Carbon Dioxide → 2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine Hydrochloride

Temperature

-78 °C

To a solution of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine (58.1 mg) in tetrahydrofuran (3.2 ml), n-butyl lithium (a 1.59N hexane solution, 320 μl) was added at −78° C., followed by stirring for 1 hour and then at 0° C. for 30 minutes. The reaction mixture was cooled to −78° C. and a carbon dioxide gas was introduced thereinto for 1 hour. After the reaction mixture was heated to room temperature over 30 minutes, it was concentrated. To a solution of the resulting residue in N,N-dimethylformamide (6.0 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (177 mg, 510 μmol) was dissolved, followed by the addition of 1-(dimethylaminopropyl)-3-ethylcarbodiimide (98.0 mg, 511 μmol) and 1-hydroxybenzotriazole (69.0 mg, 511 μmol) at room temperature and then, diisopropylethylamine (185 μl, 1.06 mmol) at 0° C. After stirring overnight at room temperature, the reaction mixture was added with methylene chloride (20 ml) and a saturated aqueous solution (50 ml) of sodium bicarbonate, whereby the organic layer was separated. The resulting organic layer was extracted with methylene chloride (2×10 ml). The organic layers were combined, washed with water (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified twice by preparative thin-layer chromatography on a silica gel (methylene chloride:acetone:methanol=10:5:1). The white solid thus obtained was dissolved in a 1N ethanol hydrochloride solution and the resulting solution was concentrated. After the addition of water, the mixture was concentrated again, whereby the title compound (74.7 mg) was obtained as a white solid.

1. waitat 0° C. for 30 minutes
2. waitfor 1 hour
3. temperatureAfter the reaction mixture was heated to room temperature over 30 minutes
4. concentrationit was concentrated
5. customat 0° C
6. stirringAfter stirring overnight at room temperature
7. customa saturated aqueous solution (50 ml) of sodium bicarbonate, whereby the organic layer was separated
8. extractionThe resulting organic layer was extracted with methylene chloride (2×10 ml)
9. washwashed with water (50 ml)
10. dry with materialdried over anhydrous sodium sulfate
11. concentrationconcentrated under reduced pressure
12. customThe residue thus obtained
13. customwas purified twice by preparative thin-layer chromatography on a silica gel (methylene chloride:acetone:methanol=10:5:1)
14. customThe white solid thus obtained
15. concentrationthe resulting solution was concentrated
16. additionAfter the addition of water
17. concentrationthe mixture was concentrated again

ORD record

ord-c035c5128a1047a0ab876aac3bb4ccfc

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06747023B1