Diethyl Ether → HCID 22710190, compound

Diethyl ether and a saturated aqueous solution of sodium bicarbonate were added to 4-bromopyridine hydrochloride (3.76 g). The organic layer thus separated was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby a diethyl ether solution of 4-bromopyridine was obtained. To the resulting solution were added (5-thiazolyl)trimethyltin (4.00 g), benzene (150 ml) and tetrakis(triphenylphosphine)palladium (950 mg), followed by heating under reflux for 12 hours. After allowed to cool down to room temperature, the reaction mixture was added with a saturated aqueous solution (100 ml) of sodium bicarbonate and ethyl acetate (50 ml). The water layer thus separated was extracted with ethyl acetate (2×50 ml) and methylene chloride (2×50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=5:1→2:1), whereby 4-(5-thiazolyl)pyridine was obtained as a colorless, transparent oil. The resulting oil was dissolved in diethyl ether (80 ml), followed by the dropwise addition of n-butyl lithium (a 1.52N hexane solution, 11.5 ml) at −78° C. After stirring for 30 minutes, a carbon dioxide gas was blown into the reaction mixture. Ten minutes later, the temperature was increased gradually to room temperature. The reaction mixture was concentrated, whereby the residue of lithium 5-(pyridin-4-yl)thiazole-2-carboxylate was obtained as a colorless solid. To a solution of the resulting residue in N,N-dimethylformamide (50 ml) were added l-(tert-butoxycarbonyl)piperazine (3.30 g), 1-hydroxybenzotriazole monohydrate (2.40 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.40 g) at room temperature. The resulting mixture was stirred for 3 days. Ethyl acetate (200 ml) and water (2000 ml) were added to the reaction mixture. The water layer thus separated was extracted with ethyl acetate (2×200 ml). The organic layers were combined, washed with water (1000 ml) and a saturated aqueous solution (400 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was reprecipitated in a methylene chloride—hexane system, whereby the title compound (3.00 g) was obtained as pale brown powder.

1. customThe organic layer thus separated
2. dry with materialwas dried over anhydrous sodium sulfate
3. concentrationconcentrated under reduced pressure, whereby a diethyl ether solution of 4-bromopyridine
4. customwas obtained
5. temperatureby heating
6. temperatureunder reflux for 12 hours
7. customThe water layer thus separated
8. extractionwas extracted with ethyl acetate (2×50 ml) and methylene chloride (2×50 ml)
9. dry with materialdried over anhydrous sodium sulfate
10. distillationdistilled under reduced pressure
11. customto remove the solvent
12. customThe residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=5:1→2:1)

ORD record

ord-b7c42e50423542058a8720636a019b03

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06747023B1