Tetrahydrofuran → HCID 58227475, compound

In a culture tube was added pyrrolidine (17.8 mg, 0.250 mmol) and benzotriazole (29.8 mg, 0.250 mmol) in ethanol (1.0 mL). After stirring at room temperature for 10 minutes, the solution was treated with 2-phenylethynyl-thiazole-5-carbaldehyde (Example 205, 53.3 mg, 0.250 mmol) and THF (0.5 to 1.0 mL) and stirred at room temperature for 1 hour. The volatiles were then removed under reduced pressure, the residue dissolved in ethanol (1.0 mL) and THF (1.0 mL) and the volatiles removed again under reduced pressure. The residue was dissolved once more in THF (1.0 mL), concentrated under reduced pressure and kept under high vacuum for about 1 hour. The residue was then dissolved in THF (1.0 mL) and treated with methyl magnesium bromide (170 μL of a 3.0 M solution in diethyl ether, 0.50 mmol) and the reaction was stirred at room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate (4 mL) and diluted with EtOAc (4 mL). After stirring vigorously for a few minutes, the layers were separated and the aqueous layer was stirred again with EtOAc (4 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system. Gradient: acetonitrile in water, 28-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 38-68% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 96 mM of ammonium formate. Column: Inertsil® C18, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)). Fractions were concentrated under reduced pressure and the solid obtained was partitioned between EtOAc (5 mL) and saturated aqueous sodium bicarbonate (5 mL). After stirring vigorously for a few seconds, the layers were separated and the aqueous layer was stirred again with EtOAc (5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound, 2-phenylethynyl-5-(1-pyrrolidin-1-yl-ethyl)-thiazole, (26 mg, 37%) as an amber oil.

1. stirringstirred at room temperature for 1 hour
2. customThe volatiles were then removed under reduced pressure
3. dissolutionthe residue dissolved in ethanol (1.0 mL)
4. customTHF (1.0 mL) and the volatiles removed again under reduced pressure
5. dissolutionThe residue was dissolved once more in THF (1.0 mL)
6. concentrationconcentrated under reduced pressure
7. waitkept under high vacuum for about 1 hour
8. dissolutionThe residue was then dissolved in THF (1.0 mL)
9. additiontreated with methyl magnesium bromide (170 μL of a 3.0 M solution in diethyl ether, 0.50 mmol) and the reaction
10. stirringwas stirred at room temperature
11. customThe reaction was quenched
12. additionby adding saturated aqueous sodium bicarbonate (4 mL)
13. additiondiluted with EtOAc (4 mL)
14. stirringAfter stirring vigorously for a few minutes
15. customthe layers were separated
16. stirringthe aqueous layer was stirred again with EtOAc (4 mL)
17. washThe combined organic layers were washed with brine
18. dry with materialdried over sodium sulfate
19. filtrationfiltered
20. concentrationconcentrated under reduced pressure
21. customThe residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system
22. waitGradient: acetonitrile in water, 28-95% in 3.6 minutes with a cycle time of 5 min
23. waitA shallow gradient between 38-68% of acetonitrile was used between 0.75-3.3 min
24. customto separate
25. washclose-eluting impurities
26. concentrationFractions were concentrated under reduced pressure
27. customthe solid obtained
28. customwas partitioned between EtOAc (5 mL) and saturated aqueous sodium bicarbonate (5 mL)
29. stirringAfter stirring vigorously for a few seconds
30. customthe layers were separated
31. stirringthe aqueous layer was stirred again with EtOAc (5 mL)
32. washThe combined organic layers were washed with brine
33. dry with materialdried over sodium sulfate
34. filtrationfiltered
35. concentrationconcentrated under reduced pressure

ORD record

ord-ff48cfb77d644c91adbeb1cac170ef6b

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08440837B2