf

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09428523B2