Hydrochloric Acid → 5-(1-Allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole

Temperature

60 °C

To a solution of N-Allyl-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboxamide (8.40 g, 21.4 mmol) in dichloromethane (200 mL) was added phosphorus pentachloride (5.05 g, 24.2 mmol) and 4M hydrochloric acid in dioxane (0.833 mL, 3.26 mmol), and the reaction was heated to 60° C. for 90 minutes under an atmosphere on nitrogen. The reaction was allowed to cool to room temperature and then aminoacetaldehyde dimethyl acetal (25.7 mL, 236 mmol) was added slowly through the condenser. The mixture was heated to 60° C. for 2 hours under an atmosphere on nitrogen. The mixture was cooled to room temperature, and water was added (200 mL). The layers were separated and the organic phase was washed with water again (2×200 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and washed with dichloromethane (200 mL). To this dichloromethane solution of the intermediate was added 4M hydrochloric acid in dioxane (17 mL, 65 mmol) and the solution was stirred at reflux for 16 hours. The solution was decanted (leaving behind an oily black residue on the flask) and then evaporated and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted 3 more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (5.93 g, 67%). LCMS: (FA) ES+, 416. 1H NMR (400 MHz, d1-chloroform) δ: 7.45-7.42 (m, 1H), 7.25-7.19 (m, 2H), 7.16-7.14 (m, 1H), 6.93-6.90 (m, 1H), 5.55-5.44 (m, 1H), 5.13-5.08 (m, 1H), 5.95-4.88 (m, 1H), 4.19-4.15 (m, 2H).

1. temperatureto cool to room temperature
2. temperatureThe mixture was heated to 60° C. for 2 hours under an atmosphere on nitrogen
3. temperatureThe mixture was cooled to room temperature
4. customThe layers were separated
5. washthe organic phase was washed with water again (2×200 mL)
6. washThe organic extracts were washed with brine
7. dry with materialdried over anhydrous sodium sulfate
8. filtrationfiltered
9. washwashed with dichloromethane (200 mL)
10. temperatureat reflux for 16 hours
11. customThe solution was decanted (
12. customleaving behind an oily black residue on the flask) and
13. customthen evaporated
14. additiondiluted with ethyl acetate and saturated sodium bicarbonate solution
15. customThe layers were separated
16. extractionthe aqueous phase was extracted 3 more times with ethyl acetate
17. washThe organic extracts were washed with brine
18. dry with materialdried over anhydrous sodium sulfate
19. filtrationfiltered
20. concentrationconcentrated in vacuo

ORD record

ord-ac645bb45c3e4445b9f3096fefa976c7

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139589B2